Data-Medicos 
Dermagic/Express No. 73 
15 Septiembre 1.999. 15 September 1.999 

~ El Ganciclovir y Cidofovir, ~ 
~ The Ganciclovir and Cidofovir ~ 


EDITORIAL ESPANOL 
================= 
Hola Amigos de la red, DERMAGIC continua el tema de los antivirales, en esta ocasion: EL GANCICLOVIR Y CIDOFOVIR. El GANCICLOVIR tambien es una prodroga estructuralmente similar al ACICLOVIR, la cual se convierte intracelularmente en su forma GANCICLOVIR trifosfato, que inhibe la DNA POLIMERASA VIRAL y ha demostrado ser efectivo contra la enfermedad por Citomegalovirus y herpes simple virus. Tambien el ganciclovir se esta usando en pacientes con HIV pues potencia la accion del antiviral didanosine en pacientes con SIDA. 
El CIDOFOVIR ((S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine,) es miembro de una nueva clase de antivirales, conocido tambien como HPMMC, es el primer antiviral analogo de nucleotidos, con una vida media intracelular de 17 a 30 horas, con actividad anti-tumoral y anti-viral, tiene un espectro de accion mas amplio: herpesvirus, adenovirus, VPH, poxvirus, poliomavirus, leucoencefalopatia progresiva multifocal (SIDA), sarcoma de Kaposi (SIDA Y herpesvirus 8), y 
TOPICAMENTE: molusco contagioso, verruga vulgar, condiloma acuminado anogenital, 
herpes genital recurrente, queratoconjuntivitis viral (Citomegalovirus y herpes virus), y Sarcoma de Kaposi. 
Ya ha sido descrita resistencia VIRAL a estos 2 nuevos agentes antivirales. Al final, la monografia de ambos productos. En estas 54 referencias bibliograficas, los hechos. 

Saludos a todos !!! 

Dr. Jose Lapenta R.,,, 

EDITORIAL ENGLISH 
================= 
Hello Friends of the net, DERMAGIC continuos the topic of the antiviral, in 
this occasion: THE GANCICLOVIR AND CIDOFOVIR. The GANCICLOVIR is also a prodrug structurally similar to the ACICLOVIR, which becomes intracellular in their form GANCICLOVIR triphosphate. He inhibits the viral DNA polymerase and it has demonstrated to be effective against the disease for Cytomegalovirus and herpes simplex virus. Also the ganciclovir it is using in patient with VIH since It INCREASES the action of the antiviral didanosine in patient with AIDS. 

The CIDOFOVIR ((S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine,) is member of a new antiviral class, also known as HPMMC, it is the first antiviral nucleotide analog 
with a intracellular life half of 17 at 30 hours, with anti-viral and/or tumoral activity, he has also a broad spectrum: herpesvirus, adenovirus, HVP, poxvirus, polyomavirus, progressive multifocal leukoencephalopathy (AIDS), Kaposi's sarcoma (AIDS AND herpesvirus 8), and TOPICALLY: contagious molluscum, vulgar wart, anogenital condyloma acuminata, recurrent genital herpes, viral keratoconjunctivitis (cytomegalovirus and herpes virus), and cutaneous Kaposi's sarcoma. 
VIRAL resistance has already been described to these 2 new antiviral agents. At the end a monograph of the products. In these 54 bibliographical references, the facts. 

Greetings to ALL, !! 
Dr. Jose Lapenta R.,,, 
=================================================================== 
REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES 
=================================================================== 
==================================================================== 
GANCICLOVIR 
==================================================================== 
1.) Oral ganciclovir for the prevention of cytomegalovirus disease inpersons with AIDS. Roche Cooperative Oral Ganciclovir Study Group. 
2.) Oral ganciclovir as maintenance treatment for cytomegalovirus retinitisin patients with AIDS. Syntex Cooperative Oral Ganciclovir 
3.) Absence of teratogenicity of oral ganciclovir used during earlypregnancy in a liver transplant recipient. 
4.) Clinical course of cytomegalovirus (CMV) viremia with and withoutganciclovir treatment in CMV-seropositive kidney transplant recipients.Longitudinal follow-up of CMV pp65 antigenemia assay. 
5.) A study of the pharmacokinetics, antiviral activity, and tolerability oforal ganciclovir for CMV prophylaxis in marrow transplantation. 
6.) Forscarnet vs ganciclovir for cytomegalovirus (CMV) antigenemia after allogeneic hemopoietic stem cell transplantation (HSCT): a randomised study. 
7.) Ganciclovir. An update of its use in the prevention of cytomegalovirus infection and disease in transplant recipients. 
8.) Superior cytotoxicity with ganciclovir compared with acyclovir and 1-beta-D- arabinofuranosylthymine in herpes simplex virus-thymidine kinase-expressing cells: a novel paradigm for cell killing. 
9.) High-dose (2000-microgram) intravitreous ganciclovir in the treatment of cytomegalovirus retinitis. 
10.) Cytomegalovirus polymerase chain reaction viraemia in patients receiving ganciclovir maintenance therapy for retinitis. 
11.) The use of oral ganciclovir in the treatment of cytomegalovirus retinitis in patients with AIDS. 
12.) Metabolism of ganciclovir and cidofovir in cells infected with drug-resistant and wild-type strains of murine cytomegalovirus. 
13.) The effect of ganciclovir on herpes simplex virus-mediated oncolysis. 
14.) Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. The Ganciclovir Implant Study Group. 
15.) Pharmacokinetics of oral ganciclovir capsules in HIV-infected persons. 
16.) Cytomegalovirus (CMV) resistance in patients with CMV retinitis and AIDS treated with oral or intravenous ganciclovir. 
17.) The pharmacokinetics and safety profile of oral ganciclovir combined with zalcitabine or stavudine in asymptomatic HIV- and CMV-seropositive patients. 
18.) GANCICLOVIR (Systemic) The product 
==================================================================== 
CIDOFOVIR 
==================================================================== 
19.) Trifluridine, cidofovir, and penciclovir in the treatment of experimental herpetic keratitis. 
20.) Bioavailability and metabolism of cidofovir following topical administration to rabbits. 
21.) Cidofovir: a new therapy for cytomegalovirus retinitis. 
22.) Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the HPMPC peripheral cytomegalovirus retinitis trial. A randomized, controlled trial. Studies of Ocular complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group. 
23.) Cidofovir and experimental herpetic stromal disease. 
24.) Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir. 
25.) Cidofovir in the treatment of cytomegaloviral disease. 
26.) Antitumor potential of acyclic nucleoside phosphonates. 
27.) Clinical uses of cidofovir. 
28.) Characterization of the DNA polymerase and thymidine kinase genesof herpes 
simplex virus isolates from AIDS patients in whom acyclovirand foscarnet therapy sequentially failed. 
29.) A case study: the use of cidofovir for the management of progressive multifocal leukoencephalopathy. 
30.) Antiinfectives update: focus on treatment and prevention of viral and associated infections. 
31.) Identification and rapid quantification of early- and late-lytic human herpesvirus 8 infection in single cells by flow cytometric analysis: characterization of antiherpesvirus agents. 
32.)Inhibiting effects of cidofovir (HPMPC) on the growth of the human cervical carcinoma (SiHa) xenografts in athymic nude mice. 
33.) Antiproliferative effects of acyclic nucleoside phosphonates on human papillomavirus (HPV)-harboring cell lines compared with HPV-negative cell lines. 
34.) Resolution of recalcitrant molluscum contagiosum virus lesions in human immunodeficiency virus-infected patients treated with cidofovir. 
35.) Therapeutic potential of Cidofovir (HPMPC, Vistide) for the treatment of DNA virus (i.e. herpes-, papova-, pox- and adenovirus) infections. 
36.) Topical and intralesional cidofovir: a review of pharmacology and therapeutic effects. 
37.) Treatment of classical Kaposi's sarcoma with intralesional injections of cidofovir: report of a case. 
38.) Selective inhibition of human papillomavirus-induced cell proliferation by (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. 
39.) Resistance of human cytomegalovirus to antiviral drugs. 
40.) Comparative antiviral efficacies of cidofovir, trifluridine, and acyclovir in the HSV-1 rabbit keratitis model. 
41.) [Human herpesvirus 8 (HHV8). II. Pathogenic role and sensitivity toantiviral drugs]. 
42.) Inhibitory effects of novel nucleoside and nucleotide analogues on Epstein-Barr virus replication. 
43.) Comparison of antiviral compounds against human herpesvirus 6 and 7. 
44.) [Advances in the diagnosis and treatment of infections caused by herpesvirus and JC virus]. 
45.) A multicenter phase I/II dose escalation study of single-dose cidofovir gel 
for treatment of recurrent genital herpes. 
46.) Cidofovir use in acyclovir-resistant herpes infection. 
47.) A randomized, double-blind, placebo-controlled trial of cidofovir gel for 
the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. 
48.) Isolation of human adenovirus type 5 variants resistant to the antiviral cidofovir. 
49.) Herpesvirus resistance to antiviral drugs: a review of the mechanisms, clinical importance and therapeutic options. 
50.) Topical cidofovir for severe molluscum contagiosum. 
51.) Abatement of cutaneous Kaposi's sarcoma associated with cidofovir treatment. 
52.) Treatment of verruca vulgaris with topical cidofovir. 
53.) Topical cidofovir for severe molluscum contagiosum. 
54.) CIDOFOVIR, The product 
==================================================================== 
==================================================================== 
GANCICLOVIR 
==================================================================== 
1.) Oral ganciclovir for the prevention of cytomegalovirus disease in 
persons with AIDS. Roche Cooperative Oral Ganciclovir Study Group. 
==================================================================== 
Journal: N Engl J Med 334:1491-7, 1996 

Publication Date: 1996 June 6 

Author(s): Spector SA, McKinley GF, Lalezari JP, Samo T, Andruczk R, 
Follansbee S, Sparti PD, Havlir DV, Simpson G, Buhles W, Wong R, Stempien M 

Abstract: 

BACKGROUND. In the advanced stages of the acquired immunodeficiency 
syndrome (AIDS), cytomegalovirus (CMV) disease, particularly 
vision-damaging retinitis due to CMV is common. We evaluated prophylactic 
treatment with orally administered ganciclovir as a way to prevent CMV 
disease. 

METHODS. We conducted a prospective, randomized, double-blind, 
placebo-controlled study of CMV infected persons with AIDS with either CD4+ 
lymphocyte counts of < or = 50 per cubic millimeter or counts of < or = 100 
per cubic millimeter in those with a history of an AIDS defining 
opportunistic infection. Patients were randomly assigned, in a 2:1 ratio, 
to receive either oral ganciclovir (1000 mg three times daily) or placebo. 

RESULTS. The study was stopped after a median 367 days of follow-up. In an 
intention-to-treat analysis, the twelve month cumulative rates of confirmed 
CMV disease were 26 percent in the placebo group (n = 239) and 14 percent 
in the ganciclovir group (n = 486), representing an overall reduction in 
risk of 49 percent in the ganciclovir group (P < 0.001). The incidence of 
CMV retinitis after 12 months was 24 percent in the placebo group and 12 
percent in the ganciclovir group (P < 0.0001). The prevalence of 
CMV-positive urine cultures at base line was 42 percent; after two months 
it was 43 percent in the placebo group and 10 percent in the ganciclovir 
group (P < 0.0001). The one year mortality rate was 26 percent in the 
placebo group and 21 percent in the ganciclovir group (P = 0.14). Therapy 
with granulocyte colony stimulating factor was more frequent in the 
ganciclovir group (24 percent) than in the placebo group (9 percent). 

CONCLUSIONS. In persons with advanced AIDS, phophylactic oral ganciclovir 
significantly reduces the risk of CMV disease. 

==================================================================== 
2.) Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis 
in patients with AIDS. Syntex Cooperative Oral Ganciclovir 
==================================================================== 
Study Group (see comments) 

Journal: N Engl J Med 333:615-20, 1995 

Publication Date: 1995 September 7 

Author(s): Drew WL, Ives D, Lalezari JP, Crumpacker C, Follansbee SE, 
Spector SA, Benson CA, Friedberg DN, Hubbard L, Stempien MJ, et al 

Abstract: 

BACKGROUND. Cytomegalovirus retinitis, a sight-threatening infection 
associated with the acquired immunodeficiency syndrome (AIDS), currently 
requires lifelong intravenous treatment. An effective oral treatment would 
be an important advance. 

METHODS. We compared oral with intravenous ganciclovir in an open-label, 
randomized study in patients with AIDS and newly diagnosed, stable 
cytomegalovirus retinitis (the disease was stabilized by three weeks of 
treatment with intravenous ganciclovir). Sixty subjects were randomly 
assigned to maintenance therapy with intravenous ganciclovir at a dose of 5 
mg per kilogram of body weight daily, and 63 to maintenance therapy with 
oral ganciclovir at a dose of 3000 mg daily. The subjects were followed for 
up to 20 weeks, with photography of the fundi conducted every other week. 
The photographs were evaluated at the completion of the study by an 
experienced grader who was unaware of the subjects' treatment assignments. 

RESULTS. Efficacy could be evaluated in 117 subjects; photographs were 
ungradable for 2 of the 117. On the basis of the masked assessment of 
photographs from 115 subjects, the mean time to the progression of 
retinitis was 62 days in those given intravenous ganciclovir and 57 days in 
those given oral ganciclovir (P = 0.63; relative risk (oral vs. 
intravenous), 1.08; 95 percent confidence interval for the difference in 
means, -22 to +12 days). On the basis of funduscopy by ophthalmologists who 
were aware of the subjects' treatment assignments, the mean time to 
progression was 96 days in subjects given intravenous ganciclovir and 68 
days in subjects given oral ganciclovir (P = 0.03; relative risk (oral vs. 
intravenous), 1.68; 95 percent confidence interval for the difference in 
means, -45 to -11 days). Survival, changes in visual acuity, the incidence 
of viral shedding, and the incidence of adverse gastrointestinal events 
were similar in the two groups. Neutropenia, anemia, 
intravenous-catheter-related adverse events, and sepsis were more common in 
the group given intravenous ganciclovir. 

CONCLUSIONS. Oral ganciclovir is safe and effective as maintenance therapy 
for cytomegalovirus retinitis and is more convenient for patients to take 
than intravenous ganciclovir. 

==================================================================== 
3.) Absence of teratogenicity of oral ganciclovir used during early 
pregnancy in a liver transplant recipient. 
==================================================================== 
Transplantation 1999 Mar 15;67(5):758-9 

Pescovitz MD 
Department of Surgery, Indiana University, Indianapolis 46202-5253, USA. 

BACKGROUND: Ganciclovir (GCV) is effective for prevention of 
cytomegalovirus (CMV) disease. In animals it may cause some teratogenicity. 
There is little information on the effect of GCV on a human fetus. METHODS: 
The chart of a liver transplant recipient who received oral GCV during the 
first trimester was reviewed as was the published literature. RESULTS: 
There was no evidence of teratogenicity in the baby or in a case reported 
elsewhere. CONCLUSIONS: GCV has been used in a few female transplant 
recipients without untoward effects. The still uncertain risk of short term 
and long term teratogenicity, however, must be weighed against the risk of 
CMV disease in the recipient and the development of congenital CMV in the 
baby. 

==================================================================== 
4.) Clinical course of cytomegalovirus (CMV) viremia with and without 
ganciclovir treatment in CMV-seropositive kidney transplant recipients. 
Longitudinal follow-up of CMV pp65 antigenemia assay. 
==================================================================== 
Author 
Yang CW; Kim YO; Kim YS; Kim SY; Moon IS; Ahn HJ; Koh YB; Bang BK 
Address 
Division of Nephrology, Department of Internal Medicine, Kangnam St. Mary's 
Hospital, Catholic University Medical College, Seoul, South Korea. 
Source 
Am J Nephrol, 18(5):373-8 1998 
Abstract 
This study was designed to evaluate the longitudinal history of 
cytomegalovirus (CMV) infection and to test the capacity of ganciclovir as 
effective therapy in CMV-seropositive renal transplant recipients. The CMV 
viremia was detected with CMV pp65 antigenemia assay in 153 renal 
transplants. The recipients were classified as having low-grade and 
high-grade CMV infections according to the severity of CMV infection. The 
recipients with low-grade CMV infections were observed without ganciclovir 
treatment, and the recipients with high-grade CMV infection were randomly 
assigned to ganciclovir-treated and untreated groups. The clinical course 
between low-grade and high-grade CMV infections was evaluated. All 
recipients with low-grade CMV infection (n = 62) showed spontaneous 
remission regardless of immunosuppresants. In high-grade CMV infection (n = 
31), the ciclosporin A treated group (n = 11) showed no evidence of CMV 
disease, and the methylprednisolone-treated group (n = 8) showed CMV 
disease in 1 (25%) of 4 ganciclovir-untreated recipients. In the OKT3 group 
(n = 12), symptomatic CMV infection was observed in 6 (100%) 
ganciclovir-untreated recipients contrary to no CMV disease in the 
ganciclovir-treated group (p < 0.05). In conclusion, the CMV antigenemia 
assay is effective in monitoring CMV viremia, and ganciclovir treatment 
should be done during early CMV viremia in OKT3-treated recipients. 

==================================================================== 
5.) A study of the pharmacokinetics, antiviral activity, and tolerability of 
oral ganciclovir for CMV prophylaxis in marrow transplantation. 
==================================================================== 
Author 
Boeckh M; Zaia JA; Jung D; Skettino S; Chauncey TR; Bowden RA 
Address 
Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. 
Source 
Biol Blood Marrow Transplant, 4(1):13-9 1998 
Abstract 
Oral ganciclovir is effective in preventing cytomegalovirus (CMV) disease 
in HIV-infected patients despite a bioavailability of only 6-9%. To 
determine safety, pharmacokinetics, and the influence of acute 
gastrointestinal graft-vs.-host disease (GI-GVHD) on the bioavailability 
and antiviral effect of oral ganciclovir after marrow transplantation, CMV 
seropositive patients received oral ganciclovir (1000 mg 3 times per day) 
from day 35 (+/- 7 days) until day 100 after transplantation. Single-dose 
(intravenous and oral) and steady-state oral pharmacokinetic profiles and 
weekly trough levels were performed. Twenty-one patients received oral 
ganciclovir (seven with GI-GVHD, 14 without); 17 had steady-state 
pharmacokinetic profiles and seven had single-dose profiles. The absolute 
bioavailability was similar in patients with or without acute GI-GVHD (7.2 
vs. 6.9%). At steady state, the extent and rate of absorption of oral 
ganciclovir were comparable in these same patient subgroups (area under the 
curve [AUC] = 13.5 and 10.2 mg x hours/L, respectively; time to peak serum 
ganciclovir concentrations = 5.5 and 3.8 hours, respectively). Breakthrough 
CMV antigenemia, viremia, or plasma polymerase chain reaction positivity 
occurred in eight of 21 (38%) patients (four of seven with GVHD and four of 
14 without). Drug discontinuation because of GI adverse effects was 
required in six of 21 (29%) patients. Neutropenia occurred in two of 15 
(13%) patients who had received oral ganciclovir for more than 10 days. In 
conclusion, the bioavailability of oral ganciclovir seems similar to that 
reported in other settings. The presence of acute GVHD of the GI tract did 
not appear to adversely affect absorption of oral ganciclovir. The use of 
oral ganciclovir was limited by the presence of GI intolerance in the early 
posttransplant period. The efficacy of oral ganciclovir in preventing CMV 
infection in marrow transplant recipients is being assessed in a separate 
randomized controlled trial. 

==================================================================== 
6.) Forscarnet vs ganciclovir for cytomegalovirus (CMV) antigenemia after 
allogeneic hemopoietic stem cell transplantation (HSCT): a randomised study. 
==================================================================== 
Author 
Moretti S; Zikos P; Van Lint MT; Tedone E; Occhini D; Gualandi F; 
Lamparelli T; Mordini N; Berisso G; Bregante S; Bruno B; Bacigalupo A 
Address 
Divisione Ematologia II, Ospedale San Martino, Genova, Italy. 
Source 
Bone Marrow Transplant, 22(2):175-80 1998 Jul 
Abstract 
This trial was designed to compare foscarnet with ganciclovir as 
pre-emptive therapy for CMV infection in patients undergoing allogeneic 
hemopoietic stem cell transplant (HSCT). Thirty-nine patients were 
randomized to receive foscarnet 90 mg/kg every 12 h (n = 20) or ganciclovir 
5 mg/kg every 12 h (n = 19) for 15 days at the time of development of 
CMVAg-emia. Primary-end points of the study were (1) outcome of CMVAg-emia; 
(2) progression to CMV disease; and (3) side-effects of treatment. The 
secondary end-point was transplant-related mortality (TRM). The two groups 
were comparable for diagnosis, status of disease, donor type, acute 
graft-versus-host (aGVHD) prophylaxis, interval between HSCT and CMVAg-emia 
and number of CMVAg positive cells; the donor and recipient age were 
borderline older in the foscarnet group. Increments of serum creatinine in 
the foscarnet group, and cytopenia in the ganciclovir group were controlled 
by reducing the administered dose: in the first 15 days of therapy 9/20 
foscarnet and 10/19 ganciclovir patients had a dose reduction greater than 
20% (P = 0.43). Clearance of CMVAg-emia was faster in the foscarnet group 
although with borderline statistical significance. Failures of treatment 
occurred in 3/20 patients in foscarnet group vs 8/19 patients in 
ganciclovir group (P= 0.06): causes of failure were the need for 
combination therapy to control antigenemia (1/20 vs 5/19), and reactivation 
during treatment for 2 vs 3 patients, respectively. CMV disease was 
diagnosed in 1 vs 2 patients (P = 0.5) who subsequently died. The actuarial 
1-year TRM was 25 vs 12%, respectively (P = 0.3). This study suggests that 
foscarnet and ganciclovir are both effective for pre-emptive therapy of 
CMVAg-emia, although the number of failures would seem to be slightly 
higher in the ganciclovir patients. Side-effects are seen in both groups 
and can be managed with appropriate dose reduction. 

==================================================================== 
7.) Ganciclovir. An update of its use in the prevention of cytomegalovirus 
infection and disease in transplant recipients. 
==================================================================== 
Author 
Noble S; Faulds D 
Address 
Adis International Limited, Auckland, New Zealand. 
Source 
Drugs, 56(1):115-46 1998 Jul 
Abstract 
Ganciclovir is a nucleoside analogue which is used to treat and prevent 
cytomegalovirus (CMV) infection. Most recent clinical studies of 
ganciclovir in transplant recipients have focused on preventive approaches. 
When ganciclovir was last reviewed in Drugs in 1994, substantial data on 
post-transplantation CMV prophylaxis with this drug were available only for 
patients undergoing allogeneic bone marrow transplantation (BMT). Two 
strategies had emerged: prophylaxis for all patients or early treatment 
started after detection of asymptomatic CMV infection. Subsequently, a 
large double-blind study has shown that ganciclovir prophylaxis is more 
effective than early treatment in preventing early CMV disease after 
allogeneic BMT and is not associated with an increased incidence of 
neutropenia. However, mortality for the 2 strategies was similar. The 
efficacy of prophylactic intravenous ganciclovir in liver transplant 
recipients [including high risk donor seropositive/recipient seronegative 
(D+/R-) or antilymphocyte-treated patients] is now well established. 
Prophylaxis with oral ganciclovir was effective both overall and in 
D+/R-patients in a large placebo controlled study, and prolonged 
intravenous ganciclovir was significantly more effective than high dose 
aciclovir (acyclovir) in seropositive liver recipients. Early treatment 
with ganciclovir has proved useful in this setting. More limited data 
indicate that CMV prophylaxis with intravenous ganciclovir may be useful 
after heart or lung transplantation but its value in D+/-patients remains 
unclear. Combined chemoimmunotherapy may be valuable in these high risk 
patients but controlled data are lacking. Targeted prophylaxis with 
intravenous ganciclovir is effective in renal transplant recipients 
receiving antilymphocyte therapy; the role of oral ganciclovir in this 
setting is less clear. The value of ganciclovir in D+/- renal transplant 
recipients and its efficacy compared with high dose aciclovir have not been 
determined. Conclusions: Ganciclovir is the only antiviral chemotherapy 
which reduces the risk of CMV infection or disease after most types of 
major transplantation. Unresolved issues include the best (and most 
cost-effective) use of ganciclovir and aciclovir after allogeneic BMT, the 
efficacy of oral ganciclovir compared with other anti-CMV regiments, the 
potential clinical effect of viral resistance during prolonged ganciclovir 
exposure and the value of ganciclovir in certain high risk transplant 
populations. In the meantime, ganciclovir has an important role in the 
prevention of CMV infection and disease after bone marrow and liver 
transplantation and is likely to gain wider clinical use in heart, lung and 
kidney transplant recipients. 

==================================================================== 
8.) Superior cytotoxicity with ganciclovir compared with acyclovir and 
1-beta-D-arabinofuranosylthymine in herpes simplex virus-thymidine 
kinase-expressing cells: a novel paradigm for cell killing. 
==================================================================== 
Author 
Rubsam LZ; Davidson BL; Shewach DS 
Address 
Department of Pharmacology, University of Michigan Medical Center, Ann 
Arbor 48109-0504, USA. 
Source 
Cancer Res, 58(17):3873-82 1998 Sep 1 
Abstract 
Enzyme-prodrug therapy using ganciclovir and herpes simplex virus-thymidine 
kinase (HSV-TK) has demonstrated excellent antitumor activity in many 
different types of malignant cells. Previously, we noted that ganciclovir 
was substantially more cytotoxic than other HSV-TK substrates. Therefore, 
we embarked on a study to determine the basis for the superior cytotoxicity 
of ganciclovir. In U251tk human glioblastoma cells that stably express 
HSV-TK, ganciclovir elicited a >4 log cell kill instead of the < or =1.5 
log cell kill mediated by two other HSV-TK substrates, 
1-beta-D-arabinofuranosylthymine (araT) and acyclovir. Study of the 
metabolism of these drugs demonstrated that acyclovir was poorly 
phosphorylated to its active triphosphate with DNA incorporation below the 
limit of detection, which may explain the < 1 log cell kill in these cells. 
Lower levels of ganciclovir triphosphate accumulated compared with araT 
triphosphate (araTTP) under conditions that induced < or =1 log cell kill 
(67 versus 1235 pmol/10(7) cells, respectively), and the half-life for the 
triphosphate of ganciclovir was shorter than that of araT (terminal 
half-lives of 15 and 41 h, respectively). Incorporation of ganciclovir 
monophosphate into DNA was less than that of araT monophosphate, and both 
analogues were retained in DNA for > or =48 h. Thus, the superior 
cytotoxicity of ganciclovir was not due to enhanced metabolism to active 
forms. Highly cytotoxic concentrations of ganciclovir produced only weak 
inhibition of DNA synthesis. This allowed cells to proceed through S and 
G2-M phases during and after drug exposure, resulting in a doubling of cell 
number by 48 h after drug washout. As they attempted to progress through 
the cell cycle a second time, ganciclovir-treated cells accumulated in 
early S-phase and remained there until cell death, suggesting that 
ganciclovir incorporation in the DNA template was important for 
cytotoxicity. In contrast, strong inhibition of DNA synthesis by araTTP 
prevented cells from traversing the cell cycle for at least 12 h after drug 
washout, when the active metabolite was largely degraded araT-treated cells 
were unable to divide for at least 72 h after drug exposure, at which point 
the surviving cells displayed a normal cell cycle distribution pattern. 
Based on the results presented here, we propose a novel paradigm in which 
the ability of ganciclovir to incorporate into DNA without inhibiting 
progression through S-phase, combined with high cytotoxicity for 
incorporated ganciclovir monophosphate, produces multilog cytotoxicity. 

==================================================================== 
9.) High-dose (2000-microgram) intravitreous ganciclovir in the treatment of 
cytomegalovirus retinitis. 
==================================================================== 
Author 
Young S; Morlet N; Besen G; Wiley CA; Jones P; Gold J; Li Y; Freeman WR; 
Coroneo MT 
Address 
Department of Ophthalmology, University of New South Wales, Sydney, 
Australia. 
Source 
Ophthalmology, 105(8):1404-10 1998 Aug 
Abstract 
OBJECTIVE: The authors prospectively studied visual outcome, relapse, 
complications, and survival of patients with acquired immune deficiency 
syndrome (AIDS)-related cytomegalovirus (CMV) treated with high-dose 
intravitreous ganciclovir (2 mg/0.1 ml) injections. The outcomes were 
compared with those of patients treated with standard doses of intravenous 
ganciclovir in the same institution. The histopathologic and 
electrophysiologic effects of high-dose intravitreous ganciclovir 
injections in rabbits also were studied. DESIGN: A nonrandomized case 
series. PARTICIPANTS: A total of 42 patients (74 eyes) were treated with 
intravitreous injections and 18 patients (27 eyes) were treated with 
intravenous ganciclovir. Five eyes of three New Zealand white rabbits were 
injected with ganciclovir, and the sixth eye was a control specimen. 
INTERVENTION: Patients treated with intravitreous injections received 
twice-weekly doses of 2 mg/0.1 ml ganciclovir for 3 weeks, then weekly 
injections. Patients treated with intravenous ganciclovir received standard 
doses. Patients were monitored with regular examinations. Rabbit eyes were 
given intravitreous injections of 1 mg/0.1 ml of ganciclovir weekly for 4 
weeks. MAIN OUTCOME MEASURES: Assessments of vision, retinal inflammation, 
and survival were made. Electroretinograms were performed on the rabbit 
eyes, and they were processed for light and electron microscopy. RESULTS: 
In the intravitreous group, visual acuity (VA) was stable in 64 of 74 eyes, 
5 improved, and 5 deteriorated. Sixty-three (85%) of 74 eyes had final VA 
of 20/20 to 20/40. Relapse occurred in five eyes (7%; median time, 42 
weeks). There were three cases of endophthalmitis. Median survival after 
diagnosis of CMV retinitis was 36 weeks. In the intravenous group, VA was 
stable in 18 eyes, 0 improved, and 9 deteriorated. Sixteen (59%) of 27 eyes 
had final VA of 20/20 to 20/40. Relapse occurred in 15 eyes (56%) at a 
median time of 21 weeks. Median survival was 21 weeks. The rabbit studies 
showed no evidence of toxicity. CONCLUSION: High-dose intravitreous 
ganciclovir effectively suppressed CMV retinitis, preserved vision, and 
prevented relapse without deterioration in survival. 

==================================================================== 
10.) Cytomegalovirus polymerase chain reaction viraemia in patients receiving 
ganciclovir maintenance therapy for retinitis. 
==================================================================== 
Author 
Bowen EF; Emery VC; Wilson P; Johnson MA; Davey CC; Sabin CA; Farmer D; 
Griffiths PD 
Address 
Department of Virology, Royal Free Hospital and School of Medicine, London, 
UK. 
Source 
AIDS, 12(6):605-11 1998 Apr 16 
Abstract 
OBJECTIVES: To determine whether recurrence of polymerase chain reaction 
(PCR) viraemia during maintenance ganciclovir for cytomegalovirus (CMV) 
retinitis correlates with (i) CMV disease at a new anatomical site, (ii) 
progression of the presenting retinitis, or (iii) acquisition of genetic 
changes in gene UL97 associated with resistance to ganciclovir. DESIGN: A 
previously described cohort of 45 patients presenting with first episode 
retinitis was followed clinically using ophthalmoscopy and serial tests for 
PCR viraemia for a median of 7 months. CMV viral load and genetic markers 
of ganciclovir resistance were measured in PCR-positive samples. METHODS: 
PCR amplification of the glycoprotein B region of CMV and quantitative 
competitive PCR assays were employed. Genetic changes in UL97 were 
identified by sequencing/point mutation assay. RESULTS: PCR viraemia 
correlated significantly with new episodes of CMV disease (P=0.011) and a 
trend was seen for the association with progression of retinitis (P=0.07). 
Amongst the 14 patients PCR-positive during maintenance ganciclovir, 10 
(71%) had genetic markers of resistance. None of these patients became 
PCR-negative in blood after reinduction ganciclovir therapy compared with 
three out of four without markers of resistance (P=0.022). CONCLUSIONS: CMV 
PCR viraemia correlated strongly with the development of new episodes of 
CMV disease. Most patients with progression of retinitis remained 
PCR-negative in blood, consistent with therapeutic failure due to poor 
intraocular penetration of ganciclovir. However, the minority who were 
PCR-positive in blood may have reinfected their eye, and frequently had 
markers of ganciclovir resistance. The implications of these findings for 
the management of patients with CMV disease are discussed. 

==================================================================== 
11.) The use of oral ganciclovir in the treatment of cytomegalovirus retinitis 
in patients with AIDS. 
==================================================================== 
Author 
Ward-Able C; Phillips P; Tsoukas CM 
Address 
BioMed Business Unit of Hoffmann-La Roche (Canada), Mississauga, Ont. 
Source 
CMAJ, 154(3):363-8 1996 Feb 1 
Abstract 
OBJECTIVE: To recommend the appropriate use of oral ganciclovir as an 
alternative to intravenous (i.v.) maintenance therapy for cytomegalovirus 
(CMV) retinitis in patients with AIDS. OPTIONS: i.v. infusion of 
ganciclovir and foscarnet have been the only approved choices for 
maintenance therapy until the introduction of oral ganciclovir. OUTCOMES: 
Ease of administering maintenance therapy and improved quality of life for 
patients with AIDS. VALUES: The medical advisory group comprised physicians 
treating patients with AIDS therapy. Ease of administration of maintenance 
therapy and quality of patients' lives were considered important. BENEFITS, 
HARMS AND COSTS: Oral ganciclovir is a safe and convenient alternative to 
i.v. maintenance therapy for patients with CMV retinitis. However, its low 
bio-availability precludes its use for induction therapy and necessitates 
careful monitoring for compliance. Compared with i.v. administration of 
ganciclovir, oral maintenance therapy is cost effective. EVIDENCE: Evidence 
for the guidelines was gathered from data presented at a symposium on CMV 
retinitis and oral ganciclovir, clinical trials of oral ganciclovir and 
input from a visiting expert. It was presented at a meeting of the advisory 
board whose members are involved in the care of patients with AIDS and the 
management of CMV retinitis. The guidelines were approved by each member of 
the advisory board. RECOMMENDATIONS: Diagnosis, treatment and follow-up of 
CMV retinitis should always be in consultation with an ophthalmologist who 
is experienced in treating this disease. The patient should be fully 
informed about the limitations of the oral form of ganciclovir; he or she 
should be involved in decision making and carefully monitored. Oral 
ganciclovir should not be used for induction therapy or for maintenance 
therapy in high-risk patients. VALIDATION: Similar guidelines have been 
produced in England where the drug has been available since January 1995. 
SPONSOR: The deliberations of the advisory board and the preparation of 
this report were funded through an educational grant from Hoffmann-La Roche 
(Canada). 

==================================================================== 
12.) Metabolism of ganciclovir and cidofovir in cells infected with 
drug-resistant and wild-type strains of murine cytomegalovirus. 
==================================================================== 
Author 
Okleberry KM; Warren RP; Smee DF 
Address 
Institute for Antiviral Research, Utah State University, Logan, USA. 
Source 
Antiviral Res, 35(2):83-90 1997 Jul 
Abstract 
Murine cytomegalovirus (MCMV) has been used extensively as an animal model 
for human cytomegalovirus (HCMV). Understanding drug resistance and its 
treatment in MCMV may lead to more effective treatments of HCMV disease. 
Most ganciclovir-resistant HCMV clinical isolates exhibit a decreased 
capacity to induce ganciclovir phosphorylation (to its biologically active 
form) in infected cells. Using an MCMV strain resistant to both ganciclovir 
and cidofovir, the intracellular metabolism of these drugs was studied to 
determine if MCMV resistance correlates with decreases in drug 
phosphorylation. The wild-type (WT) MCMV used for comparison was inhibited 
in plaque reduction assays, by ganciclovir and cidofovir by 50% at 5.1 and 
0.24 microM, respectively; the resistant strain was inhibited at 72 and 2.7 
microM, respectively. In uninfected, WT, or resistant virus-infected cells, 
the extent of metabolism of 10 microM ganciclovir or 1 microM cidofovir to 
intracellular triphosphorylated species was similar. Phosphorylation and 
catabolism (following drug removal) rates over time were also similar. 
Intracellular levels of ganciclovir triphosphate and cidofovir diphosphate 
increased less than two-fold with increasing multiplicity of virus 
infection. Because few differences in drug phosphorylation between WT and 
resistant virus-infected cells were found, virus resistance to ganciclovir 
and cidofovir apparently is not linked to altered drug phosphorylation. 
Since the viral DNA polymerase is the antiviral target for these compounds, 
the resistant MCMV is most likely a DNA polymerase mutant. 

==================================================================== 
13.) The effect of ganciclovir on herpes simplex virus-mediated oncolysis. 
==================================================================== 
Author 
Carroll NM; Chase M; Chiocca EA; Tanabe KK 
Address 
Department of Surgery, Massachusetts General Hospital, Boston 02114, USA. 
Source 
J Surg Res, 69(2):413-7 1997 May 
Abstract 
Entry of herpes simplex virus (HSV) into tumor cells results in viral gene 
expression followed by cellular lysis. Attenuated HSVs selectively destroy 
tumors with sparing of surrounding normal tissue. HSV encodes a thymidine 
kinase (TK) that converts ganciclovir to a toxic metabolite. This 
metabolite may be transferred between cells and lead to the death of 
neighboring uninfected cells, termed bystanders. We sought to determine if 
HSV-mediated oncolysis is enhanced by ganciclovir treatment. In addition, 
we examined bystander killing in cocultures of TK transfectants and 
parental cells. hrR3, an attenuated HSV, expresses TK. The 50% lethal dose 
of hrR3 for a rat gliosarcoma (9L) and three human colorectal carcinomas 
(HT29, KM12C6, and KM12L4) was determined. Cells were infected with a 50% 
lethal dose of hrR3, followed by treatment with ganciclovir, and then cell 
survival was quantitated. In separate experiments 9L and HT29 cells were 
transfected with TK. Parental cells and TK transfectants were cocultured in 
various ratios, in the presence of ganciclovir, and cell survival was 
quantitated. hrR3-mediated oncolysis was enhanced by ganciclovir in the 
gliosarcoma but not in the three colorectal carcinomas. Cocultures of both 
9L and HT29 parental cells with their corresponding TK transfectants 
demonstrated bystander killing. The mortality of 9L cocultures was 54% 
greater than that predicted for exclusive killing of transfectants. HT29 
mortality was 8% greater than predicted. The ability of ganciclovir to 
augment hrR3-mediated oncolysis varies significantly between tumor cells 
lines. The extent of ganciclovir-mediated killing of neighboring 
nontransduced parental cells similarly varies. Consideration should be 
given to these factors in the design of gene therapy strategies using HSV 
vectors as oncolytic agents. 

==================================================================== 
14.) Treatment of cytomegalovirus retinitis with a sustained-release 
ganciclovir 
implant. The Ganciclovir Implant Study Group. 
==================================================================== 
Author 
Musch DC; Martin DF; Gordon JF; Davis MD; Kuppermann BD 
Address 
Department of Ophthalmology, University of Michigan, Ann Arbor, USA. 
Source 
N Engl J Med, 337(2):83-90 1997 Jul 10 
Abstract 
BACKGROUND: Sustained-release, intraocular implants that deliver 
ganciclovir are an alternative method for the treatment of cytomegalovirus 
retinitis in patients with the acquired immunodeficiency syndrome (AIDS). 
METHODS: We conducted a randomized study of 188 patients with AIDS and 
newly diagnosed cytomegalovirus retinitis. The patients were randomly 
assigned to treatment with an implant delivering 1 microg of ganciclovir 
per hour, an implant delivering 2 microg of ganciclovir per hour, or 
intravenous ganciclovir. The primary outcome we studied was progression of 
cytomegalovirus retinitis. RESULTS: The median time to progression of 
retinitis was 221 days with the 1-microg-per-hour implant (75 eyes), 191 
days with the 2-microg-per-hour implant (71 eyes), and 71 days with 
ganciclovir administered intravenously (76 eyes; P<0.001). The risk of 
progression of retinitis was almost three times as great among patients 
treated with intravenous ganciclovir as among those treated with a 
ganciclovir implant (risk ratio, 2.8; P<0.001). However, the risk of 
disease in the initially uninvolved eye was lower with intravenous 
ganciclovir than with a ganciclovir implant (risk ratio, 0.5; P=0.19). 
Patients treated with intravenous ganciclovir were also less likely to have 
extraocular cytomegalovirus infections (0, vs. 10.3 percent in the two 
implant groups; P=0.04). CONCLUSIONS: For the treatment of cytomegalovirus 
retinitis, the sustained-release ganciclovir implant is more effective than 
intravenous ganciclovir, but patients treated with a ganciclovir implant 
alone remain at greater risk for the development of cytomegalovirus disease 
outside of the treated eye. 

==================================================================== 
15.) Pharmacokinetics of oral ganciclovir capsules in HIV-infected persons. 
==================================================================== 
Author 
Griffy KG 
Address 
Roche Bioscience, Palo Alto, California, USA. 
Source 
AIDS, 10 Suppl 4():S3-6 1996 Dec 
Abstract 
OBJECTIVES: To delineate the pharmacokinetic profile of the oral capsule 
formulation of ganciclovir, and determine whether oral ganciclovir has any 
pharmacokinetics interactions with zidovudine, didanosine or probenecid. 
MEASUREMENTS: Serum and urine concentrations of ganciclovir, zidovudine and 
didanosine were measured. From these concentrations, standard 
pharmacokinetic parameters such as peak concentration, area under the curve 
(AUC), elimination half-life and renal clearance were determined. RESULTS: 
The bioavailability of oral ganciclovir averages 6-9%. Inter- and 
intrasubject variability of AUC is low (coefficient of variation 21.8 and 
12.6%, respectively). The steady-state AUCs achieved with oral ganciclovir 
(1000 mg three times daily or 500 mg six times daily) are approximately 70% 
of the AUC achieved with the daily maintenance dose of intravenous 
ganciclovir (5 mg/kg). Serum concentrations of ganciclovir are 20% higher 
when the oral formulation is administered with a high fat meal than when 
taken following an overnight fast. Serum concentrations of didanosine (200 
mg every 12 h) are approximately doubled when taken in combination with 
oral ganciclovir (1000 mg every 8 h). CONCLUSIONS: Although bioavailability 
of the oral formulation of ganciclovir is low, the serum concentrations are 
predictable, with low inter- and intrasubject variability in peak 
concentrations and AUC. The two oral regimens studied (500 mg six times 
daily or 1000 mg three times daily) have comparable bioavailability. Food 
has a beneficial effect of increasing serum concentrations. There is a 
potentially important pharmacokinetic interaction between oral ganciclovir 
and didanosine. 

==================================================================== 
16.) Cytomegalovirus (CMV) resistance in patients with CMV retinitis and AIDS 
treated with oral or intravenous ganciclovir. 
==================================================================== 
Author 
Drew WL; Stempien MJ; Andrews J; Shadman A; Tan SJ; Miner R; Buhles W 
Address 
Clinical Microbiology and Infectious Diseases, University of California at 
San Francisco-Mt. Zion Medical Center, San Francisco, CA, USA. 
[email protected] 
Source 
J Infect Dis, 179(6):1352-5 1999 Jun 
Abstract 
Treatment of cytomegalovirus (CMV) retinitis with oral ganciclovir results 
in relatively low plasma concentrations of drug, which theoretically could 
cause more frequent viral resistance compared with intravenous (iv) 
ganciclovir. By use of a plaque-reduction assay to quantify phenotypic 
sensitivity to ganciclovir, virus isolates were studied from patients with 
CMV retinitis participating in four clinical trials of oral ganciclovir. 
Before treatment, 69% of patients were culture-positive but just 1.1% of 
patients yielded a resistant CMV, defined as a median inhibitory 
concentration (IC50) >6 microM. On treatment, the first resistant isolate 
was recovered at 50 days. Overall, 3.1% of patients receiving iv 
ganciclovir and 6. 5% of those taking oral ganciclovir shed resistant CMV 
(median ganciclovir exposures of 75 and 165 days, respectively). Since 
IC50s for clinical isolates increased proportionately with treatment 
duration, it is likely that viral resistance would be more frequent with 
longer treatment. 

==================================================================== 
17.) The pharmacokinetics and safety profile of oral ganciclovir combined with 
zalcitabine or stavudine in asymptomatic HIV- and CMV-seropositive patients. 
==================================================================== 
Author 
Jung D; AbdelHameed MH; Teitelbaum P; Dorr A; Griffy K 
Address 
Roche Global Development, Palo Alto, California, USA. 
Source 
J Clin Pharmacol, 39(5):505-12 1999 May 
Abstract 
Two open-label, randomized, multiple-dose, three-way crossover studies were 
performed to assess the pharmacokinetics and safety of oral ganciclovir 
1000 mg q8h in asymptomatic patients seropositive for human 
immunodeficiency virus and cytomegalovirus. Ganciclovir was administered 
alone and in combination with zalcitabine 0.75 mg q8h (study 1) or 
stavudine 40 mg q12h (study 2). In the presence of zalcitabine, the only 
statistically significant change in the pharmacokinetic parameters of 
ganciclovir was a 22.2% mean increase in AUC0-8. However, there was no 
significant change in the renal clearance of ganciclovir when 
coadministered with zalcitabine, suggesting that the increase in serum 
ganciclovir concentration cannot be attributed to competition for active 
renal tubular secretion. No change in zalcitabine pharmacokinetics was 
observed in combination with ganciclovir. There were no significant changes 
in the pharmacokinetics of ganciclovir or stavudine when coadministered. 
Ganciclovir was well tolerated when given alone and in combination with 
either zalcitabine or stavudine. 

==================================================================== 
18.) GANCICLOVIR (Systemic) The product 
==================================================================== 

Revised: 08/08/95 

VA CLASSIFICATION (Primary/Secondary)&frac34;AM800 

Commonly used brand name(s): 

Cytovene; 
Cytovene-IV. 

Another commonly used name is DHPG 

Note: For a listing of dosage forms and brand names by country 
availability, see Dosage Forms section(s). 

Category 

Antiviral (systemic). 

Indications 

Note: Bracketed information in the Indications section refers to uses that 
are not included in U.S. product labeling. 

Accepted 

Cytomegalovirus retinitis (treatment)&frac34;Parenteral ganciclovir is indicated 
for induction and maintenance in the treatment of cytomegalovirus (CMV) 
retinitis in immunocompromised patients, including patients with acquired 
immunodeficiency syndrome (AIDS). Oral ganciclovir is indicated only for 
the maintenance of CMV retinitis in patients who have had a complete 
resolution of active retinitis after an induction course of parenteral 
ganciclovir1,61; however, oral ganciclovir has been associated with a 
shorter time to CMV retinitis progression.1,2,15,60,62 [Intravitreal 
administration of ganciclovir has also been used in patients who have been 
unresponsive to intravenous ganciclovir, or in whom serious 
myelosuppression has precluded the continuation of intravenous 
therapy.]29,31,34 

Cytomegalovirus disease (prophylaxis)*&frac34;Parenteral ganciclovir is indicated 
for the prophylaxis of CMV disease in transplant patients who are at risk 
for the disease.1,49,50,51,52,53,54 

[Cytomegalovirus disease (treatment)]*&frac34;Parenteral ganciclovir is used in 
the treatment of severe CMV disease, including CMV pneumonia, CMV 
gastrointestinal disease, and disseminated CMV infections, in 
immunocompromised patients.3,6,11,15,20 

[Polyradiculopathy (treatment)]*&frac34;Parenteral ganciclovir is used in the 
treatment of polyradiculopathy caused by CMV in patients with AIDS.38,39,40 

Resistance to ganciclovir has been reported. One paper described CMV 
disease refractory to ganciclovir therapy due to infections with a 
resistant virus, a susceptible virus that became resistant, and an 
infection first by a susceptible strain, and later by a genetically 
distinct, resistant one.26 The primary mechanism of resistance to 
ganciclovir is the decreased ability to form the active triphosphate 
moiety.1 Recurrence may be more frequent in patients treated with 
ganciclovir for prolonged periods, (> 3 to 6 months).33,43 

*Not included in Canadian product labeling. 

Pharmacology/Pharmacokinetics 

Physicochemical characteristics: 

High pH (11).1 

Molecular weight&frac34;&frac34; 
Ganciclovir: 255.234 
Ganciclovir sodium: 277.224 

Mechanism of action/Effect: 

Ganciclovir is a prodrug6 that is structurally similar to acyclovir.8 Its 
antiviral activity results from its intracellular conversion to the 
triphosphate form. In cytomegalovirus (CMV)-infected cells, ganciclovir is 
thought to be rapidly phosphorylated to the monophosphate form by a 
CMV-encoded enzyme63, then subsequently converted to the diphosphate and 
triphosphate forms by cellular kinases. Ganciclovir is phosphorylated much 
more rapidly in infected cells7; however, uninfected cells can also produce 
low levels of ganciclovir-triphosphate.3Ganciclovir-triphosphate 
competitively inhibits DNA polymerase by acting as a substrate and becoming 
incorporated into the DNA.5 This inhibits DNA synthesis by suppressing DNA 
chain elongation.5The drug inhibits viral DNA polymerases more effectively 
than it does cellular polymerase.24 Chain elongation resumes when 
ganciclovir is removed.5 

Absorption: 

Ganciclovir is poorly absorbed after oral administration; 
bioavailability under fasting conditions is approximately 5%, and when 
administered with food, 6 to 9%.1,15,59 

Distribution: 

Ganciclovir is widely distributed to all tissues and crosses the 
placenta15,58; however, there is no marked accumulation in any one type of 
tissue. Penetration into the cerebral spinal fluid averaged 38% in one 
study9, and ranged from 7 to 67% in others.10,22 Ganciclovir also appears 
to have good intraocular penetration.3 In one patient, the subretinal fluid 
ganciclovir concentration was 7.2 micromoles per L with a corresponding 
plasma concentration of 8.2 micromoles per L 5.5 hours after a dose of 5 mg 
per kg of body weight (mg/kg), and 2.58 micromoles per L with a 
corresponding plasma concentration of 1.3 micromoles per L 8 hours after a 
subsequent dose of 5 mg/kg.28 

VolD(steady state) &frac34;Adults and neonates: Approximately 0.74 L per kg.1,57 

Protein binding: 

Low (1 to 2%).1 

Biotransformation: 

Little to no metabolism.3,6 

Half-life: 

Serum&frac34; 

Intravenous 
Adults&frac34;Normal renal function: 2.5 to 3.6 hours (average, 2.9 hours).1,3,6,7 

Adults&frac34;Renal function impairment: 9 to 30 hours (creatinine clearance of 20 
to 50 mL per minute [0.33 to 0.83 mL per second]).15 

Neonates&frac34;Approximately 2.4 hours.1,57 

Oral: 
Normal renal function&frac34;3.1 to 5.5 hours.59 

Renal function impairment&frac34;15.7 to 18.2 hours (creatinine clearance of 10 to 
50 mL per minute [0.17 to 0.83 mL per second]).1 

Vitreous fluid&frac34; 
Approximately 13 hours.34 

Time to peak concentration: 

Intravenous&frac34; 
End of infusion (approximately 1 hour).13 

Oral&frac34; 
Fasting: Approximately 1.8 hours.1 

With food: Approximately 3 hours.1 

Peak concentrations 

Intravenous&frac34; 
Adults: 5 mg/kg over 1 hour&frac34;8.3 to 9 mcg/mL.1 

Neonates: 4 and 6 mg/kg over 1 hour&frac34;Approximately 5.5 and 7 mcg/mL, 
respectively.1,57 

Oral&frac34; 
3 grams per day: 1 to 1.2 mcg/mL.1 

Intravitreal injection&frac34; 
1000 mcg administered in 5 divided doses over 15 days: 16.2 mcg/mL; 
ganciclovir was not detected in plasma.15 

Elimination: 

Renal; almost 100% excreted unchanged in the urine by glomerular filtration 
and tubular secretion.1,9,11,15 

In dialysis&frac34;Plasma ganciclovir concentrations are reduced by approximately 
50% after a single, 4-hour hemodialysis.1,12 

Precautions to Consider 

Cross-sensitivity and/or related problems 

Patients hypersensitive to acyclovir may also be hypersensitive to 
ganciclovir because of the chemical similarity of the 2 medications.1,2 

Carcinogenicity/Tumorigenicity 

Ganciclovir is carcinogenic in animals and should be considered a potential 
carcinogen in humans. Ganciclovir was carcinogenic in the mouse at oral 
doses of 20 and 1000 mg/kg per day (approximately 0.1 and 1.4 times, 
respectively, the mean drug exposure in humans following the recommended 
intravenous dose of 5 mg/kg, based on the area under the concentration-time 
curve [AUC]) comparisons. Mice given oral doses of 20 mg per kg of body 
weight (mg/kg) per day showed a slightly increased incidence of tumors in 
the preputial and harderian glands in males, forestomach in males and 
females, and liver in females. Studies in mice given oral doses of 1000 
mg/kg per day showed an increased incidence of tumors of the forestomach in 
males and females, preputial gland in males, and reproductive tissues and 
liver in females. All ganciclovir-induced tumors were of epithelial or 
vascular origin, except for histiocytic sarcoma of the liver. No 
carcinogenic effect occurred at a dose of 1 mg/kg per day.1 

Mutagenicity 

Ganciclovir was mutagenic in mouse lymphoma cells at concentrations between 
50 and 500 mcg/mL, and caused chromosomal damage in vitro in human 
lymphocytes at concentrations between 250 and 2000 mcg/mL. Parenteral 
ganciclovir was also clastogenic in the mouse micronucleus assay at doses 
of 150 and 500 mg/kg (2.8 to 10 times the human exposure based on area 
under the concentration-time curve [AUC] of a single intravenous dose of 5 
mg/kg), but not at a dose of 50 mg/kg (exposure approximately comparable to 
the human dose based on AUC). Ganciclovir was not mutagenic in the Ames 
Salmonella assay at concentrations of 500 to 5000 mcg/mL.1 

Pregnancy/Reproduction 

Fertility&frac34;Although data in humans have not been obtained, temporary or 
permanent suppression of fertility in women and spermatogenesis in men may 
occur.1 

In female mice, ganciclovir caused decreased mating behavior, decreased 
fertility, and increased death in utero at doses approximately 1.7 times 
the recommended human dose (based on the AUC of a single intravenous dose 
of 5 mg/kg). Ganciclovir was also found to cause decreased fertility in 
male mice, and hypospermatogenesis in mice and dogs following daily oral or 
intravenous administration of doses ranging from 0.2 to 10 
mg/kg.1Inhibition of spermatogenesis and subsequent infertility was 
reversible at lower doses and irreversible at higher doses in 
animals.2Systemic drug exposure (as measured by AUC) at the lowest dose 
showing toxicity in each species ranged from 0.03 to 0.1 times the AUC of 
the recommended human intravenous dose.1 

Pregnancy&frac34;Adequate and well-controlled studies in humans have not been 
done. However, ganciclovir has been found to cross the placenta.15,58 Due 
to the high toxicity and mutagenic and teratogenic potential of 
ganciclovir, use during pregnancy should be avoided whenever possible. 
Women of childbearing age should use effective contraception. Men should 
use barrier contraception during, and for at least 90 days following, 
treatment with ganciclovir.1 

Ganciclovir was found to be carcinogenic in animals and teratogenic in 
rabbits, causing cleft palate, anophthalmia/microphthalmia, aplastic organs 
(kidneys and pancreas), hydrocephaly, bradygnathia, and fetal growth 
retardation. It also was found to be embryotoxic in mice, and to cause 
death in utero and maternal toxicity in both rabbits and mice. Fetal 
resorptions occurred in at least 85% of rabbits and mice administered 60 
mg/kg per day and 108 mg/kg per day (2 times the human exposure based on 
AUC comparisons), respectively. Daily intravenous doses of 90 mg/kg 
administered to female mice prior to mating, during gestation, and during 
lactation caused hypoplasia of the testes and seminal vesicles in the 
month-old male offspring, as well as pathologic changes in the nonglandular 
region of the stomach. The drug exposure in mice as estimated by the AUC 
was approximately 1.7 times the human AUC.1 

FDA Pregnancy Category C. 

Breast-feeding 

It is not known whether ganciclovir is distributed into breast milk1; 
however, it is likely that some drug will accumulate because of its 
pharmacokinetic properties.35 Because of the potential for serious adverse 
effects in nursing infants, breast-feeding should be stopped during 
ganciclovir therapy.1 Ganciclovir has caused irreversible toxicity in 
nursing animal pups.14 

Pediatrics 

There is little information currently available on the use of ganciclovir 
in children, especially those up to the age of 12. At this time, the side 
effects seen in children appear to be similar to those seen in adults, 
especially granulocytopenia (17%) and thrombocytopenia (10%). However, the 
probability of long-term carcinogenicity and reproductive toxicity seen in 
animal studies should also be considered.1 

Geriatrics 

No information is available on the relationship of age to the effects of 
ganciclovir in geriatric patients. However, elderly patients are more 
likely to have an age-related decrease in renal function, which may require 
an adjustment of dosage or dosing interval in patients receiving 
ganciclovir.1,2 

Dental 

The neutropenic and thrombocytopenic effects of ganciclovir may result in 
an increased incidence of microbial infection, delayed healing, and 
gingival bleeding. Patients should be instructed in proper oral hygiene, 
including caution in use of regular toothbrushes, dental floss, and 
toothpicks. 

Drug interactions and/or related problems 

The following drug interactions and/or related problems have been selected 
on the basis of their potential clinical significance (possible mechanism 
in parentheses where appropriate)&frac34;not necessarily inclusive (>> = major 
clinical significance): 

Note: Combinations containing any of the following medications, depending 
on the amount present, may also interact with this medication. 

Blood dyscrasia-causing medications (See Appendix II) or 
>> Bone marrow depressants, other (See Appendix II) or 
Radiation therapy1&frac34;(concurrent use with ganciclovir may increase the bone 
marrow-depressant effects of these medications and radiation therapy) 

Didanosine&frac34;(concurrent and sequential [2 hours apart] administration of 
didanosine with ganciclovir results in a significant increase in the 
steady-state area under the concentration-time curve [AUC] of didanosine 
[range, 72 to 111%]1,19,21; when didanosine was administered 2 hours before 
oral ganciclovir, the steady-state AUC of ganciclovir was decreased by 
approximately 21%1; there was no significant change in renal clearance of 
either medication1) 

Imipenem and cilastatin combination1,2&frac34;(generalized seizures have been 
reported in patients receiving ganciclovir and imipenem and cilastatin 
combination concurrently) 

>> Nephrotoxic medications (See Appendix II)1&frac34;(concurrent use with 
ganciclovir may increase serum creatinine; concurrent use with nephrotoxic 
medications, such as cyclosporine or amphotericin B, may increase the 
chance of renal function impairment; this may also decrease elimination of 
ganciclovir and increase the risk of toxicity) 

Probenecid&frac34;(concurrent use with probenecid increases the AUC of ganciclovir 
by approximately 53%21 and decreases its renal clearance by approximately 
22%1; concurrent use of ganciclovir with probenecid, or other medications 
that inhibit renal tubular secretion, may reduce the renal clearance of 
ganciclovir and lead to toxicity1,21) 

>> Zidovudine1,2,16,18&frac34;(concurrent use of ganciclovir with zidovudine has 
been associated with severe hematologic toxicity in some patients, even 
when the zidovudine dose was reduced to 300 mg per day37; concurrent use 
increases the AUC of zidovudine by approximately 14 to 19%1,21; in 
vitrostudies found concurrent use of these 2 drugs to be synergistically 
cytotoxic48; concurrent administration should be used with caution) 

Laboratory value alterations 

The following have been selected on the basis of their potential clinical 
significance (possible effect in parentheses where appropriate)&frac34;not 
necessarily inclusive (>> = major clinical significance): 

With physiology/laboratory test values 
Alanine aminotransferase (ALT [SGPT]), serum and 
Alkaline phosphatase, serum and 
Aspartate aminotransferase (AST [SGOT]), serum and 
Bilirubin, serum&frac34;(values may be increased1,2,3,13,17) 

Blood urea nitrogen (BUN) or 
Creatinine, serum&frac34;(values may be increased1,2) 

Medical considerations/Contraindications 

The medical considerations/contraindications included have been selected on 
the basis of their potential clinical significance (reasons given in 
parentheses where appropriate)&frac34;not necessarily inclusive (>> = major 
clinical significance). 

Risk-benefit should be considered when the following medical problems exist 

>> Absolute neutrophil count (ANC) <500 cells/mm3 or platelet count 
<25,000 cells/mm31&frac34; 

>> Hypersensitivity to acyclovir or ganciclovir1&frac34; 

>> Renal function impairment1,3,6&frac34;(because ganciclovir is excreted through 
the kidneys, the dose of ganciclovir should be reduced or the dosing 
interval increased in patients with renal function impairment) 

Patient monitoring 

The following may be especially important in patient monitoring (other 
tests may be warranted in some patients, depending on condition; >> = 
major clinical significance): 

>> Complete blood counts (CBCs) and 
>> Platelet counts1,2,3,11,13,45,46,47&frac34;(because ganciclovir may cause 
granulocytopenia and thrombocytopenia, neutrophil and platelet counts 
should be monitored prior to treatment, every 2 days during induction 
therapy, then at least weekly thereafter. Neutrophil and platelet counts 
should be performed daily in patients undergoing hemodialysis, patients 
with neutrophil counts less than 1000 cells/mm3 at the beginning of 
treatment, and those in whom use of ganciclovir or other nucleoside analogs 
previously resulted in leukopenia. When severe neutropenia [absolute 
neutrophil count < 500 cells/mm3] or severe thromboctyopenia [platelet 
count < 25,000 cells/mm3] occurs, discontinuation of ganciclovir may be 
necessary; however, a small number of patients have been successfully 
treated with concurrent use of sargramostim [GM-CSF; granulocyte-macrophage 
colony stimulating factor] or filgrastin [G-CSF; granulocyte colony 
stimulating factor]61) 

Liver function tests15,17&frac34;(liver function tests, including serum ALT [SGPT] 
and AST [SGOT] values, and serum bilirubin concentration, should be 
monitored periodically since elevations, usually reversible, have occurred 
during ganciclovir therapy) 

>> Renal function determinations1&frac34;(blood urea nitrogen and serum 
creatinine determinations should be monitored at least every 2 weeks since 
patients with renal function impairment will require an adjustment in 
dosage or dosage interval) 

For treatment of cytomegalovirus [CMV] retinitis, in addition to the above 

>> Ophthalmologic examinations30,61,64&frac34;(ophthalmologic examinations should 
be performed weekly during induction and every 4 weeks during maintenance 
since ganciclovir is not a cure for cytomegalovirus [CMV] retinitis, and 
progression of retinitis may occur during or following ganciclovir 
treatment; however, the frequency of examinations may vary, depending on 
the extent of disease, activity, and proximity to the macula and optic disc) 

Side/Adverse Effects 

The following side/adverse effects have been selected on the basis of their 
potential clinical significance (possible signs and symptoms in parentheses 
where appropriate)&frac34;not necessarily inclusive: 

Those indicating need for medical attention 

Incidence more frequent 

For intravenous and oral administration 
Granulocytopenia (sore throat and fever)1,3,6,24,59; thrombocytopenia 
(unusual bleeding or bruising)1,3,6,7,24,32,59 

Note: Granulocytopenia is usually reversible, with an overall incidence of 
approximately 40%1,2,3,6; the incidence of dose-limiting toxicity is <20%.24 

Thrombocytopenia is also usually reversible, with an overall incidence of 
approximately 20%1,2,3,6,7; the incidence of dose-limiting toxicity is 5 to 
10%.24,32 

Incidence less frequent 

For intravenous and oral administration 
Anemia (unusual tiredness and weakness)1,2,59; central nervous system (CNS) 
effects (mood or other mental changes; nervousness; tremor)1,3,6,13,41; 
hypersensitivity (fever; skin rash)1,2,59phlebitis (pain at site of 
injection)1,3,6 

For intravitreal administration35 
Bacterial endophthalmitis; conjunctival scarring, mild; foreign body 
sensation; retinal detachment; scleral induration; or subconjunctival 
hemorrhage (decreased vision or any change in vision) 

Those indicating need for medical attention only if they continue or are 
bothersome 

Incidence less frequent 
Gastrointestinal disturbances (abdominal pain; loss of appetite; nausea 
and vomiting)1,2,6,7,59 

Patient Consultation 

As an aid to patient consultation, refer to Advice for the Patient, 
Ganciclovir (Systemic). 

In providing consultation, consider emphasizing the following selected 
information (>> = major clinical significance): 

Before using this medication 

>> Conditions affecting use, especially: 

Hypersensitivity to acyclovir or ganciclovir 

Pregnancy&frac34;Use of ganciclovir during pregnancy should be avoided whenever 
possible. Ganciclovir crosses the placenta and has been found to be 
carcinogenic and teratogenic in animals. Use of effective contraception by 
men and women who are undergoing treatment and in men for 90 days following 
treatment is recommended 

Breast-feeding&frac34;Because of ganciclovir's potential for severe toxicity, 
breast-feeding should be stopped during therapy 

Use in children&frac34;There is little information currently available on the use 
of ganciclovir in children, especially those up to the age of 12; long-term 
carcinogenicity and reproductive toxicity due to ganciclovir use in 
children is unknown 

Dental&frac34;The neutropenic and thrombocytopenic effects of ganciclovir may 
result in an increased incidence of microbial infection, delayed healing, 
and gingival bleeding 

Other medications, especially other bone marrow depressants, nephrotoxic 
medications, or zidovudine 

Other medical problems, especially renal function impairment, an absolute 
neutrophil count (ANC) <500 cells/mm3, or platelet count <25,000 cells/mm3 

Proper use of this medication 

>> Taking ganciclovir capsules with food 

>> Importance of receiving medication for full course of therapy and on a 
regular schedule 

>> Proper dosing 

Precautions while using this medication 

To reduce the risk of bleeding during periods of low blood counts: 
>> Checking with physician immediately if getting an infection or fever or 
chills 

>> Checking with physician immediately if unusual bleeding or bruising; 
black, tarry stools; blood in urine or stools; or pinpoint red spots on 
skin occur 

Using caution in use of regular toothbrushes, dental floss, and toothpicks; 
physician, dentist, or nurse may suggest alternative methods for cleaning 
teeth and gums; checking with physician before having dental work done 

Using caution to avoid accidental cuts with use of sharp objects such as a 
safety razor or fingernail or toenail cutters 

>> Using contraception since ganciclovir has mutagenic and teratogenic 
potential; women should use effective contraception during treatment, and 
men should use barrier contraception during and for at least 90 days 
following treatment1 

>> Regular visits to physician to check blood counts 

>> For CMV retinitis&frac34;Regular visits to ophthalmologist to examine eyes 
since progression of retinitis and visual loss may occur during ganciclovir 
therapy 

Side/adverse effects 

Signs of potential side effects, especially granulocytopenia, 
thrombocytopenia, anemia, CNS effects, hypersensitivity, and phlebitis when 
ganciclovir is administered intravenously or orally; and bacterial 
endophthalmitis, mild conjunctival scarring, foreign body sensation, 
retinal detachment, scleral induration, and subconjunctival hemorrhage when 
it is administered intravitreally 

General Dosing Information 

Ganciclovir is not a cure for cytomegalovirus infections. Maintenance 
therapy is almost always necessary in AIDS patients to prevent relapse, 
which is very common once the medication has been withdrawn.1 

Monitoring of serum ganciclovir concentrations has not been shown to be 
useful for ensuring efficacy or avoiding toxicity.24 

Ganciclovir sodium should be administered by intravenous infusion only. 
Intramuscular or subcutaneous injection will result in severe tissue 
irritation due to ganciclovir's high pH (11).1,2 

Intravenous infusions of ganciclovir should be administered at a constant 
rate over at least a 1-hour period, and patients must be adequately 
hydrated, to avoid increased toxicity. The recommended dosage, frequency, 
and infusion rate should not be exceeded.1 

Severe neutropenia or thrombocytopenia (absolute neutrophil count [ANC] 
<500 cells/mm3 or platelet count <25,000 cells/mm3) requires an 
interruption in therapy until there is evidence of bone marrow recovery 
(ANC &sup3;750 cells/mm3); however, a small number of patients have been 
successfully treated with concurrent use of sargramostim (GM-CSF; 
granulocyte-macrophage colony stimulating factor).45,46,47 

Ganciclovir capsules should be taken with food for maximum absorption.1 

The dose of ganciclovir must be decreased in patients with renal function 
impairment. 

Patients undergoing hemodialysis should not receive a dose in excess of 
1.25 mg per kg of body weight (mg/kg) every 24 hours. On dialysis days, the 
dose of ganciclovir should be administered after hemodialysis has been 
performed since dialysis will reduce plasma ganciclovir concentrations by 
approximately 50%.1,2 

Ganciclovir capsules are indicated as an alternative to intravenous 
ganciclovir for maintenance therapy of CMV retinitis in immunocompromised 
patients, including those with AIDS. Oral ganciclovir should be used in 
patients in whom retinitis is stable and quiescent following appropriate 
induction therapy and for whom the risk of more rapid progression is 
balanced by the benefit associated with avoiding long-term daily 
intravenous infusions, usually requiring indwelling intravenous catheters.1 

Intravitreal administration of ganciclovir has been used in patients who 
have been unresponsive to intravenous ganciclovir, or in whom serious 
myelosuppression has precluded the continuation of intravenous therapy. 
Intravitreal doses of 200 micrograms have resulted in improvement or 
stabilization of retinitis, and have been well tolerated. In one report 
describing a patient who received 28 intravitreal injections, plasma 
concentrations after intravitreal injections showed no significant systemic 
absorption. The elimination half-life of ganciclovir from the vitreous 
fluid was estimated to be 13.3 hours, and the intravitreal concentration 
remained above the ID 50 of cytomegalovirus for approximately 62 hours 
after a single injection.29,31,34 

Safety considerations for handling this medication 

Caution should be exercised in the handling and preparation of ganciclovir. 
Because ganciclovir shares some properties of anti-tumor agents (i.e., 
carcinogenicity and mutagenicity), it should be handled and disposed of 
according to guidelines issued for cytotoxic drugs. Ganciclovir solution is 
alkaline (pH 11). Avoid inhalation, ingestion, or direct contact of 
ganciclovir with the skin or mucous membranes. If contact does occur, wash 
area thoroughly with soap and water; rinse eyes thoroughly with plain 
water.42 Ganciclovir capsules should not be opened or crushed.1 

Oral Dosage Forms 


GANCICLOVIR CAPSULES 

Usual adult and adolescent dose 

Cytomegalovirus retinitis&frac34; 
Induction: Ganciclovir capsules should not be used for induction therapy. 
See Sterile Ganciclovir Sodium1 

Maintenance: Oral, 1000 mg three times a day with food, or 500 mg six times 
a day every three hours with food, during waking hours.1 

Note: For maintenance, patients with impaired renal function may require a 
reduction in dose as follows:1,3,12 



Creatinine Clearance (mL/min)/(mL/sec) Dose 

&sup3;70/1.17 See Usual adult and 
adolescent dose 
50-69/0.83-1.15 1500 mg once a day, or 500 
mg three times a 
day 
25-49/0.42-0.82 1000 mg once a day, or 500 
mg twice a day 
10-24/0.17-0.40 500 mg once a day 
<10/0.17 500 mg three times a week, 
following 
hemodialysis 



Usual pediatric dose 

Dosage has not been established.1 

Strength(s) usually available 

U.S.&frac34; 
250 mg (Rx)[Cytovene]. 

Canada&frac34; 
Not commercially available. 

Packaging and storage: 

Store below 40 &deg;C (104 &deg;F), preferably between 15 and 30 &deg;C (59 and 86 &deg;F), 
unless otherwise specified by manufacturer. 

Auxiliary labeling: 

&middot; Continue medicine for full time of treatment. 

Note: Ganciclovir capsules should not be opened or crushed. 

Parenteral Dosage Forms 


GANCICLOVIR SODIUM STERILE 

Usual adult and adolescent dose 

Cytomegalovirus retinitis (treatment)&frac34; 

Induction&frac34; 
Intravenous infusion, 5 mg per kg of body weight, administered over at 
least one hour, every twelve hours for fourteen to twenty-one 
days.1,2,3,6,8,20 

Note: Doses of 7.5 to 15 mg per kg of body weight per day divided into two 
or three doses have been used, and treatment has been continued for longer 
than twenty-one days; if retinitis does not show significant improvement, 
the possibility of viral resistance should be considered.32 

Intravitreal injection, 200 mcg two times a week for three weeks.35,44 

Note: For induction, patients with impaired renal function may require a 
reduction in dose as follows1: 



Creatinine Clearance (mL/min)/(mL/sec) Dose 

&sup3;70/1.17 See Usual adult and 
adolescent dose 
50-69/0.83-1.15 2.5 mg per kg every twelve 
hours 
25-49/0.42-0.82 2.5 mg per kg every 
twenty-four hours 
10-24/0.17-0.40 1.25 mg per kg every 
twenty-four hours 
<10 1.25 mg per kg three times 
a week, following 
hemodialysis 



Maintenance&frac34; 
Intravenous infusion, 5 mg per kg of body weight a day, administered over 
at least one hour, once a day for seven days per week; or 6 mg per kg of 
body weight, administered over at least one hour, once a day for five days 
of the week.1,2,3,6 

Note: If CMV retinitis progresses during maintenance therapy, patients 
should be retreated with the twice-a-day induction regimen. 

Intravitreal injection, 200 mcg once a week.35,36 

Note: For maintenance, patients with impaired renal function may require a 
reduction in dose as follows1: 



Creatinine Clearance (mL/min)/(mL/sec) Dose 
&sup3;70/1.17 See Usual adult and 
adolescent dose 

50-69/0.83-1.15 2.5 mg per kg every twelve 
hours 
25-49/0.42-0.82 1.25 mg per kg every 
twenty-four hours 
10-24/0.17-0.40 0.625 mg per kg every 
twenty-four hours 
<10 0.625 mg per kg three times 
a week, following 
hemodialysis 



Cytomegalovirus disease (prophylaxis)&frac34; 
Intravenous infusion, 5 mg per kg of body weight, administered over at 
least one hour, every twelve hours for seven to fourteen days; then 5 mg 
per kg of body weight, administered over at least one hour, once a day for 
seven days of the week, or 6 mg per kg of body weight, administered over at 
least one hour, once a day for five days of the week.49 

Usual pediatric dose 

Dosage has not been established. However, induction doses of 7.5 to 10 mg 
per kg of body weight divided into two or three doses, and maintenance 
doses of 2.5 to 5 mg per kg of body weight a day have been used in 
children.25,27,28,32 

Strength(s) usually available 

U.S.&frac34; 
500 mg (Rx)[Cytovene-IV (sodium 46 mg)]. 

Canada&frac34; 
500 mg (Rx)[Cytovene]. 

Packaging and storage: 

Store below 40 &deg;C (104 &deg;F), preferably between 15 and 30 &deg;C (59 and 86 &deg;F), 
unless otherwise specified by manufacturer. 

Preparation of dosage form: 

To prepare initial dilution for intravenous infusion, 10 mL of sterile 
water for injection (without parabens) should be added to each 500-mg vial 
to provide 50 mg per mL. To ensure complete dissolution, the vial should be 
shaken until solution is clear. The resulting solution should be further 
diluted, usually with 100 mL of 0.9% sodium chloride injection, 5% dextrose 
injection, Ringer's injection, or lactated Ringer's injection. Final 
concentrations of 10 mg per mL or less are recommended.2,23 

Note: Caution should be exercised in the handling and preparation of 
ganciclovir. Because ganciclovir shares some properties of anti-tumor 
agents (i.e., carcinogenicity and mutagenicity), it should be handled and 
disposed of according to guidelines issued for cytotoxic drugs. Ganciclovir 
solution is alkaline (pH 11). Avoid inhalation, ingestion, or direct 
contact of ganciclovir with the skin or mucous membranes. If contact does 
occur, wash area thoroughly with soap and water; rinse eyes thoroughly with 
plain water.2,42 

Stability: 

The manufacturer states that after reconstitution, solutions at 
concentrations of 50 mg per mL retain their potency for 12 hours at room 
temperature. Refrigeration is not recommended. After further dilution for 
intravenous infusion, it is recommended that solutions be used within 24 
hours since nonbacteriostatic infusion solutions must be used; refrigerate 
the diluted solution; do not freeze.2,23 

However, studies have found that ganciclovir, when diluted to 
concentrations of 1, 5, and 10 mg per mL in 5% dextrose injection and 0.9% 
sodium chloride injection, was stable when assayed at 28 and 35 days.55,56 
These solutions were refrigerated in polyvinyl chloride (PVC) bags and 
syringes. Ganciclovir was also stable when 5 and 10 mg per mL solutions 
were frozen in PVC bags for 28 days.56 

Incompatibilities: 

Parabens are incompatible with ganciclovir sodium and may cause 
precipitation.1,2 

==================================================================== 
CIDOFOVIR 
==================================================================== 
Source: HARRISON'S 14 

Cidofovir is a phosphonomethylether derivative of cytosine that is highly 
active against CMV, including some ganciclovir- and foscarnet-resistant 
strains. This agent is administered intravenously and is cleared largely by 
the kidney, with a serum half-life of 2.6 h. Concomitant administration 
with probenecid markedly prolongs the half-life of cidofovir and protects 
recipients against the major form of toxicity elicited by the drug 
(nephrotoxicity). The intracellular half-life of cidofovir diphosphate&frac34;17 
to 30 h&frac34;is the basis for its infrequent administration (once a week or once 
every other week). Cidofovir is currently being evaluated for the treatment 
of CMV retinitis in patients with AIDS. 

==================================================================== 
19.) Trifluridine, cidofovir, and penciclovir in the treatment of experimental 
herpetic keratitis. 
==================================================================== 
Author 
Kaufman HE; Varnell ED; Thompson HW 
Address 
LSU Eye Center, Louisiana State University Medical Center School of 
Medicine, New Orleans 70112-2234, USA. 
Source 
Arch Ophthalmol, 116(6):777-80 1998 Jun 
Abstract 
OBJECTIVE: To compare trifluridine eyedrops, cidofovir eyedrops, and 
penciclovir ophthalmic ointment for the treatment of herpes simplex virus 
type 1 keratitis. METHODS: New Zealand white rabbits were infected with the 
McKrae strain of herpes simplex virus type 1. Three days after viral 
inoculation, the rabbits were randomly assigned to treatment with 1% 
trifluridine, 0.2% cidofovir, 3% penciclovir ointment, or 
phosphate-buffered saline (for control) on various schedules. The severity 
of keratitis was graded in a masked manner. RESULTS: Treatment with any of 
the antiviral drugs resulted in significantly less severe keratitis than 
treatment with phosphate-buffered saline. There was no statistically 
significant difference between eyes given trifluridine 2, 4, or 7 times a 
day and eyes given cidofovir 2 times a day (P=.06, P=.43, and P=.19, 
respectively, using the F test of the analysis of variance). Cidofovir 
given twice a day was significantly more effective than penciclovir given 
either 2 or 4 times a day (P<.001 and P=.002, respectively). Even with 
once-a-day dosage, all 3 drugs were significantly more effective than 
phosphate-buffered saline (P<.001 for all). There was no significant 
difference between once-a-day trifluridine and cidofovir treatments 
(P=.17). Trifluridine administered 5 times a day was as effective as 1% 
cidofovir. A similar degree of punctate keratitis was seen after 4 to 5 
days in eyes treated with trifluridine at the highest frequency, 1% 
cidofovir, or penciclovir ointment. CONCLUSION: Trifluridine treatment was 
highly effective in this rabbit model, even when given only once a day. 
Treatment with cidofovir was as effective as that with trifluridine. 
CLINICAL RELEVANCE: Cidofovir and penciclovir treatments may prove to be 
effective against epithelial keratitis. Clinical trials of trifluridine, 
cidofovir, and penciclovir with lower treatment frequencies appear to be 
warranted. 

==================================================================== 
20.) Bioavailability and metabolism of cidofovir following topical 
administration to rabbits. 
==================================================================== 
Author 
Cundy KC; Lynch G; Lee WA 
Address 
Gilead Sciences, Foster City, CA 94404, USA. 
Source 
Antiviral Res, 35(2):113-22 1997 Jul 
Abstract 
The bioavailability and metabolism of the antiviral nucleotide analog 
cidofovir (HPMPC) were examined in New Zealand white rabbits following 
topical administration to normal and abraded skin. Male rabbits (four per 
group) received 14C-cidofovir (100 microCi/kg) intravenously (1 mg/kg) as a 
solution or topically (2 mg/animal) as a 1% w/w gel containing 
hydroxyethylcellulose (HEC) with or without propylene glycol (PG). The same 
PG/HEC formulation was applied topically to an abraded skin site in a 
fourth group of animals. All radioactivity detected in plasma and skin was 
accounted for by cidofovir. Plasma concentrations of radioactivity declined 
multiexponentially following intravenous administration, with a terminal 
half-life of 5.4 h. For intact skin, the absolute bioavailabilities of the 
HEC and PG/HEC formulations were 0.2 and 2.1%, respectively. For abraded 
skin, the bioavailability for the PG/HEC gel was 41%. Radioactivity in 
kidneys was attributed to cidofovir ( > 95%) and cyclic HPMPC. 
Concentrations in kidney following topical administration of cidofovir to 
normal skin were < 4% of those following intravenous dosing. Topical 
application of cidofovir to intact skin led to negligible systemic exposure 
to the drug. The topical bioavailability and hence the flux of cidofovir 
through intact skin was enhanced by the presence of PG in the formulation. 
Abrasion of the skin removed the principal barrier to absorption and led to 
significant systemic exposure to cidofovir. 

==================================================================== 
21.) Cidofovir: a new therapy for cytomegalovirus retinitis. 
==================================================================== 
Author 
Lalezari JP 
Address 
Department of Medicine, University of California, San Francisco 94115, U.S.A. 
Source 
J Acquir Immune Defic Syndr Hum Retrovirol, 14 Suppl 1():S22-6 1997 
Abstract 
Cidofovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, formerly 
known as HPMPC, is the first antiviral nucleotide analogue available for 
the treatment of cytomegalovirus (CMV) retinitis. Because cidofovir does 
not require viral activation, it has two advantages over nucleoside 
analogues such as ganciclovir and acyclovir. Cidofovir is active in 
uninfected cells and may act preemptively, and it may retain activity 
against ganciclovir-resistant strains. Preclinical studies showed the major 
toxicity of cidofovir to be dose-, schedule-, and species-dependent 
nephrotoxicity. These studies also showed that concomitant administration 
of probenecid protects animal models against cidofovir-induced 
nephrotoxicity. Two phase I-II studies were undertaken in HIV-positive 
patients with asymptomatic CMV excretion to evaluate several 
dose-escalation regimens. Data from both phase I-II studies showed that in 
patients receiving cidofovir at > or =3 mg/kg, the virologic response rate 
(> or =2 log reduction in CMV titer) was 93% for urine and 74% for semen. 
In addition, four treatment modifications were indicated to reduce the 
incidence of cidofovir-related nephrotoxicity: (a) dose reduction or 
interruption for changes in renal function; (b) concomitant administration 
of probenecid; (c) administration of 1 L of normal saline 1 h before 
infusion of cidofovir; and (d) extension of the dosing interval. 

==================================================================== 
22.) Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: 
the HPMPC peripheral cytomegalovirus retinitis trial. A randomized, 
controlled trial. Studies of Ocular complications of AIDS Research Group in 
Collaboration with the AIDS Clinical Trials Group. 
==================================================================== 

Source 
Ann Intern Med, 126(4):264-74 1997 Feb 15 
Abstract 
BACKGROUND: Cytomegalovirus (CMV) retinitis is a common infection and a 
major cause of visual loss in patients with the acquired immunodeficiency 
syndrome (AIDS). OBJECTIVE: To evaluate intravenous cidofovir as a 
treatment for CMV retinitis. DESIGN: Two-stage, multicenter, phase II/III, 
randomized, controlled clinical trial. SETTING: Ophthalmology and AIDS 
services at tertiary care medical centers. PATIENTS: 64 patients with AIDS 
and previously untreated, small, peripheral CMV retinitis lesions (that is, 
patients at low risk for loss of visual acuity). INTERVENTION: Patients 
were randomly assigned to one of three groups: the deferral group, in which 
treatment was deferred until retinitis progressed; the low-dose cidofovir 
group, which received cidofovir, 5 mg/kg of body weight once weekly for 2 
weeks, then maintenance therapy with cidofovir, 3 mg/kg once every 2 weeks; 
or the high-dose cidofovir group, which received cidofovir, 5 mg/kg once 
weekly for 2 weeks, then maintenance therapy with cidofovir, 5 mg/kg once 
every 2 weeks. To minimize nephrotoxicity, cidofovir was administered with 
hydration and probenecid. MEASUREMENTS: Progression of retinitis, evaluated 
in a masked manner by a fundus photograph reading center; the amount of 
retinal area involved by CMV; the loss of visual acuity; and morbidity. 
RESULTS: Median time to progression was 64 days in the low-dose cidofovir 
group and 21 days in the deferral group (P = 0.052, log-rank test). The 
median time to progression was not reached in the high-dose cidofovir group 
but was 20 days in the deferral group (P = 0.009, log-rank test). Analysis 
of the rates of increase in the retinal area affected by CMV confirmed the 
data on time to progression. The three groups had similar rates of visual 
loss. Proteinuria of 2+ or more occurred at rates of 2.6 per person-year in 
the deferral group, 2.8 per person-year in the low-dose cidofovir group (P 
> 0.02), and 6.8 per person-year in the high-dose cidofovir group (P = 
0.135). No patient developed 4+ proteinuria, but two cidofovir recipients 
developed persistent elevations of serum creatinine levels at more than 177 
mumol/L (2.0 mg/dL). Reactions to probenecid occurred at a rate of 0.70 per 
person-year. CONCLUSIONS: Intravenous cidofovir, high- or low-dose, 
effectively slowed the progression of CMV retinitis. Concomitant probenecid 
and hydration therapy, intermittent dosing, and monitoring for proteinuria 
seemed to minimize but not eliminate the risk for nephrotoxicity. 

==================================================================== 
23.) Cidofovir and experimental herpetic stromal disease. 
==================================================================== 
Author 
Kaufman HE; Varnell ED; Thompson HW 
Address 
LSU Eye Center, Louisiana State University Medical Center School of 
Medicine, New Orleans 70112-2234, USA. 
Source 
Arch Ophthalmol, 117(7):925-8 1999 Jul 
Abstract 
OBJECTIVE: To compare topical cidofovir with topical trifluridine for the 
prevention and treatment of herpes simplex type 1 stromal keratitis in 
rabbits. METHODS: The RE strain of herpes simplex virus 1 was injected into 
the central stroma of both eyes of New Zealand white rabbits. Two to 3 days 
after virus inoculation, the rabbits were randomized to treatment groups of 
10 each and treated with 1% trifluridine administered 5 or 7 times a day, 
1%, 0.5%, or 0.2% cidofovir administered twice a day, fluorometholone 
administered twice a day, or balanced salt solution (BSS) administered 
twice a day (control) until day 21 after injection. The treated corneas 
were examined 3 times a week and the severity of stromal keratitis was 
graded in a masked fashion. To evaluate the ability of cidofovir to treat 
established stromal disease, groups of 10 rabbits each were inoculated with 
herpes simplex virus and treated with 1% cidofovir twice a day, 1% 
trifluridine 5 times a day, fluorometholone twice a day, or BSS twice a day 
beginning on day 7 after virus inoculation through day 21. RESULTS: 
Treatment with 0.2% cidofovir twice a day was not effective in preventing 
the appearance of stromal disease (P = .89), whereas treatment with 0.5% 
(P<.001) or 1% (P<.001) cidofovir twice a day or 1% trifluridine 5 times a 
day (P<.001) or 7 times a day (P = .006) significantly reduced the 
appearance of stromal keratitis on the 8 evaluation days, compared with BSS 
treatment (F test analysis of variance). There was no difference between 
the eyes treated with 0.5% cidofovir twice a day and those treated with 1% 
trifluridine 5 times a day. Treatment with 1% cidofovir was not effective 
in treating established stromal disease. CONCLUSIONS: Cidofovir and 
trifluridine are highly effective in preventing the appearance of herpetic 
stromal disease. Cidofovir is as effective as, but no more effective than, 
trifluridine in this model. Neither cidofovir nor trifluridine benefits 
established stromal disease, however. CLINICAL RELEVANCE: Cidofovir is a 
new, potent antiviral that seems similar in efficacy to trifluridine and is 
effective in the prevention of the development of stromal herpes, but is 
not effective in the treatment of established stromal disease in which 
hypersensitivity predominates. 

==================================================================== 
24.) Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir 
and adefovir. 
==================================================================== 
Author 
Cundy KC 
Address 
Gilead Sciences Inc., Foster City, California, USA. [email protected] 
Source 
Clin Pharmacokinet, 36(2):127-43 1999 Feb 
Abstract 
Cidofovir and adefovir are members of a new class of antiviral compounds. 
They are acyclic phosphonate analogues of deoxynucleoside monophosphates. 
Both compounds undergo intracellular activation to form diphosphates that 
are potent inhibitors of viral DNA polymerases. Cidofovir has broad 
spectrum antiviral activity against herpesviruses, papillomaviruses and 
poxviruses, whereas adefovir has potent activity against retroviruses and 
certain DNA viruses, including herpesviruses and hepadnaviruses. 
Intravenous cidofovir is approved for treatment of cytomegalovirus 
retinitis in patients with AIDS. Cidofovir and adefovir are dianionic at 
physiological pH and have low oral bioavailability in animals and humans. 
After intravenous administration to HIV-infected patients, the 
pharmacokinetics of both drugs are independent of dose and are consistent 
with preclinical data. Systemic exposure is proportional to the intravenous 
dose and both drugs are cleared by the kidney and excreted extensively as 
unchanged drug in the urine. Intracellular activation of a small fraction 
(< 10%) of the dose by cellular kinases leads to prolonged antiviral 
effects that are not easily predicted from conventional pharmacokinetic 
studies. The observed rate of elimination of cidofovir and adefovir from 
serum may not reflect the true duration of action of these drugs, since the 
antiviral effect is dependent on concentrations of the active 
phosphorylated metabolites that are present within cells. For both drugs, > 
90% of an intravenous dose is recovered unchanged in the urine over 24 
hours. Metabolism does not contribute significantly to the total clearance 
of either drug. Concomitant oral probenecid decreases both the renal 
clearance of cidofovir and the incidence of nephrotoxicity, presumably by 
blocking its active tubular secretion. This is the basis of the clinical 
use of concomitant probenecid as a nephroprotectant during cidofovir 
therapy. Subcutaneous administration produces exposure equivalent to that 
following intravenous administration. Drug interaction studies with 
cidofovir are ongoing, but there is no evidence of an interaction between 
zidovudine and either cidofovir or adefovir. Clearance of cidofovir in 
patients with renal impairment showed a linear relationship to creatinine 
clearance. The low oral bioavailability of adefovir has led to the 
development of an oral prodrug, adefovir dipivoxil, currently in 
development for the treatment of HIV and hepatitis B infections. 

==================================================================== 
25.) Cidofovir in the treatment of cytomegaloviral disease. 
==================================================================== 
Author 
Kendle JB; Fan-Havard P 
Address 
Division of Pharmacy Practice and Administration, College of Pharmacy, Ohio 
State University, Columbus 43210, USA. 
Source 
Ann Pharmacother, 32(11):1181-92 1998 Nov 
Abstract 
OBJECTIVE: To review the clinical pharmacology and microbiology of 
cidofovir in the therapy of cytomegalovirus (CMV) disease. DATA SOURCES: 
Pertinent literature was identified via a MEDLINE search (October 
1986-February 1997), and data from abstracts presented at recent scientific 
meetings were also included; unpublished information was provided by the 
manufacturer. STUDY SELECTION: Antiviral activity data were included if 
widely accepted methodology was used. All clinical data currently available 
from human studies were also included. DATA SYNTHESIS: Cidofovir is similar 
to ganciclovir in mechanism of action; however, cidofovir does not require 
viral enzymes for activation. Although the half-life of cidofovir in plasma 
is only 2.6 hours, the intracellular half-life may be much longer, allowing 
efficacy with biweekly maintenance dosing. In vitro, cidofovir appears to 
be equally or more effective than the other agents currently available for 
the treatment of CMV. In vivo, cidofovir appears to be effective in 
delaying the progression of CMV retinitis, although no clinical trials to 
date have directly compared cidofovir with either ganciclovir or foscarnet. 
Current intravenous dose recommendations are 5 mg/kg once weekly for two 
doses (induction), and then 5 mg/kg once every other week (maintenance). 
Since cidofovir is cleared almost entirely by the kidneys, dosage 
adjustments must be made in patients with impaired renal function. 
Disadvantages of cidofovir primarily include its risks of adverse drug 
reactions, such as nephrotoxicity, which is likely to occur in up to 50% of 
patients if appropriate preventative measures are not taken. Neutropenia 
and constitutional reactions to probenecid are also commonly encountered 
during the course of cidofovir therapy. CONCLUSIONS: Cidofovir is the first 
acyclic phosphonate nucleoside antiviral agent to be approved for general 
use in the US. In addition to delaying the progression of CMV retinitis, 
cidofovir may provide some protective benefits to patients at risk for 
developing the disease and may be active against certain strains of virus 
resistant to other currently available therapies. Another advantage of 
cidofovir is its infrequent dosage schedule, which may prove beneficial in 
patients who are not compliant with daily intravenous dosing regimens. When 
determining the appropriate treatment for a patient with CMV retinitis, the 
benefits of using cidofovir must be weighed carefully against the risk of 
potentially serious adverse effects. 

==================================================================== 
26.) Antitumor potential of acyclic nucleoside phosphonates. 
==================================================================== 
Nucleosides Nucleotides 1999 Apr-May;18(4-5):759-71 

De Clercq E, Andrei G, Balzarini J, Hatse S, Liekens S, Naesens L, Neyts J, 
Snoeck R 
Rega Institute for Medical Research, K.U. Leuven, Belgium. 

Acyclic nucleoside phosphonates such as HPMPC (cidofovir) and PMEA 
(adefovir) have been identified as broad-spectrum antiviral agents that are 
effective against herpes-, retro- and hepadnavirus infections (PMEA) and 
herpes-, pox-, adeno-, polyoma-, and papillomavirus infections (HPMPC). 
Here we show that HPMPC and PMEA also offer great potential as antitumor 
agents, through the induction of tumor cell differentiation (PMEA), 
inhibition of angiogenesis (HPMPC) and induction of apoptosis (HPMPC). In 
vivo tumor regressions have been noted for choriocarcinoma (PMEA) in rats, 
hemangioma (HPMPC) in rats and papillomatous lesions (HPMPC) in humans. 
Acyclic nucleoside phosphonates can be considered as a new dimension to the 
discipline of chemotherapy. They have a unique mode of action that is 
targeted at (viral or tumoral) DNA synthesis. They exhibit a pronounced and 
prolonged anti-viral and/or tumoral activity that can persist for days or 
weeks after a single administration. Most importantly, they have a uniquely 
broad spectrum of indications for clinical use, encompassing both DNA- and 
retrovirus infections, as well as various forms of cancer of both viral and 
non-viral origin. 

==================================================================== 
27.) Clinical uses of cidofovir. 
==================================================================== 
Rev Med Virol 1997 Sep;7(3):145-156 

Safrin S, Cherrington J, Jaffe HS 
Gilead Sciences, Foster City, CA, USA. 

Cidofovir is a cytidine nucleotide analogue recently licensed as an 
intravenous treatment for CMV retinitis in AIDS patients. Three controlled 
clinical trials have demonstrated efficacy of cidofovir for this 
indication, and have generated data useful as a guideline to prevent 
potential toxicity. Although de novo emergence of resistance to cidofovir 
has not been observed clinically in patients receiving cidofovir, 
cross-resistance to cidofovir in ganciclovir-resistant clinical DNA 
polymerase mutants has been identified. Cross-resistance of cidofovir and 
foscarnet has not been identified to date. A broad spectrum agent with in 
vitro activity against human herpesviruses, adenovirus, HPV, polyomaviruses 
and human poxviruses, cidofovir is under clinical investigation for a 
variety of potential applications. Examples include intravenous 
administration of cidofovir for treatment of progressive multifocal 
leukoencephalopathy and Kaposi's sarcoma, intraocular injection for 
treatment of CMV retinitis, intralesional injection for treatment of 
respiratory papillomatosis, topical application for treatment of molluscum 
contagiosum, anogenital condyloma acuminata, and recurrent genital herpes, 
and ophthalmic instillation for treatment of viral keratoconjunctivitis. 

==================================================================== 
28.) Characterization of the DNA polymerase and thymidine kinase genesof 
herpes 
simplex virus isolates from AIDS patients in whom acyclovirand foscarnet 
therapy sequentially failed. 
==================================================================== 
J Infect Dis 1999 Aug;180(2):487-90 

Schmit I, Boivin G 
Infectious Disease Research Center, Centre Hospitalier de l'Universite 
Laval, Quebec, Canada, G1V 4G2. [email protected]. 

Herpes simplex virus (HSV) isolates were characterized from 8 AIDS patients 
in whom acyclovir and foscarnet therapy sequentially failed. The 6 
postacyclovir (prefoscarnet) HSV isolates were resistant to acyclovir and 
susceptible to foscarnet. Of the 9 postfoscarnet isolates, 8 were 
foscarnet-resistant and acyclovir-susceptible, 1 was resistant to both 
drugs. Acyclovir- or foscarnet-resistant isolates retained susceptibility 
to cidofovir. The acyclovir-resistant isolates contained single-base 
substitutions or frameshift mutations in G or C homopolymer nucleotide 
repeats of the thymidine kinase gene. In contrast, the foscarnet-resistant 
strains contained single-base substitutions in conserved (II, III, or VI) 
or, more rarely, nonconserved (between I and VII) regions of the DNA 
polymerase (pol) gene. The single isolate exhibiting resistance to 
acyclovir and foscarnet contained mutations in both genes. In this study of 
clinical HSV isolates, DNA pol mutations conferring foscarnet resistance 
were not associated with decreased acyclovir or cidofovir susceptibility. 

==================================================================== 
29.) A case study: the use of cidofovir for the management of progressive 
multifocal leukoencephalopathy. 
==================================================================== 
J Assoc Nurses AIDS Care 1999 Jul-Aug;10(4):70-4 

Dodge RT 
Max Robinson Center, Whitman-Walker Clinic, Inc. 

Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic 
infection of the brain in advanced stages of AIDS. PML is caused by the JC 
virus, which leads to a decline in mental acuity and motor functions over a 
period of weeks or months. Currently, there is no treatment or cure for 
PML. Cidofovir, an antiviral agent, at the standard dosages for the 
treatment of cytomegalovirus (CMV) was implemented in the treatment and 
management of a 35-year-old, newly diagnosed AIDS, White male with PML. The 
patient presented with impaired motor functions of the left upper and lower 
extremities, which resulted in hemiparalysis and hemiparesis. The use of 
cidofovir infusions at standard recommendations for treatment and 
management of CMV has resulted in improvement and some resolution of the 
patient's paralysis and paresthesia. The patient has remained on the 
cidofovir for more than a year, with no signs of advancement of his PML or 
AIDS. Further investigation and extensive clinical trials are needed in the 
treatment and management of PML with the use of cidofovir. 

==================================================================== 
30.) Antiinfectives update: focus on treatment and prevention of viral and 
associated infections. 
==================================================================== 
Ann Pharmacother 1999 May;33(5):607-14 

McNicholl IR, Palmer SM, Ziska DS, Cleary JD 
Division of Pharmacy Practice, St. Louis College of Pharmacy, MO, USA. 

OBJECTIVE: To review the clinically significant antiinfectives approved by 
the Food and Drug Administration (FDA) since 1996, with an emphasis on 
agents used for treatment, prevention, or suppression of infection in 
immunocompromised individuals. DATA SOURCES: A MEDLINE search covering 
November 1994 to March 1998 was conducted to identify all antiinfectives 
(new medications and old medications with new indications) and the 
pertinent literature for review. The search was updated in August 1998 and 
supplemented with an FDA listing of approved drugs to enhance completeness. 
STUDY SELECTION: Clinically relevant studies were selected to highlight 
specific points about each medication. Preclinical publications were used 
when sufficient information was not available from clinical trials and this 
information was needed for clinical practice. CONCLUSIONS: Several new and 
promising antiretroviral agents (stavudine, lamivudine, saquinavir soft-gel 
capsules, nelfinavir, efavirenz) have been approved, which may allow more 
options to control HIV viremia. New options for treatment, prevention, and 
suppression of infections in immunocompromised individuals include 
azithromycin, cidofovir, famciclovir, valacyclovir, and itraconazole 
suspension. Liposomal-based amphotericin products may be associated with 
less toxicity than conventional amphotericin B; however, superior efficacy 
has not been proven. 

==================================================================== 
31.) Identification and rapid quantification of early- and late-lytic human 
herpesvirus 8 infection in single cells by flow cytometric analysis: 
characterization of antiherpesvirus agents. 
==================================================================== 
J Virol 1999 Jul;73(7):5894-902 

Zoeteweij JP, Eyes ST, Orenstein JM, Kawamura T, Wu L, Chandran B, Forghani 
B, Blauvelt A 
Dermatology Branch, National Cancer Institute,National Institutes of 
Health, Bethesda, Maryland 20892, USA. 

Human herpesvirus 8 (HHV-8) infection is associated with Kaposi's sarcoma, 
primary effusion lymphoma (PEL), and multicentric Castleman's disease. In 
this study, we used monoclonal antibodies (MAbs) directed against HHV-8 
lytic cycle-associated proteins encoded by open reading frame (ORF) 59 
(nuclear PF-8 protein) and ORF K8.1 (viral envelope glycoprotein K8.1 
[gpK8.1]) to investigate HHV-8 lytic infection in single cells. Lytically 
infected cells were labeled with MAbs, stained with fluorescently 
conjugated secondary Abs, and analyzed by flow cytometry. A 3-day 
stimulation of HHV-8-positive PEL cell lines (BCBL-1 and BC-3) with 
12-O-tetradecanoylphorbol-13-acetate (30 nM) or n-butyric acid (0.3 mM) 
maximized the expression of lytic-phase viral proteins and minimized cell 
toxicity. The absolute number of expressing cells was inducer and cell line 
dependent. Expression of PF-8 occurred earlier and more frequently (in up 
to 20% of cells) than did expression of gpK8.1. A subset of PF-8 positive 
cells (25%) co-expressed gpK8.1, representing the majority of gpK8.1 
expressing cells. Acyclovir, foscarnet, cidofovir, and PMEA reduced the 
number of cells expressing gpK8.1, but not the number expressing the 
nonstructural early lytic gene product PF-8. By contrast, alpha interferon 
(IFN-alpha) and IFN-beta reduced expression of both PF-8 and gpK8.1, 
implying an overall inhibitory effect on viral gene transcription or 
translation. In summary, we have characterized and quantified HHV-8 lytic 
infection in single cells by dual measurement of early- and 
late-lytic-cycle HHV-8 protein expression. This technique should prove 
useful for screening of possible antiherpesvirus agents and for detailed 
phenotypic characterization of HHV-8-infected cells in vitro and in 
patients with HHV-8-associated diseases. 

==================================================================== 
32.)Inhibiting effects of cidofovir (HPMPC) on the growth of the human 
cervical 
carcinoma (SiHa) xenografts in athymic nude mice. 
==================================================================== 
Oncol Res 1998;10(10):533-9 

Andrei G, Snoeck R, Piette J, Delvenne P, De Clercq E 
Rega Institute for Medical Research, Katholieke Universiteit, Leuven, 
Belgium. [email protected] 

At present more than 70 human papillomaviruses (HPV) genotypes have been 
described and each shows a predilection for a cutaneous or mucosal surface. 
There is a strong association between infection with specific genital 
viruses (i.e., types 16 and 18) and the development of cervical cancer. 
Thus, intervention with the natural history of HPV infection in the genital 
tract may form the basis for an effective anticancer strategy. We have 
shown that treatment of cell lines derived from human cervical carcinomas 
[i.e., SiHa and CaSki (HPV-16-positive)] and HeLa (HPV-18-positive)] with 
HPMPC (cidofovir) results in a concentration- and time-dependent inhibition 
of cell proliferation. We report here the effects of HPMPC on the growth of 
cervical carcinoma (SiHa) xenografts in athymic nude mice. Athymic mice 
between the age of 6 and 8 weeks were injected SC with 5 to 10x10(6) cells. 
Once tumors were established, the mice were injected with PBS (placebo), 
HPMPC, or cytarabine (AraC) at the tumor site. Animals that were injected 
intratumorally with HPMPC at a dose of 5 mg/ml (0.25 mg/injection) or 10 
mg/ml (0.5 mg/injection) three or five times per week, once daily, during 4 
weeks showed a statistically significant reduction in tumor size compared 
to the placebo group or AraC group. However, when HMPC was administered 
topically (as a cream) or systemically (intraperitoneally), no reduction of 
tumor growth was observed at nontoxic concentrations, suggesting that a 
high local concentration of HPMPC is required to achieve a significant 
decrease of tumor growth. 

==================================================================== 
33.) Antiproliferative effects of acyclic nucleoside phosphonates on human 
papillomavirus (HPV)-harboring cell lines compared with HPV-negative cell 
lines. 
==================================================================== 
Oncol Res 1998;10(10):523-31 

Andrei G, Snoeck R, Piette J, Delvenne P, De Clercq E 
Rega Institute for Medical Research, Katholieke Universiteit, Leuven, 
Belgium. [email protected] 

Acyclic nucleoside phosphonates (ANPs) possess a broad-spectrum activity 
against DNA viruses and retroviruses. HPMPC (cidofovir) has proved to be 
effective in the treatment of HPV-associated diseases. We have evaluated 
the effects of various ANPs [i.e., 3-hydroxy-2-phosphonylmethoxypropyl 
derivatives of adenine (HPMPA) and cytosine (HPMPC, cidofovir)]; cyclic 
HPMPC (cHPMPC); 9-(2-phosphonylmethoxyethyl) derivatives of adenine (PMEA, 
adefovir), guanine (PMEG), and 2,6-diaminopurine (PMEDAP); and cyclo-propyl 
PMEDAP (cPr-PMEDAP), several other antiviral drugs [i.e., acyclovir (ACV), 
ganciclovir (GCV), foscarnet (PFA), and ribavirin]; the antitumor agents 
cytarabine (AraC) and 5-fluorouracil (5-FU); and the immunosuppressant 
mycophenolic acid (MPA) on the proliferation of human cervical 
keratinocytes immortalized by HPV-33 (CK-1 cells) and the cervical 
carcinoma cell lines containing HPV-16 (CaSki and SiHa) or HPV-18 (HeLa). 
In vitro incubation of these cell lines with ANPs resulted in a 
concentration- and time-dependent inhibition of cell proliferation. This 
inhibitory effect was most striking for HPMPC. The 50% inhibitory 
concentration (IC50) of HPMPC decreased from 20-50 microg/ml at day 3 to 
0.6-2 microg/ml at day 7. When the IC50 values of the ANPs for the various 
HPV-harboring cells were compared with those for primary human 
keratinocytes isolated from normal cervix, HPMPC emerged as the most 
selective ANP, with a selectivity index (SI) in the range of 15-42. When 
IC50 values as a function of time were determined for several tumor cell 
lines (i.e., human melanomas, lung, colon, and breast carcinomas), ANPs 
again showed an antiproliferative effect as a function of time, although of 
a lower extent (5- to 25-fold decrease in the IC50 values between days 3 
and 7) than for the HPV-positive cells. Treatment of SV40- and 
adenovirus-transformed cells with ANPs resulted in the inhibition of cell 
proliferation as a function of time, similar to that observed with 
HPV-positive cells, HPMPC and cHPMPC being the most potent 
antiproliferative agents. These results suggest that the antiproliferative 
activity of ANPs, in particular HPMPC, against HPV-bearing tumor cells may 
be explained, at least in part, by a specific inhibitory effect on rapidly 
proliferating cells, and the presence of the HPV genome might enhance the 
sensitivity of cells to HPMPC due to interactions of the viral-transforming 
proteins with products of the tumor suppressor genes. 

==================================================================== 
34.) Resolution of recalcitrant molluscum contagiosum virus lesions in human 
immunodeficiency virus-infected patients treated with cidofovir. 
==================================================================== 
Arch Dermatol 1997 Aug;133(8):987-90 

Meadows KP, Tyring SK, Pavia AT, Rallis TM 
Department of Dermatology, University of Utah Health Sciences Center, Salt 
Lake City, USA. 

BACKGROUND: Molluscum contagiosum virus (MCV) causes cutaneous skin growths 
that mainly affect children, sexually active adults, and immunocompromised 
individuals. Lesions of MCV in patients infected with human 
immunodeficiency virus can be large and numerous, and response to available 
treatments is often unsatisfactory. OBSERVATIONS: We describe 3 men 
infected with human immunodeficiency virus who presented with extensive MCV 
lesions that were not responsive to various treatments. Patient 1 
demonstrated dramatic clearing of his MCV lesions when intravenous 
cidofovir therapy was started for his treatment-resistant bilateral CMV 
retinitis and because of cidofovir's possible activity against MCV. In case 
2, cidofovir was compounded as a 3% cream in a combination vehicle 
(Dermovan) for extensive facial involvement, and complete resolution of MCV 
was seen after 1 month of therapy. In case 3, intravenous cidofovir therapy 
was started both for CMV retinitis and in an attempt to clear 90% facial 
MCV involvement; after 1 month of treatment, all clinical evidence of MCV 
had resolved. All 3 patients remain clear of recurrence. CONCLUSIONS: 
Cidofovir, a nucleotide analog of deoxycytidine monophosphate, appears to 
have contributed to clearing of advanced MCV lesions in these 3 patients, 
thus providing suggestive evidence of clinical activity against MCV. 
Controlled trials of cidofovir therapy for MCV in persons infected with 
human immunodeficiency virus are warranted. 

==================================================================== 
35.) Therapeutic potential of Cidofovir (HPMPC, Vistide) for the treatment of 
DNA virus (i.e. herpes-, papova-, pox- and adenovirus) infections. 
==================================================================== 
Verh K Acad Geneeskd Belg 1996;58(1):19-47; discussion 47-9 

De Clercq E 
Rega Institute for Medical Research, Katholieke Universiteit, Leuven. 

(S)-1-(3-Hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC, Cidofovir, 
Vistide) is an acyclic nucleoside phosphonate with broad-spectrum activity 
against a wide variety of DNA viruses including herpesviruses [Herpes 
simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus 
(VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 
type 6 (HHV-6) and equine and bovine herpesviruses], papovaviruses [human 
polyoma virus and human papilloma virus (HPV)], adeno-, irido-, hepadna-, 
and poxviruses. HPMPC has proved effective against these viruses in 
different cell culture systems and/or animal models. The mechanism of 
action of HPMPC is based upon the interaction of its active intracellular 
metabolite, the diphosphorylated HPMPC derivative HPMPCpp, with the viral 
DNA polymerase. HPMPCpp has been shown to block CMV DNA synthesis by DNA 
chain termination following incorporation of two consecutive HPMPC 
molecules at the 3'-end of the DNA chain. HPMPC confers a prolonged 
antiviral action, which lasts for several days or weeks, thus allowing 
infrequent dosing (i.e. every week or every two weeks). This prolonged 
antiviral action is probably due to the very long intracellular half-life 
of the HPMPC metabolites, particularly the HPMPCp-choline adduct. In 
clinical studies, HPMPC has proved efficacious in the treatment of CMV 
retinitis, following both intravenous injection (3 or 5 mg/kg, every other 
week) and intravitreal injection (single dose of 20 micrograms per eye). 
Initial clinical trials also point to the efficacy of both systemic 
(intravenous) and topical HPMPC (1% ointment) in the treatment of 
acyclovir-resistant HSV infections, and of topical HPMPC (ointment or 
injection) in the treatment of pharyngeal, laryngeal and anogenital HPV 
infections. HPMPC is now being pursued in the topical and/or systemic 
(intravenous) treatment of various infections due to CMV, HSV, VZV, EBV, 
HPV, polyoma-, adeno- and poxviruses. 

==================================================================== 
36.) Topical and intralesional cidofovir: a review of pharmacology and 
therapeutic effects. 
==================================================================== 
J Am Acad Dermatol 1998 Nov;39(5 Pt 1):741-5 

Zabawski EJ Jr, Cockerell CJ 
University of Texas Southwestern Medical Center, Dallas, USA. 

BACKGROUND: Cidofovir is a potent nucleoside analog antiviral drug approved 
for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. 
It is currently available only for intravenous infusion. Several small 
studies and case reports describe the successful use of cidofovir applied 
either topically or intralesionally in several virally induced cutaneous 
diseases. OBJECTIVE: Our purpose was to review the usefulness of topical 
and intralesional cidofovir for the treatment of viral infections caused by 
human papillomavirus, herpesviruses (including acyclovir-resistant 
strains), Kaposi's sarcoma-associated herpesvirus, and molluscum 
contagiosum. METHODS: We performed a review of recent literature. RESULTS: 
Cidofovir is a potent topical intralesional antiviral agent with activity 
against several DNA viruses that cause cutaneous disease. No significant 
systemic side effects have been noted, although application site reactions 
are common and can occasionally be severe. CONCLUSION: The effective use of 
topical and intralesional cidofovir for the treatment of diseases of the 
skin caused by DNA viruses has been demonstrated in a limited number of 
patients including those infected with HIV. Although larger studies will be 
necessary to determine the specific function that topical cidofovir will 
have in the treatment of cutaneous diseases caused by DNA viruses, the drug 
offers significant promise. 

==================================================================== 
37.) Treatment of classical Kaposi's sarcoma with intralesional injections of 
cidofovir: report of a case. 
==================================================================== 
J Med Virol 1998 Jul;55(3):215-8 

Simonart T, Noel JC, De Dobbeleer G, Parent D, Van Vooren JP, De Clercq E, 
Snoeck R 
Department of Dermatology, Erasme University Hospital, Brussels, Belgium. 

The effect of intralesional injections of cidofovir, a nucleotide analog 
with potent in vitro activity against human herpesvirus 8 (HHV-8), was 
studied in vivo in an HIV-negative patient with classical Kaposi's sarcoma 
(KS). After five weekly injections of the drug, no clinical, histological, 
immunohistological, or virological changes could be detected in comparison 
with saline-injected lesions. These findings suggest that, once the KS 
tumor has developed, active viral replication is no longer involved in the 
pathogenesis of the disease. Alternative hypotheses are that HHV-8 
replication in blood-borne cells may foster growth of spindle cells in the 
skin, or that blocking HHV-8 may not affect existing lesions but may 
prevent new lesions from developing. 

==================================================================== 
38.) Selective inhibition of human papillomavirus-induced cell 
proliferation by 
(S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. 
==================================================================== 
Antimicrob Agents Chemother 1999 May;43(5):1198-205 

Johnson JA, Gangemi JD 
Department of Microbiology and Molecular Medicine and the Greenville 
Hospital System Biomedical Cooperative, Clemson University, Clemson, South 
Carolina 29634, USA. 

(S)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) is a 
nucleoside phosphonate analog which in its active diphosphorylated form is 
known to inhibit herpesvirus DNA polymerase. In this study, we have 
demonstrated that, in a dose-dependent manner, this compound irreversibly 
suppressed proliferation of cells infected with human papillomavirus (HPV), 
which does not possess a viral DNA polymerase. To elucidate the mechanism 
of cell growth inhibition, cell cycle indicator-regulator expression, 
thymidine incorporation, transcript levels of apoptosis factors, and 
anabolic products of HPMPC following drug treatment were evaluated. HPMPC 
treatment reduced WAF1 (p21) levels independent of those of p53, while 
proliferating cell nuclear antigen increased. However, in comparison to 
controls, HPMPC-treated cells displayed a decrease in thymidine 
incorporation, indicating an inhibition of host DNA polymerase activity. In 
normal primary keratinocytes, HPMPC predominantly accumulated in the form 
of the choline adduct HPMPCp-choline. However, in HPV type 16-transformed 
keratinocytes, HPMPCpp was the most abundant anabolic product, with little 
HPMPCp-choline having formed. The data imply that an unrecognized viral 
factor is modulating the conversion of nucleotides, including HPMPC, to the 
triphosphorylated form. 

==================================================================== 
39.) Resistance of human cytomegalovirus to antiviral drugs. 
==================================================================== 
Clin Microbiol Rev 1999 Apr;12(2):286-97 

Erice A 
Department of Laboratory Medicine & Pathology and Department of Medicine, 
University of Minnesota Medical School, Minneapolis, Minnesota 55455, 
[email protected] 

Resistance of cytomegalovirus (CMV) to antiviral agents is a 
well-recognized phenomenon that has been observed in the laboratory and in 
the clinical setting. Infections caused by antiviral-resistant CMV have 
been found exclusively among immunocompromised individuals, including 
patients with AIDS, bone marrow and solid-organ transplant recipients, and 
patients with hematologic malignancies, and in individuals with primary 
immunodeficiencies. The majority of these infections have been described to 
occur in patients with AIDS receiving prolonged antiviral therapy for CMV 
end-organ disease. Antiviral agents currently licensed for the treatment of 
CMV infections include ganciclovir, foscarnet, and cidofovir. Resistance of 
CMV to ganciclovir is related to mutations in the UL97 region of the viral 
genome and/or mutations in the viral DNA polymerase. Resistance to 
foscarnet and cidofovir is associated with mutations in the viral DNA 
polymerase. Antiviral susceptibility of CMV strains containing DNA 
polymerase mutations is dependent on the region of the DNA polymerase where 
the mutations are located. Some DNA polymerase mutant viruses are 
cross-resistant to ganciclovir, foscarnet, and cidofovir. The recognition 
that specific UL97 and UL54 mutations are associated with resistance to 
antiviral agents has led to the development of molecular methods for 
detection of mutant viruses. This article reviews the mechanisms of 
resistance of CMV to antiviral agents, the laboratory methods for detection 
of resistant CMV, and the clinical aspects of infections caused by 
antiviral-resistant CMV. 

==================================================================== 
40.) Comparative antiviral efficacies of cidofovir, trifluridine, and 
acyclovir 
in the HSV-1 rabbit keratitis model. 
==================================================================== 
Invest Ophthalmol Vis Sci 1999 Feb;40(2):378-84 

Romanowski EG, Bartels SP, Gordon YJ 
Department of Ophthalmology, University of Pittsburgh School of Medicine, 
Pennsylvania, USA. 

PURPOSE: To determine the relative antiviral inhibitory activity of topical 
1% and 0.5% cidofovir, topical trifluridine (Viroptic; Burroughs-Wellcome, 
Research Triangle Park, NC), and topical acyclovir (Zovirax; The Wellcome 
Foundation, London, UK) during a 7-day period for the treatment of herpes 
simplex virus type 1 (HSV-1) keratitis and HSV-1 replication in the New 
Zealand rabbit ocular model. METHODS: In a series of four experiments using 
a two-eye design, a total of 80 New Zealand rabbits were inoculated in both 
eyes with HSV-1 McKrae after epithelial scarification. Forty-eight hours 
after inoculation, the rabbits were randomly assigned to a treatment group. 
Five treatment groups (16 rabbits/group) were evaluated: I, 1% cidofovir, 
twice daily for 7 days; II, 0.5% cidofovir, twice daily for 7 days; III, 3% 
acyclovir ointment, five times daily for 7 days; IV, 1% trifluridine, nine 
times daily for 3 days, then 4 times daily for 4 days; and V, control 
vehicle twice daily for 7 days. HSV-1 dendritic keratitis was graded in a 
masked fashion by slit-lamp examination on days 2, 3, 5, 7, 9, 11, and 14. 
Ocular viral cultures were obtained after slit-lamp examination on days 1, 
3, 5, 7, 9, 11, and 14. RESULTS: Compared with the control group, all four 
treatment groups demonstrated significantly lower viral titers, fewer 
HSV-1-positive eyes/total during the treatment period, lower keratitis 
scores, fewer eyes with keratitis/total, and a shorter time to resolution 
of keratitis. Within the treatment groups, the 1% and 0.5% cidofovir 
treatments were significantly more effective than acyclovir and 
trifluridine as measured by the previous viral and keratitis parameters. 
CONCLUSIONS: Topical 1% and 0.5% cidofovir both appeared to be 
significantly more efficacious than topical trifluridine and acyclovir, 
during a 7-day course, in the treatment of experimental HSV-1 ocular 
disease in the New Zealand rabbit keratitis model. 

==================================================================== 
41.) [Human herpesvirus 8 (HHV8). II. Pathogenic role and sensitivity to 
antiviral drugs]. 
==================================================================== 
Ann Biol Clin (Paris) 1999 Jan-Feb;57(1):19-28 

Boulanger E 
Service d'hematologie clinique, hopital Saint-Louis, Paris. 

Human herpesvirus 8 (HHV8) has been found to be associated with three 
different diseases observed in Aids patients: Kaposi's sarcoma, primary 
effusion lymphoma, which is a rare type of non-Hodgkin lymphomas affecting 
the body cavities, and multicentric Castleman's disease. The role of this 
new herpesvirus and other lymphoid proliferations, like angioimmunoblastic 
lymphadenopathy or multiple myeloma, is much debatable. To date, there are 
several evidences for a direct role of this virus in the occurrence of the 
Kaposi's sarcoma, although the hypothesis of a passenger virus hypothesis 
cannot be totally excluded. In vitro, HHV8 is sensitive to some 
anti-herpesvirus drugs like foscarnet, cidofovir and adefovir, but the 
indications of these therapies in the prevention or the treatment of the 
Kaposi's sarcoma have not been documented so far. 

==================================================================== 
42.) Inhibitory effects of novel nucleoside and nucleotide analogues on 
Epstein-Barr virus replication. 
==================================================================== 
Antivir Chem Chemother 1998 May;9(3):275-82 

Meerbach A, Holy A, Wutzler P, De Clercq E, Neyts J 
Institute for Antiviral Chemotherapy, Friedrich-Schiller-University Jena, 
Erfurt, Germany. 

The anti-Epstein-Barr virus (EBV) activity of different classes of 
compounds was assessed by means of an EBV DNA hybridization assay using a 
digoxigenin-labelled probe specific for the BamHI W fragment of the EBV 
genome, as well as by measuring viral capsid antigen (VCA) expression after 
a 7 day incubation period of P3HR-1 producer cells with the test 
substances. Acyclovir, ganciclovir, cidofovir and zidovudine were included 
as reference compounds. Several compounds proved to be potent and selective 
inhibitors of EBV DNA synthesis and VCA expression. Of the new compounds 
that were evaluated for their anti-EBV activity, the highest efficacy 
(lowest EC50) and highest selectivity index (SI) were shown by the purine 
nucleoside analogue 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine 
(S2242) (EC50 0.6 ng/ml; SI 600), the acyclic nucleoside phosphonate 
analogues 9-(2-phosphono -methoxyethyl)-6-dimethylaminopurine (EC50 1.1 
micrograms/ml; SI 91), 9-(2-phosphonomethoxyethyl)-2- 
amino-6-benzhydrylaminopurine (EC50 1.3 micrograms/ml; SI 29), 
7-(2-phosphonomethoxyethyl)-6-dimethyl-aminopurine (EC50 0.8 microgram/ml; 
SI 56), 9-(R)-(2-phosphonomethoxypropyl)-6-(2-dimethylaminoethyl)-aminopur 
ine (EC50 0.5 microgram/ml; SI 42), the 2',3'-dideoxythymidine derivative 
3'-oximino-2',3'-dideoxythymidine (EC50 1.5 micrograms/ml; SI 65), and 
1-(2,3- dideoxy-3-N-hydroxyamino-beta-D-threo-pentafuranyl)pentafuranos 
yl)thymine (EC50 4.1 micrograms/ml; SI > 24). 

==================================================================== 
43.) Comparison of antiviral compounds against human herpesvirus 6 and 7. 
==================================================================== 
Antiviral Res 1998 Dec;40(1-2):73-84 

Yoshida M, Yamada M, Tsukazaki T, Chatterjee S, Lakeman FD, Nii S, Whitley RJ 
Department of Virology, Okayama University Medical School, Japan. 
[email protected] 

Four classes of antiviral compounds were evaluated for inhibitory activity 
against two variants of human herpesvirus 6 (HHV-6A and -6B) and human 
herpesvirus 7 (HHV-7). These included: (1) a pyrophosphate analog, 
phosphonoformic acid (PFA); (2) beta-guanine analogs, 
9-(2-hydroxyethoxymethyl)guanine (acyclovir or ACV), 
9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (ganciclovir or GCV) and 
9-(4-hydroxy-3-hydroxy-3-hydroxymethylbutylyl)guanine (penciclovir or PCV); 
(3) acyclic nucleoside phosphonates, 
(S)-1-[(3-hydroxy-2-phosphonylmethoxy)propyl]cytosine [cidofovir or 
(S)-HPMPC] and its cyclic derivative (S)-cyclic-HPMPC (cHPMPC), 
9-[[2-hydroxy-1-phosphonomethoxy)ethoxy]methyl]guanine (HPMEMG) and 
9-[(2-phosphonylmethoxy)ethyl]-2,6-diaminopurine (PMEDAP), and the seven 
other related compounds; and (4) a series of benzimidazole ribonucleosides, 
including 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole 
(BDCRB). End-point inhibitory concentration (EPC) and 50% effective 
inhibitory concentration (EC50) values were determined by a dot-blot 
antigen detection method in cord blood mononuclear cells infected with 
HHV-6A, HHV-6B or HHV-7 at a multiplicity of infection of 0.004 
CCID50/cell. (S)-HPMPC and cHPMPC had an EC50 value of approximately 0.3 
microg/ml for HHV-6A, 1.2 microg/ml for HHV-6B and 3.0 microg/ml for HHV-7. 
These compounds were the most active of those tested against each virus. 
The EC50 value of GCV for HHV-6A was 0.65 microg/ml, 1.33 microg/ml for 
HHV-6B, and >7 microg/ml for HHV-7. The EC50 values of ACV and PCV were 
approximately 6-8 microg/ml for HHV-6A, 16-24 microg/ml for HHV-6B and 
121-128 microg/ml for HHV-7. These drugs were the least active. The 
sensitivity of HHV-7 to the guanine analogs was different from HHV-6, 
suggesting a difference in selectivity of specific viral enzymes. 

==================================================================== 
44.) [Advances in the diagnosis and treatment of infections caused by 
herpesvirus and JC virus]. 
==================================================================== 
Enferm Infecc Microbiol Clin 1998;16 Suppl 1:11-9 

Arribas JR, Arrizabalaga J, Mallolas J, Lopez-Cortes LF 
Hospital La Paz, Madrid. [email protected] 

During the last two years important advances in the diagnosis and treatment 
of cytomegalovirus (CMV) disease have occurred. Several studies have 
suggested that biologic markers of CMV viremia (PCR, branched DNA and pp65 
antigenemia) might be useful both to stratify the risk of developing CMV 
disease and to follow the response of CMV retinitis to therapy. It has been 
shown that patients who are plasma CMV PCR positive have a risk of 
developing CMV disease three times higher than patients who are plasma CMV 
PCR negative. In addition, for each log10 increase of the CMV viral load 
there is a 3-fold higher risk of developing CMV disease. Currently, 
therapeutic options for induction treatment of CMV retinitis (CMVR) are: 
i.v. ganciclovir (GCV), i.v. foscarnet, i.v. cidofovir or GCV intraocular 
implant combined with oral GCV. For maintenance therapy options are: i.v. 
GCV (3, 5 or 7 days per week), oral GCV (only for peripheral retinitis), 
i.v. foscarnet (daily), i.v. cidofovir (biweekly) and GCV intraocular 
implant (replaced every 6-8 months) combined with oral GCV. There is 
currently enough evidence to allow the diagnosis of progressive multifocal 
leukoencephalopathy (PML) based on the finding of JC virus DNA in CSF by 
PCR. There are still no drugs with proven clinical efficacy against JC 
virus but the possibility that HAART treatments might improve the control 
of this disease appear promising. 

==================================================================== 
45.) A multicenter phase I/II dose escalation study of single-dose 
cidofovir gel 
for treatment of recurrent genital herpes. 
==================================================================== 
Antimicrob Agents Chemother 1998 Nov;42(11):2996-9 

Sacks SL, Shafran SD, Diaz-Mitoma F, Trottier S, Sibbald RG, Hughes A, 
Safrin S, Rudy J, McGuire B, Jaffe HS 
Viridae Clinical Sciences, Inc., and Department of Pharmacology and 
Therapeutics, Faculty of Medicine, The University of British Columbia, 
Vancouver, British Columbia, Canada. [email protected] 

A randomized, double-blind, clinic-initiated, sequential dose-escalation 
pilot study was performed to compare the safety and efficacy of single 
applications of 1, 3, and 5% cidofovir gel with placebo in the treatment of 
early, lesional, recurrent genital herpes at five Canadian outpatient 
sites. Ninety-six patients began treatment within 12 h of lesion appearance 
and were evaluated twice daily until healing of the lesion occurred. 
Cidofovir gel at all strengths significantly decreased the median time to 
negative virus culture in a dose-dependent fashion (3.0 days in the placebo 
group versus 2.2, 1.3, and 1.1 days in the 1, 3, and 5% cidofovir gel 
treatment groups, respectively; P = 0.02, 0.0001, and 0.0003, 
respectively). A trend toward a reduction in the median time to complete 
healing in association with treatment was present, but the differences were 
not statistically significant (5.0 days in the placebo group versus 4.3, 
4.1, and 4.6 days in the 1, 3, and 5% cidofovir gel treatment groups, 
respectively). Application site reactions occurred in 3, 5, 19, and 22% of 
the patients in these four groups, respectively. Treatment-associated 
lesion recrudescence with delayed healing, which is suggestive of local 
toxicity, was observed in three patients treated with 5% cidofovir gel and 
one patient treated with 3% cidofovir gel. In summary, single-dose 
application of cidofovir gel confers a significant antiviral effect on 
lesions of recurrent genital herpes. Additional studies are warranted to 
further identify the optimal efficacious dose of cidofovir in association 
with the maximum gel strength that can be tolerated. 

==================================================================== 
46.) Cidofovir use in acyclovir-resistant herpes infection. 
==================================================================== 
Ann Pharmacother 1997 Dec;31(12):1519-21 

Martinez CM, Luks-Golger DB 
Montefiore Medical Center, Bronx, NY, USA. 

Herpes infections continue to be prevalent, especially in immunocompromised 
patients. Some of these patients will develop resistant HSV infections. 
Therefore, it is important to explore new treatment options. Animal studies 
have shown cidofovir to be effective in the treatment and prevention of HSV 
infections. Human data are limited, with only one randomized, double-blind, 
placebo-controlled trial performed to date. The results from this study 
look promising; however, due to the small sample size, a larger clinical 
trial is warranted. The human data available as case reports are suboptimal 
in the quality of reporting time frames for resolution of lesions/symptoms 
and outcomes of therapy. Another problem with the case report data is that 
the TK status of the herpes simplex isolates was not reported. This would 
have helped substantiate the acyclovir resistance seen in these patients. 
It was evident in these case reports that acyclovir resistance can be 
overcome, as acyclovir-resistant strains became sensitive following 
cidofovir therapy. This may be because TK(+) viruses have been shown to 
establish latency more readily than do TK(-) viruses. This pattern suggests 
that alternating between acyclovir and cidofovir therapies may provide a 
strategy to manage the emergence of alternatively acyclovir-sensitive and 
-resistant infections. At present, only the intravenous formulation of 
cidofovir is commercially available. Advantages of the intravenous 
formulation include weekly dosing and efficacy. Disadvantages are the 
complexity of administration and the adverse effect profile. The most 
common adverse effects with this formulation include nephrotoxicity 
manifested as proteinuria (12%), and increased creatinine (5%) and 
neutropenia (15%). Administration of probenecid and NaCl 0.9% hydration are 
used to reduce the incidence and severity of nephrotoxicity in patients who 
are receiving cidofovir. Probenecid also has toxicities, including nausea, 
vomiting, headache, fever, and flushing. The topical formulation of 
cidofovir looks promising for mucocutaneous HSV infection because it is 
usually undetectable in the blood following topical administration. 
Therefore, systemic adverse effects should be minimized. A cidofovir gel 
product (Forvade, Gilead Sciences) is currently being reviewed by the Food 
and Drug Administration for the treatment of refractory HSV. Ultimately, 
more controlled clinical studies are necessary to determine whether routine 
cidofovir use can be justified in patients with acyclovir-resistant HSV 
infection. 

==================================================================== 
47.) A randomized, double-blind, placebo-controlled trial of cidofovir gel for 
the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus 
infection in patients with AIDS. 
==================================================================== 
J Infect Dis 1997 Oct;176(4):892-8 

Lalezari J, Schacker T, Feinberg J, Gathe J, Lee S, Cheung T, Kramer F, 
Kessler H, Corey L, Drew WL, Boggs J, McGuire B, Jaffe HS, Safrin S 
Mt. Zion Medical Center and San Francisco General Hospital, University of 
California, USA. 

The safety and efficacy of cidofovir gel for treatment of 
acyclovir-unresponsive herpes simplex virus infections in AIDS patients was 
evaluated in a randomized, double-blind, multicenter trial. Cidofovir (0.3% 
or 1%) or placebo gel was applied once daily for 5 days. Ten of 20 
cidofovir-treated and none of 10 placebo-treated patients had complete 
healing or >50% decreased area (P = .008); 30% of cidofovir-treated 
patients versus 0 placebo recipients had complete healing (P = .031). Viral 
shedding ceased in 13 (87%) of 15 cidofovir-treated and 0 of 9 
placebo-treated patients (P = .00004). For cidofovir-treated patients, 
median time to complete or good response was 21 days, and median time to 
negative viral culture was 2 days (P = .025, P = .0001, respectively). 
Median lesion area decreases were 58% for cidofovir-treated versus 0 for 
placebo-treated patients (P = .005), and mean pain score changes were -1.84 
versus -0.34 (P = .042). Application site reactions occurred in 25% of 
cidofovir-treated and 20% of placebo-treated patients; none was 
dose-limiting. Cidofovir therapy provided significant benefits in lesion 
healing, virologic effect, and pain reduction. 

==================================================================== 
48.) Isolation of human adenovirus type 5 variants resistant to the antiviral 
cidofovir. 
==================================================================== 
Invest Ophthalmol Vis Sci 1996 Dec;37(13):2774-8 

Gordon YJ, Araullo-Cruz TP, Johnson YF, Romanowski EG, Kinchington PR 
Department of Ophthalmology, Eye and Ear Institute, University of 
Pittsburgh Medical Center, Pennsylvania 15213, USA. 

PURPOSE: Cidofovir (S-HPMPC) is a potent broad-spectrum antiviral drug with 
potential clinical application against infections caused by human 
cytomegalovirus, herpes simplex virus, and adenovirus (AD). This study 
sought to determine whether variants of AD5 could be isolated in vitro that 
demonstrated increased resistance to this new antiviral drug. METHODS: 
Homogenous stocks of wild-type AD5 (ATCC strain VR-5) were generated from 
isolated plaques grown in A549 cells. The stocks subsequently were serially 
passaged in cells containing increasing levels (from 5 to 75 micrograms/ml) 
of cidofovir. The recovered virus either was passaged, titrated, or assayed 
for 50% inhibitory concentration (IC50) of cidofovir. RESULTS: Three 
independently isolated variants were obtained that demonstrated increased 
resistance to cidofovir. Viral resistance to the drug increased on stepwise 
passage in higher concentrations. Compared to the ATCC AD5 reference (IC50 
= 6.2 micrograms/ml), stable cidofovir-resistant variants showed fivefold 
to eightfold resistance (AD5 RI IC50 = 36.5 micrograms/ml; AD5 R2 IC50 = 
36.7 micrograms/ml; and AD5 R3 IC50 = 32.6 micrograms/ml; analysis of 
variance, P = 0.000001). However, a variable number of passages (1 to 13) 
at each concentration of cidofovir was performed to obtain robust 
infectious virus suitable for testing at the next higher concentration. All 
resistant virus isolates grew to levels of virus titer comparable to the 
parental virus and showed no apparent phenotypic changes in growth rates, 
plaque size, or efficiency of plaque formation. CONCLUSIONS: The successful 
isolation of AD5 variants in tissue culture resistant to cidofovir has 
important clinical implications with respect to the anticipated use of this 
antiviral drug in treating adenoviral ocular infections. 

==================================================================== 
49.) Herpesvirus resistance to antiviral drugs: a review of the mechanisms, 
clinical importance and therapeutic options. 
==================================================================== 
J Hosp Infect 1996 Aug;33(4):235-48 

Reusser P 
Department of Medicine, University Hospital, Basel, Switzerland. 

During the past decade, potent agents against herpes simplex virus (HSV) 
types 1 and 2, varicella zoster virus (VZV), and cytomegalovirus (CMV) have 
become available. The increasing clinical use of acyclovir, ganciclovir, 
and foscarnet has been associated with the emergence of drug-resistant 
herpesvirus strains. Resistance to acyclovir or ganciclovir most frequently 
results from deficient intracellular phosphorylation of these agents which 
is required for drug activation. Resistance to foscarnet is due to viral 
DNA polymerase mutants that permit viral replication despite the presence 
of the drug. In immunocompetent patients, herpesvirus resistance is rare 
and generally does not correlate with clinical outcome. In contrast, in 
immunocompromised hosts, resistance of HSV, VZV, and CMV is increasingly 
detected, and may be associated with disease refractory to antiviral 
therapy. Foscarnet treatment has been used with some clinical benefit in 
patients with acyclovir-resistant HSV or VZV, or ganciclovir-resistant CMV. 
For therapy of resistant mucocutaneous HSV disease, topical 
trifluorothymidine, and topical or intravenous cidofovir (HPMPC) have 
yielded encouraging results that warrant further investigation. Improved 
methods for detection of herpesvirus resistance, and validation of 
alternative therapy for patients with documented resistance are required to 
reduce the clinical impact of drug-resistant herpesviruses. 

==================================================================== 
50.) Topical cidofovir for severe molluscum contagiosum. 
Lancet 1999 Jun 12;353(9169):2042 

Davies EG, Thrasher A, Lacey K, Harper J 
==================================================================== 
==================================================================== 
51.) Abatement of cutaneous Kaposi's sarcoma associated with cidofovir 
treatment. 
Clin Infect Dis 1998 Dec;27(6):1562 

Simonart T, Noel JC, De Clercq E, Snoeck R 
==================================================================== 
==================================================================== 
52.) Treatment of verruca vulgaris with topical cidofovir. 
JAMA 1997 Oct 15;278(15):1236 

Zabawski EJ Jr, Sands B, Goetz D, Naylor M, Cockerell CJ 
==================================================================== 

==================================================================== 
53.) Topical cidofovir for severe molluscum contagiosum. 
Lancet 1999 Jun 12;353(9169):2042 

Davies EG, Thrasher A, Lacey K, Harper J 
==================================================================== 

==================================================================== 
54.) CIDOFOVIR, The product 
==================================================================== 
VA CLASSIFICATION (Primary/Secondary)&frac34;AM800 

Commonly used brand name(s): 

Vistide. 

Note: For a listing of dosage forms and brand names by country 
availability, see Dosage Forms section(s). 

Category 

Antiviral (systemic). 

Indications 

General considerations 

All cidofovir-resistant cytomegalovirus (CMV) isolates have been found to 
be resistant to ganciclovir, but remained susceptible to foscarnet1. 

Accepted 

Cytomegalovirus retinitis (treatment)&frac34;Cidofovir is indicated, in 
combination with probenecid, for the treatment of cytomegalovirus (CMV) 
retinitis in patients with acquired immunodeficiency syndrome1. Safety and 
efficacy have not been established for the treatment of CMV disease in 
non-HIV infected people, other CMV infections, or congenital or neonatal 
CMV disease1. 

Pharmacology/Pharmacokinetics 

Physicochemical characteristics: 

Molecular weight&frac34; 
Cidofovir: 315.221 
Cidofovir anhydrous: 279.191 

Mechanism of action/Effect: 

Cidofovir diphosphate, the active intracellular metabolite of cidofovir, 
suppresses cytomegalovirus (CMV) replication by selectively inhibiting 
viral DNA polymerase1. Cidofovir diphosphate inhibits herpesvirus 
polymerases at concentrations that are 8- to 600-fold lower than those 
needed to inhibit the human cellular polymerases alpha, beta, and gamma1. 
Reduction in the rate of viral DNA synthesis is due to incorporation of 
cidofovir into the growing viral DNA chain1. 

Distribution: 

Volume of distribution is 537 mL per kg (mL/kg) without concurrent 
probenecid administration and 410 mL/kg with concurrent probenecid 
administration1. 

Concentrations of cidofovir were undetectable 15 minutes after the end of a 
1-hour infusion in one patient who had a corresponding serum concentration 
of 8.7 mcg per mL (mcg/mL)1. 

Protein binding: 

Low (less than 6%)1. 

Time to peak concentration: 

End of infusion1. 

Peak serum concentration: 

With concurrent probenecid administration&frac34; 
3 mg per kg of body weight (mg/kg): 9.8 mcg/mL1. 

5 mg/kg: 19.6 mcg/mL1. 

Without concurrent probenecid administration&frac34; 
3 mg/kg: 7.3 mcg/mL1. 

5 mg/kg: 11.5 mcg/mL1. 

Elimination: 

Renal (without concurrent probenecid administration)&frac34;Approximately 80 to 
100% of an administered cidofovir dose was recovered unchanged in the urine 
within 24 hours1. 

Renal (with concurrent probenecid administration)&frac34;Approximately 70 to 85% 
of an administered cidofovir dose was recovered unchanged in the urine 
within 24 hours. The renal clearance of cidofovir was reduced to that of 
creatinine clearance, suggesting that probenecid blocks active renal 
tubular secretion of cidofovir1. 

In dialysis&frac34;The effect of hemodialysis on the pharmacokinetics of cidofovir 
is not known1. 

Precautions to Consider 

Carcinogenicity 

Cidofovir should be considered a carcinogen in rats and a potential 
carcinogen in humans1. 

Chronic, two-year carcinogenicity studies in rats and mice have not been 
done. However, a 26-week toxicology study was done in rats evaluating once 
weekly subscapular subcutaneous injections of cidofovir. The study was 
terminated at 19 weeks because palpable mammary adenocarcinomas were 
detected in females after only six doses. These masses developed at doses 
as low as 0.6 mg per kg (mg/kg) per week, which is equivalent to 0.04 times 
the human systemic exposure at the recommended cidofovir dose based on area 
under the plasma concentration-time curve (AUC) comparisons.1 

There was also a significant increase in mammary adenocarcinomas in female 
rats and a significant incidence of Zymbal's gland carcinomas in male and 
female rats administered 15 mg/kg of cidofovir once weekly; this was not 
seen at the 0.6 or 3 mg/kg doses. The 15 mg/kg dose is equivalent to 1.1 
times the human systemic exposure at the recommended dose of cidofovir, 
based on AUC.1 

Tumorigenicity 

No tumors were detected in cynomologus monkeys who received intravenous 
cidofovir, alone and in conjunction with concomitant oral probenecid, once 
a week for 52 weeks. This dose is equivalent to approximately 0.7 times the 
human systemic exposure. However, due to the small number of animals and 
the short duration of treatment, this study was not designed as a 
carcinogenicity study.1 

Mutagenicity 

There was no mutagenic response observed in microbial mutagenicity assays 
involving Salmonella typhimurium (Ames) and Escherichia coli in the 
presence and absence of metabolic activation. There was an increase in 
micronucleated polychromatic erythrocytes in vivo seen in mice receiving &sup3; 
2000 mg/kg, a dose approximately 65-times higher than the maximum 
recommended clincial dose of cidofovir, based on body surface area 
estimations. Cidofovir induced chromosomal aberrations in human peripheral 
blood lymphocytes in vitro without metabolic activation. At the four doses 
tested, the percentage of damaged metaphases and the number of aberrations 
per cell increased in a concentration-dependent manner.1 

Pregnancy/Reproduction 

Fertility&frac34;&frac34; 
Cidofovir was shown to cause inhibition of spermatogenesis in rats and 
monkeys. However, there were no reported adverse effects on fertility or 
reproduction in male rats administered once-weekly intravenous injections 
for thirteen consecutive weeks at doses up to 15 mg/kg per week; this is 
equivalent to 1.1 times the recommended human dose based on AUC 
comparisons. Female rats dosed intravenously at 1.2 mg/kg per week 
(equivalent to 0.09 times the recommended human dose based on AUC) or 
higher for up to six weeks prior to mating, and for two weeks after mating, 
had decreased litter size and live births per litter, as well as an 
increased incidence of early resorptions per litter. Peri- and postnatal 
development studies in which female rats were administered subcutaneous 
cidofovir at doses up to 1 mg/kg per day from day 7 of gestation through 
day 21 postpartum (approximately five weeks) resulted in no adverse effects 
on viability, growth, behavior, sexual maturation, or reproductive capacity 
in the offspring.1 

Pregnancy&frac34;Adequate and well-controlled studies in humans have not been 
done. Cidofovir should be administered only if the potential benefit 
justifies the potential risk to the fetus.1 

Cidofovir was found to be embryotoxic (reduced fetal body weight) in rats 
administered 1.5 mg/kg per day and in rabbits given 1 mg/kg per day during 
the period of organogenesis; these doses were also maternotoxic. There was 
also an increased incidence of fetal external soft tissue and skeletal 
anomalies, such as meningocele, short snout, and short maxillary bones, 
seen in rabbits administered 1 mg/kg per day, which was also maternally 
toxic. The no-observable-effect levels for embryotoxicity in rats (0.5 
mg/kg per day) and in rabbits (0.25 mg/kg per day) were approximately 0.04 
and 0.05 times the human maintenance dose, respectively, based on AUC. 

FDA Pregnancy Category C.1 

Breast-feeding 

It is not known whether cidofovir is distributed into breast milk. However, 
it is recommended that HIV-infected women not breast-feed their infants to 
avoid postnatal transmission of HIV to a child who may not be infected.1 

Pediatrics 

No information is available on the relationship of age to the effects of 
cidofovir in pediatric patients. Safety and efficacy have not been 
established. However, cidofovir should be used with caution in children 
with HIV infection because of the potential risk of long-term 
carcinogenicity and reproductive toxicity.1 

Geriatrics 

No studies have been done assessing the safety and efficacy of cidofovir in 
patients over the age of 601. However, elderly patients are more likely to 
have age-related renal function impairment, which may require adjustment of 
dosage in patients receiving cidofovir1. 

Drug interactions and/or related problems 

The following drug interactions and/or related problems have been selected 
on the basis of their potential clinical significance (possible mechanism 
in parentheses where appropriate)&frac34;not necessarily inclusive (>> = major 
clinical significance): 

Note: Combinations containing any of the following medications, depending 
on the amount present, may also interact with this medication. 

>> Nephrotoxic medications (see Appendix II)&frac34;(because cidofovir has been 
reported to be associated with severe renal function impairment, concurrent 
use with other nephrotoxic medications, such as aminoglycosides, 
amphotericin B, foscarnet, nonsteroidal anti-inflammatory drugs, and 
pentamidine, may increase the risk of nephrotoxicity and is 
contraindicated; it is recommended that patients undergo at least a 7-day 
washout period before receiving cidofovir2) 

>> Probenecid&frac34;(probenecid must be administered concurrently with 
cidofovir; probenecid is known to interact with the metabolism or renal 
tubular excretion of many medications, such as acetaminophen, acyclovir, 
aminosalicylic acid, angiotensin-converting enzyme inhibitors, 
barbiturates, benzodiazepines, bumetanide, clofibrate, famotidine, 
furosemide, methotrexate, nonsteroidal anti-inflammatory agents, 
theophylline, and zidovudine; these medications should be used with caution 
when used concurrently with probenecid1) 

Zidovudine&frac34;(concurrent use with cidofovir, without probenecid, showed no 
evidence of an effect on the pharmacokinetics of zidovudine1) 

Laboratory value alterations 

The following have been selected on the basis of their potential clinical 
significance (possible effect in parentheses where appropriate)&frac34;not 
necessarily inclusive (>> = major clinical significance): 

With physiology/laboratory test values 
Creatinine, serum and1 
Protein, urine1&frac34;(may be increased) 

Bicarbonate, serum and1 
Neutrophils1&frac34;(may be decreased) 

Medical considerations/Contraindications 

The medical considerations/contraindications included have been selected on 
the basis of their potential clinical significance (reasons given in 
parentheses where appropriate)&frac34;not necessarily inclusive (>> = major 
clinical significance). 

Except under special circumstances, this medication should not be used when 
the following medical problem exists 

>> Hypersensitivity to cidofovir or probenecid1&frac34; 

Risk-benefit should be considered when the following medical problem exists 

>> Renal function impairment1&frac34;(because cidofovir has been reported to be 
associated with severe renal function impairment, cidofovir is 
contraindicated in patients with a serum creatinine > 1.5 mL per dL, a 
creatinine clearance &pound; 55 mL per minute [0.92 mL per second], or a urine 
protein &sup3; 100 mg per dL [equivalent to &sup3; 2+ proteinuria]2) 

Patient monitoring 

The following may be especially important in patient monitoring (other 
tests may be warranted in some patients, depending on condition; >> = 
major clinical significance): 

>> Creatinine, serum and1 
>> Protein, urine and1 
>> White blood cell count with differential1&frac34;(because cidofovir has been 
reported to cause severe renal function impairment and cause neutropenia, 
these laboratory parameters should be monitored prior to each dose of 
cidofovir) 

>> Intraocular pressure1 
>> Visual acuity1&frac34;(because cidofovir can cause ocular hypotony, especially 
in patients with preexisting diabetes, intraocular pressure and visual 
acuity should be monitored periodically) 

Side/Adverse Effects 

Note: Nephrotoxicity, the major dose-limiting toxicity of cidofovir 
therapy, was manifested as > 1+ proteinuria, serum creatinine concentration 
&sup3; 0.4 mg per dL, or a decrease in creatinine clearance to &pound; 55 mL per min 
(0.92 mL per second) in 53% of patients receiving a maintenance dose of 5 
mg per kg of body weight every other week1. Proteinuria may be an early 
indicator of cidofovir-related nephrotoxicity and continued administration 
may lead to additional proximal tubular cell injury, resulting in 
glycosuria, decreases in serum phosphate, uric acid, and bicarbonate, and 
elevations in serum creatinine. Patients with these side effects and 
meeting a criteria of Fanconi's syndrome have been reported.1 There have 
also been reports of severe renal function impairment associated with 
cidofovir use2. To help reduce the risk of nephrotoxicity, patients must be 
pre-hydrated with at least 1 liter of 0.9% sodium chloride solution and 
probenecid must be administered at proper times.2 Dosage adjustment or 
discontinuation is necessary when changes in renal function occur during 
therapy. 

Neutropenia (&pound; 500 cells/mm3) occurred in 20% of patients receiving the 5 
mg per kg of body weight maintenance dose in clinical trials. Granulocyte 
colony stimulating factor was used in 34% of patients.1 

Ocular hypotony (&sup3; 50% change from baseline) was reported in 5 of 42 
patients receiving the 5 mg per kg of body weight maintenance dose in 
clinical studies. Hypotony was reported in one patient with concomitant 
diabetes mellitus; the risk of ocular hypotony may be increased in patients 
with pre-existing diabetes.1 

Two percent of study patients were diagnosed with Fanconi's syndrome, 
manifested by multiple abnormalities of proximal tubule function. Decreases 
in serum bicarbonate to &pound; 16 milliequivalents per liter associated with 
evidence of renal tubular damage occurred in approximately 9% of patients.1 

The following side/adverse effects have been selected on the basis of their 
potential clinical significance (possible signs and symptoms in parentheses 
where appropriate)&frac34;not necessarily inclusive: 

Those indicating need for medical attention 

Incidence more frequent 
Nephrotoxicity1 decreased urination; increased thirst and urination); 
neutropenia1 (fever, chills, or sore throat) 

Incidence less frequent 
Fever 

Incidence rare 
Ocular hypotony decreased vision or any change in vision) 

Those indicating need for medical attention only if they continue or are 
bothersome 

Incidence more frequent 
Gastrointestinal effects (diarrhea; loss of appetite; nausea; 
vomiting); headache 

Incidence less frequent 
Asthenia (generalized weakness; loss of strength) 

Overdose 

Overdosage with cidofovir has not been reported. However, probenecid may 
reduce potential nephrotoxicity through reduction of active tubular 
secretion. Hemodialysis and hydration may reduce plasma cidofovir 
concentrations.1 

For more information on the management of overdose or unintentional 
ingestion, contact a Poison Control Center (see Poison Control Center 
Listing). 

Patient Consultation 

In providing consultation, consider emphasizing the following selected 
information (>> = major clinical significance) 

Before using this medication 

>> Conditions affecting use, especially: 

Hypersensitivity to cidofovir or probenecid 

CarcinogenicityCidofovir is a carcinogen in animals and should be 
considered a potential carcinogen in humans 

Pregnancy&frac34;Cidofovir was embryotoxic and maternotoxic in animals; cidofovir 
should be administered only if the potential benefit justifies the 
potential risk to the fetus 

Breast-feeding&frac34;It is not known whether cidofovir is distributed into breast 
milk; however, it is recommended that HIV-infected women not breast-feed 
their infants to avoid postnatal transmission of HIV to a child who may not 
be infected 

Use in children&frac34;Safety and efficacy have not been established; however, 
cidofovir should be used with caution in HIV-infected children because of 
the potential risk of long-term carcinogenicity and reproductive toxicity 

Other medications, especially nephrotoxic medications and probenecid 

Other medical problems, especially renal function impairment 

Proper use of this medication 

>> Importance of receiving medication for full course of therapy and on a 
regular schedule 

>> Proper dosing 

Precautions while using this medication 

>> Regular visits to physician to check blood counts 

>> Regular visits to ophthalmologist to examine eyes since progression of 
retinitis and visual loss may occur during cidofovir therapy 

Side/adverse effects 

Signs of potential side effects, especially, nephrotoxicity, neutropenia, 
fever, and ocular hypotony 

General Dosing Information 

Cidofovir must not be administered by intraocular injection. Direct 
injection may result in significant decreases in intraocular pressure and 
vision impairment.1 

Because cidofovir has been reported to be associated with severe renal 
function impairment, the recommended dosage, frequency, or infusion rate 
must not be exceeded. Cidofovir must be diluted in 100 mL of 0.9% sodium 
chloride injection prior to administration. Probenecid and intravenous 
sodium chloride prehydration must be administered with each cidofovir 
infusion to minimize potential nephrotoxicity. The dose of cidofovir must 
be reduced or discontinued if changes in renal function occur during 
therapy. Serum creatinine and urine protein must be monitored within 48 
hours prior to each dose of cidofovir.1,2 

The dose of cidofovir must be reduced or discontinued if changes in renal 
function occur during therapy. For increases in serum creatinine of 0.3 to 
0.4 mg per dL (mg/dL) above baseline, the dose of cidofovir must be reduced 
from 5 mg per kg (mg/kg) to 3 mg/kg. Cidofovir must be discontinued for an 
increase in serum creatinine of 0.5 mg/dL above baseline or development of 
3+ proteinuria. Patients with 2+ proteinuria should be observed carefully; 
dose reduction or temporary discontinuation of treatment should be 
considered.2 

Two grams of probenecid should be administered 3 hours prior to each dose 
of cidofovir and 1 gram should be administered 2 and 8 hours after the 
completion of the 1-hour infusion (total 4 grams)1. 

Each dose of cidofovir should be administered with 1 liter of 0.9% sodium 
chloride injection, infused over 1 to 2 hours immediately before the 
cidofovir infusion. If the patient can tolerate the fluid load, a second 
liter of 0.9% sodium chloride injection should be started either at the 
beginning of the cidofovir infusion or immediately afterwards, over a 1- to 
3-hour period.1 

Ingestion of food before each dose of probenecid may reduce nausea and 
vomiting associated with probenecid administration. Administration of an 
antiemetic may also reduce the potential for nausea. 

Safety considerations for handling this medication 

Due to the mutagenic potential of cidofovir, use of appropriate safety 
equipment is recommended for the preparation, administration, and disposal 
of cidofovir. The National Institutes of Health recommends that cidofovir 
be prepared in a Class II laminar flow biological safety cabinet and that 
personnel preparing this medication wear surgical gloves and a closed-front 
surgical-type gown with knit cuffs. If cidofovir contacts the skin, 
membranes should be washed and flushed thoroughly with water. Excess 
cidofovir and materials used in the admixture and administration procedures 
should be placed in a leak-proof, puncture-proof container. High 
temperature incineration is the recommended method of disposal.1 

Parenteral Dosage Forms 

CIDOFOVIR INJECTION 

Usual adult dose 

Antiviral&frac34; 
Induction: Intravenous infusion, 5 mg per kg of body weight, administered 
continuously over one hour, once a week for two consecutive weeks. 
Probenecid must be administered with each dose of cidofovir. Two grams of 
probenecid should be administered three hours prior to each dose of 
cidofovir and 1 gram should be administered two and eight hours after the 
completion of the one-hour infusion (total 4 grams).1 

Maintenance: Intravenous infusion, 5 mg per kg of body weight, administered 
continuously over one hour, once every two weeks. Probenecid must be 
administered with each dose of cidofovir. Two grams of probenecid should be 
administered three hours prior to each dose of cidofovir and 1 gram should 
be administered two and eight hours after the completion of the one-hour 
infusion (total 4 grams).1 

Note: Cidofovir has not been studied in patients with pre-existing renal 
function impairment. The most appropriate dose of cidofovir for patients 
with a serum creatinine > 1.5 mg per mL or a creatinine clearance &pound; 55 mL 
per min (mL/min) is not known. However, the following doses (in mg per kg 
of body weight) are recommended when the benefits of cidofovir exceed the 
potential risks1: 



Creatinine Induction (once Maintenance (once every 2 
Clearance weekly for 2 weeks) 
(mL/min) weeks) 
41-55 2 mg per kg 2 mg per kg 
30-40 1.5 mg per kg 1.5 mg per kg 
20-29 1 mg per kg 1 mg per kg 
&pound; 19 0.5 mg per kg 0.5 mg per kg 



Usual pediatric dose 

Safety and efficacy have not been established.1 

Strength(s) usually available 

U.S.&frac34; 
375 mg per 5 mL (Rx)[Vistide]. 

Packaging and storage: 

Store at room temperature between 20 and 25 &deg;C (68 and 77 &deg;F).1 

Preparation of dosage form: 

The vial should be visually inspected for particulate matter and 
discoloration prior to administration and discarded if particulate matter 
or discoloration is observed.1 

The appropriate volume of cidofovir should be extracted from the vial and 
the dose transferred to an infusion bag containing 100 mL of 0.9% sodium 
chloride solution. The entire volume should be infused into the patient at 
a constant rate over a 1-hour period. It is recommended that a standard 
infusion pump be used for administration.1 

Stability: 

It is recommended that cidofovir admixtures be administered within 24 hours 
of preparation and that refrigeration or freezer storage not be used to 
extend this 24-hour limit.1 

If admixtures are not intended for immediate use, they may be refrigerated 
(between 2 and 8 &deg;C [36 and 46 &deg;F]) for no more than 24 hours. Refrigerated 
admixtures should be allowed to equilibrate to room temperature prior to use.1 

Incompatibilities: 

Compatibility with Ringer's solution, Lactated Ringer's solution, or 
bacteriostatic infusion fluids has not been evaluated.1 

The chemical stability of cidofovir admixtures was determined in polyvinyl 
chloride composition and ethylene/propylene copolymer composition 
commercial infusion bags, and in glass bottles.1 

Note: Great care should be taken to prevent exposure of the skin to 
cidofovir. The use of gloves is recommended. Any cidofovir that comes in 
contact with the skin should be washed off thoroughly with soap and water.1 
=================================================================== 
DATA-MEDICOS/DERMAGIC-EXPRESS No (73) 15/09/99 DR. JOSE LAPENTA R. 
===================================================================