AHFS Class:

• Nucleosides and Nucleotides 8:18.32

Generic Name(s):

• Ganciclovir Sodium

Chemical Name:

• 2-Amino-1,9-dihydro-9-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-6 H -purin-6-one sodium salt

Ganciclovir, a synthetic nucleoside analog of guanine, is an antiviral agent active against herpesviruses.1,2,14,85,86

Treatment of Cytomegalovirus Infection and Disease

Ganciclovir is used for the management of cytomegalovirus (CMV) retinitis in immunocompromised patients, including individuals with human immunodeficiency virus (HIV) infection.1,2,4,5,8,9,11,14,20,21,23,28,70,85,86,94,100,103,104,105,108,109,110,117,118,126,127,139,151,155,156,164,174,175,176,187,203,207,225,243,259,311 Ganciclovir also has been used for the management of other CMV infections (e.g., GI infections†, pneumonitis†, CNS infections†) in immunocompromised patients, but experience with the drug in these extraocular infections is less extensive.3,4,5,6,8,10,11,15,16,19,20,21,26,33,43,64,68,69,70,85,86,92,102,106,107,108,110,121,122,134,137,145,146,149,151,154,155,156,157,159,165,166,171,180,188,193,194,199,201,202,207,219,220,225,231,243

Like other herpesviruses, CMV usually establishes a site(s) of latent infection following primary infection with the virus.8,86,155,174,241 Latency usually persists for life and the virus can be reactivated by various stimuli (e.g., immunosuppression), especially during periods of impaired cell-mediated immunity.4,5,8,86,100,155,174,241 Reactivation of the virus may result in subclinical infections or active end-organ CMV disease (e.g., retinitis, GI infections, pneumonitis, encephalitis), including serious, potentially life-threatening CMV disease.4,5,8,86,155

Cytomegalovirus Retinitis

Ganciclovir is used for initial treatment (induction therapy) and maintenance therapy (secondary prophylaxis) of CMV retinitis in immunocompromised adults, including those with HIV infection and acquired immunodeficiency syndrome (AIDS), those with iatrogenic (e.g., chemotherapy-induced) immunosuppression, and transplant recipients.1,2,4,5,11,14,21,23,28,85,86,94,100,103,104,105,117,118,126,127,139,155,164,187,207,311 The drug also is used for the management of CMV retinitis in HIV-infected pediatric patients†.156

Like other antivirals, ganciclovir is not a cure for CMV retinitis.1 Although ganciclovir can induce stabilization or improvement of ocular manifestations, 1,3,4,5,8,9,11,13,21,23,27,28,37,63,65,94,99,100,108,113,126,128,129,139,167,187 the retinitis may relapse and/or progress during or after discontinuance of the drug.1,3,4,5,8,11,28,116,126,139,206,207

Retinitis is the most common clinical manifestation of CMV end-organ disease in HIV-infected patients and ideally should be managed in consultation with an ophthalmologist familiar with the diagnosis and treatment of retinal diseases.155,156 Antiviral regimens for initial treatment of CMV retinitis in HIV-infected individuals should be selected based on the location and severity of CMV retinal lesions, severity of underlying immunosuppression, concomitant drug therapy, and the patient's ability to adhere to the treatment regimen.155,156 The antiviral regimen used for maintenance therapy of CMV retinitis in HIV-infected individuals should be selected with consideration for the location of the CMV retinal lesions, vision in the contralateral eye, the patient's immunologic and virologic status, and the patient's response to antiretroviral therapy.155,156

For the management of immediate sight-threatening CMV retinal lesions (i.e., within 1.5 mm of the fovea) in HIV-infected adults and adolescents, the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and the HIV Medicine Association of the Infectious Diseases Society of America (IDSA) state that the preferred regimen is initial treatment (induction therapy) with intravitreal ganciclovir† or intravitreal foscarnet (1-4 doses given over a period of 7-10 days) in conjunction with oral valganciclovir (twice daily for 14-21 days) followed by maintenance therapy (secondary prophylaxis) with oral valganciclovir (once daily).155 One alternative regimen recommended by these experts for management of sight-threatening CMV retinitis in HIV-infected adults and adolescents is intravitreal ganciclovir† or intravitreal foscarnet (1-4 doses given over a period of 7-10 days) in conjunction with IV ganciclovir (twice daily for 14-21 days) followed by maintenance therapy (secondary prophylaxis) with oral valganciclovir (once daily).155 Use of systemic antivirals (without an intravitreal antiviral) usually is adequate for the management of CMV retinitis in patients who have only small peripheral lesions.155

For the management of CMV retinitis in HIV-infected pediatric patients†, CDC, NIH, IDSA, and others state that IV ganciclovir is the drug of choice for initial treatment (induction therapy) and is one of several options for maintenance therapy (secondary prophylaxis).156 These experts state that oral valganciclovir is an option for the management of CMV retinitis in HIV-infected pediatric patients and can be considered for induction and/or maintenance therapy in adolescents and older children who can receive the recommended adult dosage of the drug and can also be considered in children who are able to transition from initial IV ganciclovir therapy to an oral regimen to complete treatment and/or for maintenance therapy.156 Data are limited regarding use of intravitreal antivirals in children, and intravitreal injections are impractical in most children.156

Because of the risk of relapse, HIV-infected patients who have received adequate initial treatment of CMV retinitis should receive chronic maintenance therapy (secondary prophylaxis) until immune reconstitution occurs as a result of effective antiretroviral therapy.155,156 CDC, NIH, and IDSA state that consideration can be given to discontinuing maintenance therapy of CMV retinitis in HIV-infected adults and adolescents if CMV lesions have been treated for at least 3-6 months and are inactive and there has been a sustained (i.e., 3-6 months) increase in CD4⁺ T-cell count to greater than 100/mm³ in response to antiretroviral therapy.155 The safety of discontinuing maintenance therapy of CMV retinitis in HIV-infected pediatric patients has not been well studied; however, CDC, NIH, IDSA, and others state that consideration can be given to discontinuing such maintenance therapy in HIV-infected children who are receiving antiretroviral therapy and have a sustained (i.e., greater than 6 months) increase in CD4⁺ T-cell percentage to greater than 15% (children younger than 6 years of age) or an increase in CD4⁺ T-cell count to greater than 100/mm³ (children 6 years of age or older).156 These experts state that a decision to discontinue maintenance therapy of CMV retinitis should be made in consultation with an ophthalmologist and, if maintenance therapy is discontinued, the patient should continue to receive regular ophthalmologic monitoring (optimally every 3-6 months) for early detection of CMV relapse or immune reconstitution uveitis.155,156 If CD4⁺ T-cell count decreases to less than 100/mm³ (adults, adolescents, children 6 years of age or older) or if CD4⁺ T-cell percentage decreases to less than 15% (children younger than 6 years of age), maintenance therapy of CMV retinitis should be reinitiated.155,156

For additional information on management of CMV retinitis and other CMV infections in HIV-infected individuals, the current clinical practice guidelines from CDC, NIH, and IDSA on the prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web] should be consulted.155,156

Clinical Experience

Efficacy of IV ganciclovir for the management of CMV retinitis has been established in uncontrolled and randomized controlled studies.1,5,11,20,21,23,27,28,94,100,103,104,105,108,109,110,117,118,122,126,133,139,151,164,187,207,243,262

Initial ocular response (improvement or stabilization of vision and/or other ophthalmologic findings) reportedly occurs in 70-80% or more of immunocompromised patients receiving IV ganciclovir induction therapy.3,4,5,8,11,12,21,23,28,94,105,106,110,118,120,122,125,126,127,139,143,176,207,209,225,243 Stabilization of retinal lesions usually is apparent within 2 weeks of initiating ganciclovir therapy,11,71,125 although optimum clinical response to induction therapy may be delayed for several weeks to a month after initiating the drug.3,21,23,28,71 Ophthalmologic evidence of response to ganciclovir therapy may include decreased retinal opacification and inflammation, improvement in ocular hemorrhage and vasculitis (vascular sheathing) and in visual acuity, and development of atrophic changes in previously inflamed retinal areas,4,11,21,94,105,209,265 although reversal of resultant visual abnormalities may not occur.8,105,125,126 Stabilization or improvement in visual acuity reportedly occurs in 50% or more of patients receiving induction therapy with the drug94,105,126 and depends in part on the extent of macular (more specifically, foveal) and optic nerve involvement;105,125 however, such visual improvement rarely is dramatic,126,262 and rhegmatogenous retinal detachment can develop as a consequence of ganciclovir-induced resolution of retinitis,1,71,94,105,125,127,167,172,177,203,244 especially in patients with AIDS.125,203,244 (See Cautions: Ocular Effects.) In one study, visual acuity stabilized in 73%, improved (by more than 2 lines on the Snellen chart) in 15%, and deteriorated in 12% of ganciclovir-treated AIDS patients; there was no foveal involvement in those patients whose acuity improved.105 Extraocular (e.g., blood, urine) virologic response (negative cultures and/or decreased viral shedding) reportedly occurs in almost all ganciclovir-treated patients with CMV retinitis8,20,21,23,28,100,122,126,139,243 and usually is apparent within several days to 2 weeks after initiating therapy;3,8,11,13,20,21,23,28,63,100,106,128,139,207 however, a direct relationship between extraocular virologic response and clinical improvement of the retinitis has not been demonstrated.105,262

In a retrospective, nonrandomized analysis of data from a study in 41 patients with AIDS and CMV retinitis who received IV ganciclovir induction therapy (5 mg/kg every 12 hours) for 14-21 days followed by IV ganciclovir maintenance therapy (5 mg/kg once daily every day or 6 mg/kg once daily 5 days each week), treatment with ganciclovir resulted in a delay in median time from diagnosis to initial retinitis progression compared with untreated patients (71 days versus 29 days).1

In a randomized, prospective study in a limited number of patients with AIDS and peripheral CMV retinitis who received IV ganciclovir that was either initiated immediately or deferred, the median time to retinitis progression was 50 versus 13.5 days for those receiving immediate versus deferred ganciclovir treatment.1,311 This study indicates that all patients with HIV-related CMV retinitis, regardless of whether the lesions are peripheral or central, should be offered CMV treatment.85

Extraocular Cytomegalovirus Infections

Although safety and efficacy of ganciclovir have not been established for the treatment of extraocular CMV infections,1,2,14 the drug has been used in immunocompromised patients for the management of CMV GI disease†3,4,5,6,8,11,16,20,21,26,68,69,70,86,92,102,108,110,122,134,146,155,166,193,194,207 and/or pneumonitis†,3,4,5,8,10,11,15,16,17,18,19,20,21,33,43,64,66,72,73,106,107,108,109,110,111,121,122,137,140 145,146,149,151,154,155,159,180,188,193,198,199,201,202,205,207,219,220,225 and, less frequently, for the management of CMV encephalitis†,4,5,8,11,21,86,110,155,156,165,207,231 hepatic†,4,5,8,20,21,68,106,108,146,166,219 cardiac†,110,171,220 and/or other CMV infections†.3,5,8,15,19,108,140

GI Infections

Ganciclovir has been used for the management of CMV GI infections†, including colitis†,3,4,6,8,11,16,21,70,102,106,108,110,122,134,155,157,166,193,315 esophagitis†,4,6,8,11,21,68,70,102,106,110,146,155,315 gastritis†,4,11,8,106,110 and rectal disease†.6,106

There is evidence that the clinical response rate of CMV GI infections† to ganciclovir is similar to or less than that of CMV retinitis.5,6,11,16,21,68,92,106,108,110,122,134,157,207,243 Approximately 70% or more of immunocompromised patients with CMV GI infections exhibit stabilization or improvement of the infection with ganciclovir induction therapy.3,4,5,6,11,16,21,68,92,106,108,122,134,166,193,194,195,196,197,198,199,201,202,203,204,205,206,207,243 Similarly, there is clearing of viremia and/or viruria and decreased viral shedding,3,5,6,16,20,21,68,92,106,122,146,157,243 with the frequency of virologic response usually exceeding clinical response.3,5,6,11,20,122,243 Response generally is apparent within 1-2 weeks of initiating therapy with the drug.6,21,68,92,102,106,122,134,146,159,166 In patients with colitis, response to ganciclovir therapy usually manifests as a reduction in stool frequency and diarrhea4,6,21,92,102,106,134,166,243 and in abdominal pain.4,92,243 In patients with esophagitis, response to the drug usually manifests as a reduction in dysphagia4,6,68,92,106,114 and odynophagia102,114 and in esophageal and epigastric pain.4,21,92,106 Improvement in rectal ulcers usually is observed in those with rectal disease,6,106 and weight gain also may be observed in response to ganciclovir therapy in patients with CMV GI infections.69,92,108,262

Relapse, usually based on symptomatic recurrence or worsening but occasionally confirmed histologically, has occurred following ganciclovir induction therapy and discontinuance of the drug in immunosuppressed patients with CMV GI infections†.4,6,8,21,102,106,122,157 In some patients, particularly those with AIDS, long-term maintenance and/or intermittent induction therapy with the drug may be required.102,106,157,243,262

CDC, NIH, and IDSA state that IV ganciclovir usually is the preferred antiviral for initial management of CMV GI disease† in HIV-infected adults and that a transition to oral valganciclovir may be considered when the patient can tolerate and absorb oral drugs.155 These experts state that IV foscarnet is a possible alternative to IV ganciclovir for the management of CMV esophagitis or colitis in those who cannot receive ganciclovir or have infections caused by ganciclovir-resistant CMV.155

Pneumonitis

Ganciclovir has been used for the treatment of CMV pneumonitis† with variable results; in part, this variability in response appears to depend on the patient's underlying immunologic disorder.3,4,5,8,10,11,15,16,17,18,19,20,21,33,43,64,66,72,73,106,107,108,109,110,111,121,122,137,140,145,146,149,151,154,155,159,180,188,193,198,199,201,202,205,207,219,220,225 Clinical outcome in bone marrow transplant (BMT) recipients treated with ganciclovir alone has been particularly disappointing.17,64,73,108,137,149,151,199,201 Although CMV can be isolated from the respiratory tract of many AIDS patients,4,17,197 the virus rarely is the only pulmonary pathogen recovered, and its role as the principal pathogen in these patients has not been fully defined;4,17,197 in one study in AIDS patients with serious pulmonary disorders, CMV was isolated in 17% of patients but was the sole pathogen isolated in only 4%.197 Coexistent infections also may be present in organ (e.g., kidney) and BMT recipients, but presence of the virus as the principal pulmonary pathogen in these patients is better defined, especially in BMT recipients.4,17,72,73,107,146 Response to ganciclovir therapy appears to be better if the infection is treated early in its course;19,21,43,64,72,107,108,121,122,140,145,180,193,198 therefore, prompt recognition and diagnosis of the infection and initiation of ganciclovir therapy appear important.19,21,64,72,107,108,121,145,193,198

There is some evidence that the clinical response rate of CMV pneumonitis† to ganciclovir therapy alone generally is less than that of CMV retinitis,5,8,10,11,122,207,225 especially in BMT recipients.5,17,72,73,107,108,146 In some studies, approximately 50-60% of immunocompromised patients with CMV pneumonitis exhibited clinical improvement with ganciclovir induction therapy alone.3,5,8,10,11,110,122,207,225 Up to about 80% of patients whose immunodeficiency resulted from AIDS or organ transplantation exhibited a clinical response to therapy with the drug alone,3,145,154 whereas response rates reportedly have ranged from 10-45% in BMT recipients receiving the drug alone.64,108,137,149,151,199,201 Response to ganciclovir therapy usually manifests as improvement in respiratory symptoms and function;73 radiographic evidence of response usually is somewhat delayed.73 Evidence of virologic response occurs in almost all ganciclovir-treated patients with CMV pneumonitis,5,17,33,110 even in those who do not respond clinically.17,33 CMV pneumonitis may be less likely to require maintenance therapy after initial treatment than CMV retinitis.8,73,145,202

The reasons for the poor response to ganciclovir monotherapy in BMT recipients with CMV pneumonitis† have not been fully elucidated,17,27,33,64 but in part the poor response may depend on differences in immunologic responses to the infection.17,33 Untreated CMV pneumonitis may be fatal in 85% or more of BMT recipients.17,73,146,149 These patients are more prone than AIDS or organ transplant recipients to develop respiratory failure and die despite pulmonary and extrapulmonary (e.g., blood, urine) clearing of the virus during ganciclovir therapy.5,17,64,106,108,137 There is animal and human evidence to suggest that CMV pneumonitis in BMT recipients is a complex immunopathologic disease.17,66,73,148,249 While it is possible that poor response in these patients may result from progressive infection, it has been suggested that a pulmonary immunologic reaction to the infection (e.g., secondary to a T-cell-mediated cytotoxic effect against viral and/or HLA antigens expressed on infected pulmonary cells) and/or exacerbation of the infection by some underlying factor not related to CMV (e.g., graft-versus-host disease, radiation/chemotherapy-induced inflammation, pulmonary toxicity from high oxygen concentrations used during ventilatory support) may be responsible.17,64,66,73,175,249 An association between graft-versus-host disease and development of CMV pneumonitis has been observed in humans and animals.17,249 In addition, an association between presence of functional T cells and development of CMV pneumonitis has been observed in animals17,249 and is further supported by the more favorable clinical response of the pneumonitis observed in AIDS patients in whom cytotoxic cellular immune responses generally are poorer.17,249

For the management of well-documented CMV pneumonitis† in HIV-infected adults, CDC, NIH, and IDSA state that either IV ganciclovir or IV foscarnet is a reasonable choice.155

Neurologic Disease

Ganciclovir has been used with variable results in immunosuppressed patients with CMV encephalitis†.4,11,21,165,207 Neurologic and magnetic resonance imaging findings improved with induction and/or maintenance therapy with the drug in some of these patients,4,165,207 while other patients failed to respond.11 Many patients with CMV encephalitis also have other active CMV infections.4,21,165,207

A combination regimen of IV ganciclovir and IV foscarnet has been used for the management of CMV neurologic disease† (e.g., CMV encephalitis or myelitis),85 and is recommended by CDC, NIH, IDSA, and others for such infections in HIV-infected individuals.155,156

Congenital Cytomegalovirus Disease

Although safety and efficacy of ganciclovir have not been established in neonates or infants with congenital CMV infection,1,2,14 the drug has been used for the management of symptomatic congenital CMV disease† when an antiviral was indicated.85,156,292

Transmission of CMV from infected mothers to their fetuses occurs as a result of maternal viremia and transplacental infection.1,2,14 Perinatal infection also can occur from exposure of the neonate to CMV shedding in the mother's genital tract.1,2,14 Approximately 10% of neonates with congenital CMV infection are symptomatic at birth;1,2,14 mortality in symptomatic infants is about 10% and approximately 50-90% of symptomatic surviving neonates experience substantial morbidity (e.g., mental retardation, sensorineural hearing loss, microcephaly, seizures).1,2,14 The risk of congenital CMV infection resulting from primary maternal CMV infection may be higher and the disease may be more severe than that resulting from reactivation of maternal CMV infection.1,2,14

Because there is some evidence that antivirals (i.e., ganciclovir, valganciclovir) may help prevent hearing deterioration and/or improve developmental delay in neonates and infants with moderate to severe symptomatic congenital CMV disease, the American Academy of Pediatrics (AAP) and other clinicians state that use of an antiviral regimen should be considered in such neonates if it can be initiated within the first month of life.84,292 Antivirals are not usually recommended for neonates with asymptomatic congenital CMV infection or only mildly symptomatic infection without evidence of CNS involvement.84,292

AAP and others recommend that a 6-month regimen of oral valganciclovir be considered in neonates with moderate to severe symptomatic congenital CMV disease (with or without CNS involvement).84,85,292 A 6-week regimen of IV ganciclovir either alone or followed by a regimen of oral valganciclovir (continued until up to 12 months of age) also has been used in neonates with symptomatic congenital CMV disease.85

CDC, NIH, IDSA, and others state that IV ganciclovir can be considered for initial treatment of symptomatic congenital CMV disease with CNS involvement in HIV-exposed or HIV-infected infants†.156

Decisions regarding antiviral treatment in neonates with congenital CMV disease should be made in consultation with a pediatric infectious diseases specialist.156 Because of the risk of serious sequelae (e.g., late-onset hearing loss), long-term ophthalmologic and audiologic monitoring is necessary in patients with congenital CMV infection, regardless of antiviral treatment.84,156

Prevention of Cytomegalovirus Infection and Disease

IV ganciclovir is used for prophylaxis to prevent CMV infection and disease in solid organ transplant recipients, BMT recipients, and hematopoietic stem cell transplant (HSCT) recipients considered at high risk for the disease.1,2,14,74,76,81,82,85,86,271,283,284,286,287,288,304,305,306,307,313,324 The drug also has been used for preemptive treatment of CMV infection and disease† in transplant recipients.74,76,81,82,85

CMV infection in transplant recipients can occur either as a primary infection in CMV-seronegative recipients of organs and cells from CMV-positive donors or as reactivation of latent CMV infection in CMV-seropositive recipients.74,76,81,82,86 CMV infection in transplant recipients is associated with substantial morbidity and mortality.74,76,82,85,86 The risk for CMV infection or reactivation is greatest during the first 3 months after transplantation and depends on several factors, including the serologic status of the recipient and donor, CMV-specific T-cell immunity in the recipient, and immunosuppressive regimens used in the recipient.74,76,81,82,86 Certain antiviral strategies have been used to prevent severe, life-threatening CMV disease in transplant recipients, including antiviral prophylaxis (initiated posttransplantation and continued for at least 3 months) and/or preemptive antiviral treatment (i.e., initiated when CMV infection is detected, but before clinical progression to symptomatic CMV disease).74,76,81,82,86 These antiviral strategies each have certain advantages and disadvantages.74,76,81,82

Specialized references should be consulted for specific information regarding prevention and management of CMV infections in BMT, HSCT, or solid organ transplant recipients.74,76,81,82

Clinical Experience

In a randomized, double-blind, placebo-controlled study in 149 cardiac allograft recipients at risk for developing CMV disease (i.e., CMV-seropositive or CMV-seronegative recipients of an organ from a CMV-seropositive donor), patients who received IV ganciclovir (5 mg/kg twice daily for 14 days beginning 1 day after cardiac allotransplantation, followed by 6 mg/kg once daily for 5 days per week for an additional 2 weeks) had a substantial decrease in the overall incidence of CMV disease compared with those receiving placebo.1,283 During the 120-day period following transplantation, 16% of patients who received ganciclovir developed acute CMV disease (GI infection, pneumonitis, myocarditis, CMV syndrome) compared with 43% of patients who received placebo.1,283 However, a clinically important decrease in the incidence of CMV disease was evident only in those cardiac allograft recipients who were CMV-seropositive before transplantation; patients who were at highest risk for serious disease (CMV-seronegative recipients of hearts from CMV-seropositive donors) did not have a clinically important decrease in the incidence of CMV disease.283,288 In patients who were CMV-seropositive prior to transplantation, 9% of those who received ganciclovir developed CMV disease compared with 46% who received placebo.283 In patients who were CMV-seronegative prior to transplantation and received hearts from CMV-positive donors, 35% of those who received ganciclovir developed CMV disease compared with 29% who received placebo.283 If acute CMV disease developed in patients receiving placebo, it occurred at an average of 45 or 56 days after transplantation in CMV-seropositive patients or CMV-seronegative recipients of CMV-seropositive hearts, respectively.283 If it developed in patients receiving ganciclovir, it occurred at an average of 71 days after transplantation.283

In a randomized study in patients undergoing liver transplantation, IV ganciclovir (6 mg/kg daily from day 1-30 after transplantation, then 6 mg/kg daily 5 days weekly until day 100) was more effective than acyclovir (10 mg/kg IV every 8 hours from day 1 after transplantation until discharge, then 800 mg orally 4 times daily until day 100) in preventing CMV disease in these patients.324 During the first 120 days after the procedure, CMV infection occurred in only 5% of patients receiving ganciclovir but occurred in 38% of those receiving acyclovir.324 Symptomatic CMV disease developed in less than 1% of patients receiving ganciclovir and in 10% of those receiving acyclovir.324 Ganciclovir reduced the incidence of CMV disease in both CMV-seropositive and -seronegative individuals.324

In several randomized, double-blind, placebo-controlled studies in bone marrow allograft recipients with asymptomatic CMV infection (CMV-positive culture of urine, throat, or blood) who were at risk for developing CMV disease, patients who received IV ganciclovir (5 mg/kg twice daily for 5-7 days, followed by 5 mg/kg once daily until 100 days after transplantation) had a substantial decrease in the incidence of CMV disease compared with those receiving placebo.1,284,306 During the 100-day period following transplantation, 0-3% of patients receiving ganciclovir and 29-43% of patients receiving placebo developed CMV disease.1,284,306 During the first 6-month period following transplantation, 9-16% of patients who had received ganciclovir and 32-43% of patients who had received placebo developed CMV disease.1,284,306 In one study, the overall survival rate 100 and 180 days after transplantation was higher in patients who had received ganciclovir.1,284 In another study, mortality at 100 and 180 days after transplantation was similar in both groups; it was suggested that this lack of difference in survival may have occurred because of a reduction in excess deaths in the placebo group since any patient who began to excrete the virus was removed from the study and given ganciclovir.306 The incidence of neutropenia was higher in patients receiving ganciclovir compared with those receiving placebo.1,284,306 In another study in bone marrow allograft recipients, patients were evaluated for presence of pulmonary CMV by bronchoscopy with bronchoalveolar lavage at days 35 and 49 after transplantation.1,271 Those patients with histologic, immunologic, or virologic evidence of asymptomatic pulmonary CMV infection were identified as at risk for developing interstitial pneumonia and randomly assigned to receive IV ganciclovir (5 mg/kg twice daily for 14 days followed by 5 mg/kg once daily 5 days per week until 120 days after transplantation) or no ganciclovir treatment.1,271 The incidence of subsequent interstitial pneumonia was lower in patients who received ganciclovir; interstitial pneumonia developed in 20% of those who received ganciclovir and 70% of those who received no antiviral therapy.1

Varicella-Zoster Virus Infections

Although optimal regimens for the management of progressive outer retinal necrosis caused by varicella-zoster virus† (VZV) in HIV-infected individuals have not been identified, CDC, NIH, and IDSA recommend treatment with at least one IV antiviral (acyclovir, ganciclovir, foscarnet, cidofovir) used in conjunction with at least one intravitreal antiviral (ganciclovir or foscarnet).155 Some experts recommend a regimen of IV ganciclovir and/or IV foscarnet used in conjunction with intravitreal† ganciclovir and/or intravitreal foscarnet.155,156 The prognosis for visual preservation in patients with progressive outer retinal necrosis caused by VZV is poor and such infections should be managed in consultation with an ophthalmologist.155,156

Reconstitution and Administration

Ganciclovir is administered by IV infusion.1,2,14

Ganciclovir should not be administered by rapid IV infusion or direct IV injection since potentially toxic plasma concentrations of the drug may result. 1,2,14

Ganciclovir should not be administered by IM or subcutaneous injection because reconstituted and diluted solutions of the drug are alkaline (pH of 11) and may cause severe tissue irritation.1,2

Ganciclovir has been administered by intravitreal injection†;4,5,8,25,67,85,117,129,135,155,170 however, a preparation of the drug specifically for intravitreal administration is not commercially available in the US.

Ganciclovir has been administered orally,85,86,321,325,347 but oral preparations of the drug are no longer commercially available in the US.

Females of childbearing potential should be tested for pregnancy prior to initiation of ganciclovir.1,2,14 (See Cautions: Pregnancy, Fertility, and Lactation.)

Renal function should be assessed prior to initiation of ganciclovir and monitored during therapy with the drug; dosage should be adjusted as necessary.1,2,14

Complete blood counts with differential and platelet counts should be performed frequently during ganciclovir therapy, especially in those who developed cytopenias during previous therapy with ganciclovir or other nucleoside analogs and in those with neutrophil counts less than 1000/mm³ prior to initiation of ganciclovir.1,2,14 (See Cautions: Hematologic Effects.)

Patients receiving ganciclovir should be adequately hydrated.1,2,14

The recommended dosage of ganciclovir and the recommended frequency and rate of administration of the drug should not be exceeded.1,2,14

IV Infusion

IV infusions of ganciclovir should be given via a large peripheral or central vein.1,4 To avoid phlebitis and pain at the IV infusion site, the drug preferably should be administered using a plastic cannula and infused into a vein that will provide adequate blood flow for rapid dilution and distribution of the drug.1,2,14

For IV infusion, single-dose vials of lyophilized ganciclovir sodium labeled as containing 500 mg of ganciclovir are reconstituted by adding 10 mL of preservative-free sterile water for injection to provide a solution containing 50 mg/mL.1 The vial should be gently swirled until the drug is completely wetted and a clear reconstituted solution is obtained.1 Bacteriostatic water for injection containing parabens should not be used to reconstitute ganciclovir sodium.1 (See Chemistry and Stability: Stability.) The appropriate dose of reconstituted solution should then be withdrawn from the vial and diluted in a compatible IV infusion solution (usually 100 mL).1 Solutions containing ganciclovir concentrations exceeding 10 mg/mL are not recommended for IV infusion.1

Alternatively, if the commercially available ganciclovir sodium concentrate for injection for IV use containing 500 mg of ganciclovir (50 mg/mL) is used, the single-dose vial of solution should be shaken and the appropriate dose withdrawn from the vial and diluted in a compatible IV infusion solution (usually 100 mL).2 Solutions containing ganciclovir concentrations exceeding 10 mg/mL are not recommended for IV infusion.2

Alternatively, commercially available single-dose IV bags containing 500 mg of ganciclovir in 250 mL of 0.8% sodium chloride (2 mg/mL) can be used for IV infusion without further dilution.14 The premixed solution in the bag should appear clear.14 If any crystals have formed in the solution, the bag should be gently shaken to redissolve the crystals prior to use.14 Any unused portions of the premixed solution should be discarded.14

Ganciclovir solutions should be inspected visually for discoloration and particulate matter prior to administration; if either is present, the solution should be discarded.1,2,14

Ganciclovir lyophilized powder and solutions of the drug should be handled cautiously because of the high pH of some preparations and because of the mutagenic and/or carcinogenic potential of the drug (see Cautions: Mutagenicity and Carcinogenicity).1,2 The use of disposable gloves is recommended.1,2 If ganciclovir powder or solutions of the drug contact the skin or mucous membranes, the affected area should be washed immediately and thoroughly with soap and water.1,2 If the drug comes in contact with the eyes, the eyes should flushed thoroughly with water.1,2

Since ganciclovir shares some of the properties of cytotoxic drugs (i.e., mutagenicity, carcinogenicity), the manufacturers state that consideration should be given to handling and disposing the drug according to guidelines issued for cytotoxic drugs.1,2,14 For further information on the handling of cytotoxic drugs, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Rate of Administration

Ganciclovir solutions should be administered by IV infusion at a constant rate over 1 hour.1,2,14

Dosage

Ganciclovir is commercially available as the base and as ganciclovir sodium;1,2 dosage is expressed in terms of ganciclovir.1,2,14

Adult Dosage

Cytomegalovirus Retinitis

For the treatment of cytomegalovirus (CMV) retinitis in adults with normal renal function (creatinine clearance of 70 mL/minute or greater), including those with human immunodeficiency virus (HIV) infection, the recommended dosage of IV ganciclovir for initial treatment (induction therapy) is 5 mg/kg every 12 hours for 14-21 days.1,2,14,155,262 In patients with immediate sight-threatening CMV retinal lesions (i.e., within 1.5 mm of the fovea), the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and HIV Medicine Association of the Infectious Diseases Society of America (IDSA) recommend that initial treatment also include an appropriate intravitreal antiviral.155 (See Cytomegalovirus Retinitis under Uses: Treatment of Cytomegalovirus Infection and Disease.)

After completion of initial treatment, the usual dosage of IV ganciclovir for maintenance therapy (secondary prophylaxis) of CMV retinitis in adults with normal renal function is 5 mg/kg once daily.1,2,14,155 Alternatively, IV ganciclovir can be given in a dosage of 6 mg/kg once daily 5 days each week for maintenance therapy.1,2,14,262

Decisions regarding discontinuance of maintenance therapy of CMV retinitis in HIV-infected individuals who have received CMV treatment for at least 3-6 months, have inactive CMV retinal lesions, and have achieved immune reconstitution as the result of antiretroviral therapy should be made in consultation with an ophthalmologist.155 (See Cytomegalovirus Retinitis under Uses: Treatment of Cytomegalovirus Infection and Disease.)

Cytomegalovirus Esophagitis or Colitis

For the treatment of CMV GI infections† in adults with normal renal function, a ganciclovir dosage of 5 mg/kg IV every 12 hours for 14-21 days has been used for initial treatment (induction); alternatively, a dosage of 2.5 mg/kg IV every 8 hours also has been used.6,8,11,13,15,16,20,33,68,70,92,110,140,145,146 If maintenance therapy is required, dosages comparable to those used for maintenance therapy of CMV retinitis have been used.6,11

For the management of CMV esophagitis† or colitis† in HIV-infected adults, CDC, NIH, and IDSA recommend that IV ganciclovir be given in a dosage of 5 mg/kg every 12 hours and state that a switch to oral valganciclovir can be made after the patient can absorb and tolerate oral therapy.155 These experts recommend that antiviral therapy be continued for 21-42 days or until signs and symptoms of the infection have resolved.155 Maintenance therapy (secondary prophylaxis) usually is not necessary, but should be considered if relapse occurs.155

Cytomegalovirus Pneumonitis

For the treatment of CMV pneumonitis† in adults with normal renal function, a ganciclovir dosage of 5 mg/kg IV every 12 hours for 14-21 days has been used for initial treatment (induction); alternatively, a dosage of 2.5 mg/kg IV every 8 hours also has been used.8,11,13,15,16,20,33,68,70,110,140,145,146 If maintenance therapy is required, dosages comparable to those used for maintenance therapy of CMV retinitis have been used.11

If IV ganciclovir is used for the management of well-documented CMV pneumonitis† in HIV-infected adults, CDC, NIH, and IDSA state that the same dosage recommended for the management of CMV retinitis in HIV-infected adults should be used.155 The optimal duration of treatment in such patients has not been established.155

Cytomegalovirus Neurologic Disease

If IV ganciclovir is used for the management of CMV neurologic disease† in HIV-infected adults, CDC, NIH, and IDSA state that the same dosage recommended for the management of CMV retinitis in HIV-infected adults should be used in conjunction with IV foscarnet.155 The optimal duration of treatment in such patients has not been established.155

Prevention of Cytomegalovirus Infection and Disease in Transplant Recipients

For prophylaxis to prevent CMV infection and disease in transplant recipients with normal renal function, the manufacturers recommend that IV ganciclovir be given in a dosage of 5 mg/kg every 12 hours for 7-14 days followed by a maintenance dosage of 5 mg/kg once daily 7 days each week or 6 mg/kg once daily 5 days each week.1,2,14 Prophylaxis should be continued until 100-120 days posttransplantation.1,2,14

Some experts recommend that IV ganciclovir be given in a dosage of 5 mg/kg once daily for prophylaxis of CMV infection and disease in transplant recipients with normal renal function.76,81,82 These experts recommend that antiviral prophylaxis be continued for 3 months in CMV-seropositive recipients of solid organs (kidney, pancreas, kidney/pancreas, liver, heart) and for 3-6 months in CMV-seronegative recipients of solid organs (kidney, pancreas, kidney/pancreas, liver, heart) from CMV-seropositive donors.81,82

If IV ganciclovir is used for preemptive treatment of CMV infection in solid organ transplant recipients†, a dosage of 5 mg/kg twice daily is recommended in those with normal renal function.82

Varicella-Zoster Virus Infections

For the management of progressive outer retinal necrosis caused by varicella-zoster virus† (VZV) in HIV-infected adults, CDC, NIH, and IDSA state that a regimen that includes IV ganciclovir in a dosage of 5 mg/kg every 12 hours (used with or without IV foscarnet) in conjunction with intravitreal ganciclovir† (used with or without intravitreal foscarnet) can be considered.155

Pediatric Dosage

Cytomegalovirus Retinitis

For initial treatment (induction therapy) of CMV retinitis in pediatric patients†, including HIV-infected children†, CDC, NIH, IDSA, and others recommend that IV ganciclovir be given in a dosage of 5 mg/kg IV every 12 hours for 14-21 days (may be increased to 7.5 mg/kg every 12 hours if needed).156,292 After completion of initial treatment, these experts recommend that pediatric patients receive IV ganciclovir in a dosage of 5 mg/kg once daily for 5-7 days each week for maintenance therapy (secondary prophylaxis).156,292

Decisions regarding discontinuance of maintenance therapy of CMV retinitis in HIV-infected individuals who have inactive CMV retinal lesions and have achieved immune reconstitution as the result of antiretroviral therapy should be made in consultation with an ophthalmologist.156 (See Cytomegalovirus Retinitis under Uses: Treatment of Cytomegalovirus Infection and Disease.)

CNS or Disseminated Cytomegalovirus Infections

For initial treatment (induction therapy) of CNS infections caused by CMV in HIV-infected children†, CDC, NIH, IDSA, and others recommend that IV ganciclovir be given in a dosage of 5 mg/kg every 12 hours in conjunction with IV foscarnet.156 Initial treatment should be continued until symptomatic improvement.156

For initial treatment (induction therapy) of disseminated CMV infections in HIV-infected children†, CDC, NIH, IDSA, and others state that IV ganciclovir be given in a dosage of 5 mg/kg IV every 12 hours (may be increased to 7.5 mg/kg every 12 hours if needed).156 Initial treatment should be continued for 14-21 days.156

After completion of initial treatment, the recommended dosage of IV ganciclovir for maintenance therapy (secondary prophylaxis) of CNS or disseminated CMV infections in HIV-infected children† is 5 mg/kg once daily for 5-7 days each week.156

Congenital Cytomegalovirus Disease

If IV ganciclovir is used for the management of symptomatic congenital CMV disease† when an antiviral is indicated (see Congenital Cytomegalovirus Disease under Uses: Treatment of Cytomegalovirus Infection and Disease), the American Academy of Pediatrics (AAP) and other clinicians recommend a dosage of 6 mg/kg twice daily.84,292,350

AAP and other clinicians recommend that, if an antiviral is indicated, it should be initiated within the first month of life and continued for a total of 6 months.84,292 If IV ganciclovir is used initially, treatment should be transitioned to oral valganciclovir when the infant is able to tolerate and absorb oral drugs.84,292

Prevention of Cytomegalovirus Infection and Disease in Transplant Recipients

For prophylaxis to prevent CMV infection and disease in pediatric transplant recipients†, some clinicians recommend that IV ganciclovir be given in a dosage of 5 mg/kg every 12 hours for 5-7 days (or 7-14 days) followed by a maintenance regimen of 5 mg/kg once daily 7 days each week or 6 mg/kg once daily 5 days each week.292,350 Prophylaxis should be continued for 100-120 days posttransplantation.292,350

Other clinicians recommend that IV ganciclovir be given in a dosage of 5 mg/kg once daily for prophylaxis in pediatric transplant recipients† and that antiviral prophylaxis be continued for 3 months or longer depending on the immune status of the recipient and type of transplant.81

If IV ganciclovir is used for preemptive treatment of CMV infection in pediatric patients†, a dosage of 5 mg/kg twice daily for 7-14 days followed by 5 mg/kg once daily has been recommended.292

Varicella-Zoster Virus Infections

For the management of progressive outer retinal necrosis caused by VZV in HIV-infected children†, CDC, NIH, IDSA, and others state that a regimen that includes IV ganciclovir given in a dosage of 5 mg/kg every 12 hours (used with IV foscarnet) in conjunction with intravitreal ganciclovir† (used with or without intravitreal foscarnet) can be considered.156

Dosage in Renal Impairment

In patients with impaired renal function, doses and/or frequency of administration of ganciclovir must be modified in response to the degree of impairment.1,2,14

Dosage should be based on the patient's measured or estimated creatinine clearance.1,2,14 The patient's creatinine clearance (Ccr) can be estimated by using the following formulas:

Ccr male = [(140 - age) × weight (in kg)] / [72 × serum creatinine (in mg/dL)]

Ccr female = 0.85 × Ccr male

When IV ganciclovir is used for the management of CMV retinitis in adults with renal impairment, the manufacturers recommend the following dosage for initial treatment (induction therapy) and maintenance therapy (secondary prophylaxis) based on creatinine clearance.1,2,14 (See Table 1.)

In adults undergoing hemodialysis, dosage of IV ganciclovir for initial treatment (induction therapy) of CMV retinitis should not exceed 1.25 mg/kg 3 times weekly and dosage for maintenance therapy should not exceed 0.625 mg/kg 3 times weekly.1,2,14 Because hemodialysis may reduce ganciclovir plasma concentrations by approximately 50% (see Pharmacokinetics: Elimination),1,2,14,60,124 dosing of the drug should be timed so that doses administered on the days of dialysis are given shortly after completion of dialysis.1,2,14

Adverse reactions to ganciclovir occur frequently,1,3,5,8,9,11,12,13,21,23,33,59,72,75,85,91,92,94,100,102,103,104,105,106,107,108,109,110,118,122,127,128,131,133,136,140,149,151,164,172,174,188,201,205,206,207,209,225,243,248 but usually are reversible following discontinuance of therapy with the drug.3,5,8,85,100,102,104,105,106,122,140,164 Because most patients receiving ganciclovir have serious underlying disease with multiple baseline symptomatology and clinical abnormalities and are receiving multiple drugs concomitantly and because clinical studies generally did not include a placebo control, it is difficult to establish whether a causal relationship to ganciclovir exists for many reported adverse effects.6,8,11,20,64,106,122,159

Adverse effects reported in 20% of more of patients receiving ganciclovir in clinical trials include hematologic effects (leukopenia, neutropenia, thrombocytopenia, anemia), pyrexia, GI effects (diarrhea, nausea, decreased appetite, abdominal pain), catheter-associated effects (sepsis), hyperhidrosis, asthenia, headache, cough, dyspnea, and increased creatinine concentrations.1,2,14 In clinical trials evaluating ganciclovir in patients with cytomegalovirus (CMV) retinitis, adverse reactions necessitated discontinuance of the drug in 9% of patients.1

Hematologic Effects

Hematologic toxicity, including granulocytopenia (neutropenia), anemia, thrombocytopenia, and pancytopenia, have been reported in patients receiving ganciclovir.1 Hematologic effects, which may be severe, are one of the most common adverse reactions to the drug.1,3,5,8,9,11,13,21,23,33,72,85,92,94,100,102,103,104,105,106,107,108,109,110,118,122,127,128,131,133,136,140,149,151,164,172,188,201,205,206,207,243,248

Neutropenia (absolute neutrophil count less than 1000/mm³), which is potentially fatal,3,4,85,122 has been reported in up to 25-60% of patients receiving ganciclovir and is the most common dose-limiting adverse effect of the drug.1,3,4,5,8,9,11,13,20,21,23,33,72,85,92,94,100,102,103,104,105,106,107,108,109,118,122,127,131,133,136,140,149,151,164,188,201,205,206,207,225,243,248 Absolute neutrophil count declines to less than 500/mm³ in approximately 15-25% of patients receiving the drug for the treatment of CMV infection.1,3,8,92,122 Granulocytopenia (neutropenia) usually develops early in treatment (e.g., during the first or second week of induction therapy),1,3,5,20,23,66,85,122 but can occur at any time.1,5,20,23,66 In most cases, interruption of ganciclovir therapy3,4,8,23,66,85,92,122,149,248 or a decrease in dosage4,6,8,140,149,248 will result in increased neutrophil counts, which usually is evident within 3-7 days; however, prolonged or irreversible neutropenia has occurred,3,4,66,92,122,174 and bacterial or fungal sepsis and subsequent death have been reported occasionally in patients with ganciclovir-induced neutropenia.3,4,66,122,174 Neutropenia has recurred following reinitiation of ganciclovir therapy,3,33 occasionally even at reduced dosage.3 If severe neutropenia (absolute neutrophil count less than 500/mm³) occurs, ganciclovir therapy is not recommended.1

Patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) may be at greater risk of developing neutropenia compared with other immunosuppressed patients receiving the drug.3,108,151 There also is limited evidence to suggest that bone marrow transplant (BMT) recipients may be at greater risk than organ transplant recipients for developing ganciclovir-induced neutropenia, but the possibility exists that other factors (e.g., concurrently administered drugs) may have contributed to the observed differences.20 In controlled studies in patients who received IV ganciclovir for prevention of CMV disease following transplantation, the absolute neutrophil count decreased to 1000/mm³ or less in 7% of cardiac allograft recipients (mean duration of IV ganciclovir 28 days) and in 41% of bone marrow allograft recipients (mean duration of IV ganciclovir 45 days); 11% of cardiac allograft recipients who received placebo and 23% of bone marrow allograft recipients who did not receive ganciclovir therapy also had neutrophil counts this low.1

Thrombocytopenia1,3,8,11,21,33,75,85,109,110,122,133,149,172,248,264,265 occurs frequently in patients receiving ganciclovir, developing in approximately 20% of patients who receive the drug.3,8,11,21,33,75,85,109,110,122,133,149,172,248 Interruption of ganciclovir therapy or a decrease in dosage usually results in increased platelet counts.4,149,248 Patients with low baseline platelet counts (less than 100,000/mm³) appear to be more prone to develop this reaction.33,109,122 In addition, patients who are iatrogenically immunosuppressed appear to be at greater risk than AIDS patients of developing thrombocytopenia,1,3,122,225 which occurred in 46 and 14% of such patients, respectively, in one study.1 In controlled studies in patients who received IV ganciclovir for prevention of CMV disease following transplantation, platelet counts decreased to less than 25,000/mm³ in 3% of cardiac allograft recipients (mean duration of IV ganciclovir 28 days) and in 32% of bone marrow allograft recipients (mean duration of IV ganciclovir 45 days); 1% of cardiac allograft recipients who received placebo and 28% of bone marrow allograft recipients who did not receive ganciclovir therapy in these studies also had platelet counts this low.1 If the platelet count declines to less than 25,000/mm³, ganciclovir therapy is not recommended.1

Leukopenia has been reported in 41% and anemia has been reported in 25% of patients receiving ganciclovir for maintenance therapy of CMV retinitis.1 Anemia with hemoglobin concentrations less than 6.5 g/dL occurred in 5% of patients.1 If hemoglobin concentrations decline to less than 8 g/dL, ganciclovir therapy is not recommended.1

Pancytopenia and bone marrow failure have been reported in clinical studies in patients receiving ganciclovir for the treatment of CMV retinitis or in transplant recipients receiving the drug for prophylaxis of CMV.1 Hemolytic anemia, agranulocytosis, and granulocytopenia have been reported during postmarketing experience in patients receiving ganciclovir.1

Although experience is limited,4,5,25,129,135,170 intravitreal injection† of ganciclovir does not appear to be associated with appreciable systemic toxicity and this route has been suggested as an alternative to IV ganciclovir in patients with CMV retinitis in whom hematologic toxicity is not tolerated.4,5,25,129,135,170,262,264,265

Ganciclovir-induced neutropenia and thrombocytopenia appear to result from a direct, dose-dependent myelotoxic effect of the drug.1,3,85,96,113,133 This effect probably results from nonspecific activation of the drug by cellular (host cell) enzymes and subsequent inhibition of cellular DNA synthesis, particularly in rapidly dividing cells (e.g., in bone marrow).1,21,48,113 In vitro, ganciclovir has been shown to exhibit dose-dependent inhibitory effects on both myeloid and erythroid human progenitor cells, with erythroid precursors being slightly less sensitive than myeloid precursors to the cytotoxic effects.96 In one in vitro study, ganciclovir exhibited substantial and acyclovir minimal cytotoxic effects as determined by inhibition of colony formation of human granulocyte-macrophage precursors, which could in part explain the apparent differences in in vivo hematologic toxicity of these drugs.96,262

Careful monitoring for potential hematologic toxicity is necessary during ganciclovir therapy.1 (See Cautions: Precautions and Contraindications.)

Ocular Effects

Rhegmatogenous retinal detachment has been reported in patients with CMV retinitis, both before and after initiation of ganciclovir therapy;1,71,94,105,127,167,172,177,203,244 however, the relationship between ganciclovir and retinal detachment is not known.1 Such detachment is thought to result from the hastening of the involutional stage of the disease in which the retina thins as necrotic tissue is mobilized and edema fluid resorbs;94,105,244 these changes predispose the retina to tears and detachment.94,105,244 Retinal detachment has been reported in 11-30% of ganciclovir-treated patients with CMV retinitis.1,94,105,127,166,177,203 This complication appears to occur more frequently in AIDS patients than in other immunosuppressed patients and may be related to the inability of AIDS patients to form firm scar tissue, secondary to impaired inflammatory responses, as the retina heals.125,203,244

Intravitreal injection† of ganciclovir (0.05-0.1 mL of a solution containing 2-8 mg/mL) did not produce any apparent oculotoxic effects in animal studies or in a limited number of patients being treated for CMV retinitis.4,25,67,87,129,135,170,253,264,265 In one study in several patients with CMV retinitis, there was no evidence during 77-244 days of observation of oculotoxic effects (e.g., lens changes, anterior segment or vitreal inflammation, retinal detachment) associated with intravitreal injection of 9-30 (mean: 16.6) doses of the drug per eye.129 In a study in rabbits, intravitreal injection of single ganciclovir doses ranging from 10-400 mcg at concentrations of 1-20 mcg/mL produced no discernible ophthalmologic or histologic changes in the eye or in electroretinographic B waves.87

Although intravitreal injection† of ganciclovir has been well tolerated, local reactions, such as foreign body sensation,129 small conjunctival129 or vitreal170 hemorrhage, and mattering,129 have been associated with such administration. In addition, conjunctival scarring and scleral induration have been observed occasionally in patients receiving multiple intravitreal injections of the drug.129 Staphylococcal endophthalmitis, which responded to intravitreal antibacterial therapy alone or combined with systemic therapy, has been reported in several patients receiving intravitreal ganciclovir.129,264 In addition, rhegmatogenous retinal detachment occurred in several patients during intravitreal injection; while this complication also has been associated with IV ganciclovir therapy, the possibility exists that local trauma associated with intravitreal injection may have contributed to its occurrence in these patients.135,264

Nervous System Effects

Adverse nervous system effects, including headache, insomnia, dizziness, paresthesia, hypoesthesia, seizures, somnolence, and tremor, have been reported in clinical studies in patients receiving ganciclovir for the treatment of CMV retinitis or in transplant recipients receiving the drug for prophylaxis of CMV.1 Peripheral neuropathy has been reported in 9% of patients receiving IV ganciclovir for maintenance therapy of CMV retinitis.1 Dysesthesia, dysphasia, extrapyramidal disorder, facial paralysis, amnesia, anosmia, myelopathy, cerebrovascular accident, third cranial nerve paralysis, aphasia, encephalopathy, and intracranial hypertension have been reported during postmarketing experience in patients receiving ganciclovir.1 In some cases, observed nervous system effects may have resulted from causes other than the drug itself, such as opportunistic infections (e.g., toxoplasmosis,6,10,31,106,207 cryptococcosis)6,21,31,165 or HIV encephalopathy,6,8,18,106 and this possibility should be considered in any ganciclovir-treated patient who develops such effects.3,6,23,207

Psychiatric disorders, including depression, confused state, anxiety, agitation, psychotic disorder, abnormal thinking, and abnormal dreams, have been reported in clinical studies in patients receiving ganciclovir for the treatment of CMV retinitis or in transplant recipients receiving the drug for prophylaxis of CMV.1 Irritability and hallucinations have been reported during postmarketing experience in patients receiving ganciclovir.1

GI Effects

Diarrhea,1 decreased appetite,1 and vomiting1,3,8,11,21,122 have been reported in 44, 14, and 13%1,3 of patients, respectively, receiving IV ganciclovir for maintenance treatment of CMV retinitis.1 Other adverse GI effects that have been reported in clinical studies in patients receiving ganciclovir for the treatment of CMV retinitis or in transplant recipients receiving the drug for prophylaxis of CMV include nausea,1 GI perforation,1 abdominal pain,1 dyspepsia,1 flatulence,1 constipation,1 mouth ulceration,1 dysphagia,1 abdominal distention,1 pancreatitis,1 eructation,1 dysgeusia,1 and dry mouth.1 Intestinal ulcer has been reported during postmarketing experience in patients receiving ganciclovir.1

Renal and Genitourinary Effects

Increased serum creatinine concentrations have been reported when IV ganciclovir was used in geriatric patients or in transplant patients, including transplant patients receiving concomitant therapy with nephrotoxic drugs (e.g., cyclosporine, amphotericin B).1 In a placebo-controlled study in cardiac allograft recipients, increased serum creatinine concentrations (2.5 mg/dL or greater) occurred in 18% of those receiving IV ganciclovir and 4% of those receiving placebo.1 In a study in bone marrow allograft recipients, 20% of patients receiving ganciclovir had serum creatinine concentrations of 2.5 mg/dL or greater whereas no patients receiving placebo had these increased concentrations.1 In a study in bone marrow allograft recipients, increased serum creatinine concentrations were not reported in patients receiving ganciclovir.1

Kidney failure,1 abnormal renal function,1 urinary frequency,1 and hematuria1 have been reported in clinical studies in patients receiving ganciclovir for the treatment of CMV retinitis or in transplant recipients receiving the drug for prophylaxis of CMV.1 Renal tubular disorder and hemolytic uremic syndrome have been reported during postmarketing experience in patients receiving ganciclovir.1

Local Effects

Inflammation, edema, phlebitis, and/or pain at the site of IV infusion have been reported in patients receiving ganciclovir1,21,122,133 and probably are related to the high pH of the infusion solution.1 (See Dosage and Administration: Reconstitution and Administration.) To minimize the risk of phlebitis, the use of a vein with adequate blood flow is recommended to allow for rapid dilution and distribution of the drug.1,8

Infection at the IV catheter site and other catheter-associated events (e.g., sepsis) have been reported in patients receiving IV ganciclovir.1

Intravitreal injection† of ganciclovir in a limited number of animals and humans did not appear to produce oculotoxic effects,4,25,67,87,129,135,170,253 although other local ocular effects occasionally were observed.129,135,170 (See Cautions: Ocular Effects.)

Other Adverse Effects

Pyrexia has been reported in 48% of patients receiving IV ganciclovir for maintenance therapy of CMV retinitis.1 Other adverse effects reported in 5-13% of patients receiving IV ganciclovir include sepsis,1 infection,1 hyperhidrosis,1 chills,1 and pruritus.1

Hypersensitivity, including anaphylactic or allergic reactions, have been reported in patients receiving ganciclovir.1

Precautions and Contraindications

Ganciclovir is contraindicated in patients who have had a clinically important hypersensitivity reaction (e.g., anaphylaxis) to ganciclovir, valganciclovir, or any component of the formulation.1,2,14

Because ganciclovir therapy is associated with hematologic toxicity (e.g., neutropenia, anemia, and/or thrombocytopenia), complete blood counts with differential and platelet counts should be monitored frequently in all patients,1,2,14,20,279 especially in those with renal impairment, baseline neutrophil counts less than 1000/mm³, or a history of leukopenia during treatment with ganciclovir or other nucleoside analogs and in those receiving myelosuppressive drugs or radiation therapy.1,2,14 Ganciclovir is not recommended in patients with absolute neutrophil counts less than 500/mm³, platelet counts less than 25,000/mm³, or hemoglobin concentrations less than 8 g/dL.1,2,14 Patients should be informed about the potential hematologic toxicities of the drug and the importance of close monitoring of blood cell counts.1,2,14

Because plasma concentrations and half-life of ganciclovir are increased in patients with renal impairment, the drug should be used with caution in such patients and dosage should be adjusted based on the degree of renal impairment.1,2,14 (See Dosage and Administration: Dosage in Renal Impairment.) Renal function monitoring is essential in all patients receiving ganciclovir therapy, especially in geriatric patients and in transplant recipients receiving concomitant nephrotoxic drugs (e.g., cyclosporine, amphotericin B).1,2,14 (See Drug Interactions.) Patients receiving ganciclovir should be adequately hydrated since the drug is almost entirely excreted renally and normal clearance depends on adequate renal function.1,2,14,5,6,9,11,28 Patients should be informed that ganciclovir has been associated with decreased renal function and that serum creatinine concentrations or creatinine clearance should be monitored during treatment with the drug and that dosage adjustments are necessary in patients with renal impairment.1,2,14

Safety and efficacy of ganciclovir have not been evaluated in patients with hepatic impairment.1,2,14

Frequent ophthalmologic examinations are necessary in patients being treated for CMV retinitis to monitor status of the CMV retinitis and assess for other retinal abnormalities.1,2,14 Patients should be informed that ganciclovir is not a cure for CMV retinitis and that they may continue to experience progression and/or recurrence of the retinitis during or following treatment with the drug.1 Patients also should be advised about the necessity of frequent ophthalmologic examinations and that some patients may require more frequent ophthalmologic follow-up.1,2,14

Patients should be advised that ganciclovir may cause seizures, dizziness, and/or confusion, which may affect cognitive abilities (e.g., ability to drive or operate machinery).1,2,14

Patients should be advised that animal data suggest that ganciclovir is a potential carcinogen.1,2,14 (See Cautions: Mutagenicity and Carcinogenicity.)

Patients should be advised that ganciclovir may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females.1,2,14 (See Cautions: Pregnancy, Fertility, and Lactation.)

Because of the mutagenic potential of ganciclovir and the potential for fetal harm, women of reproductive potential should undergo pregnancy testing before initiation of ganciclovir.1 In addition, females of childbearing potential should use effective contraception during and for at least 30 days after ganciclovir therapy and male patients should use barrier contraceptive methods during and for at least 90 days after ganciclovir therapy.1,2,14,262 (See Cautions: Pregnancy, Fertility, and Lactation.)

Pediatric Precautions

Safety and efficacy of ganciclovir have not been established in pediatric patients.1,2,14

Granulocytopenia and thrombocytopenia were the most common adverse effects reported in pediatric patients† who received ganciclovir in clinical trials.1

Although the pharmacokinetics of IV ganciclovir reported in pediatric patients are similar to those reported in adults (see Pharmacokinetics), safety and efficacy of such ganciclovir exposures in pediatric patients have not been established.1

Geriatric Precautions

Clinical studies of ganciclovir did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger adults.1,2,14 Dosage in geriatric patients generally should be selected carefully, taking into account the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in the elderly.1,2

Because geriatric patients may have decreased renal function and because patients with renal impairment may be at increased risk of ganciclovir-induced toxicity, particular attention should be paid to evaluating renal function prior to and during ganciclovir therapy in this age group.1,2,14 If evidence of renal impairment exists or develops, appropriate dosage adjustments should be made.1,2,14 (See Dosage and Administration: Dosage in Renal Impairment.)

Mutagenicity and Carcinogenicity

Based on animal data, ganciclovir should be considered a potential carcinogen in humans.1,2,14

Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro at concentrations between 50-500 and 250-2000 mcg/mL, respectively. 1 In the mouse micronucleus assay, ganciclovir was clastogenic at doses of 150 and 500 mg/kg (2.8-10 times exposures attained in humans with the recommended human dose), but such effects were not observed at doses comparable to the recommended human dose.1 Ganciclovir was not mutagenic in the Ames Salmonella assay at concentrations of 500-5000 mcg/mL.1

Ganciclovir was carcinogenic in mice at mean drug exposures equal to those attained in humans with the recommended dose of 5 mg/kg.1 At exposures 1.4 times the human exposure at the recommended human dose, there was a significant increase in the incidence of tumors of the preputial gland in males, forestomach (nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus, mammary gland, clitoral gland, vagina) and liver in females.1 At exposures 0.1 times the human exposure at the recommended human dose, there was a slightly increased incidence of tumors in the preputial and harderian glands in males, forestomach in males and females, and liver in females.1 Carcinogenic effects were not observed in mice at exposures estimated to be 0.01 times those attained in humans with the recommended human dose.1

Pregnancy, Fertility, and Lactation

Pregnancy

Animal data indicate that ganciclovir has the potential to cause fetal toxicity, including birth defects, in humans.1,2,14 Data regarding use of ganciclovir in pregnant women are inadequate to establish whether the drug poses a risk to pregnancy outcomes.1,2,14 Ganciclovir appears to cross the placenta based on ex vivo experiments with human placenta and at least one case report in a pregnant woman.1,2,14

In animal studies, ganciclovir caused maternal and fetal toxicity and embryofetal mortality in pregnant mice and rabbits and teratogenic effects in rabbits at systemic exposures that were approximately 2 times those attained in humans at the recommended human dose.1,2,14 IV ganciclovir administered to pregnant mice (108 mg/kg daily) and rabbits (60 mg/kg daily) and administered to female mice (90 mg/kg) prior to mating, during gestation, and during lactation resulted in fetal resorptions in at least 85% of the mice and rabbits.1,2,14 Fetal growth retardation, embryolethality, and teratogenic effects (cleft palate, anophthalmia/microphthalmia, hydrocephaly, brachygnathia, aplastic organs [kidney, pancreas]) were reported in the rabbits.1,2,14 In pre/postnatal development studies in mice, maternal/fetal toxicity and embryolethality were observed and included hypoplasia of the testes and seminal vesicles in male offspring, as well as pathologic changes in the nonglandular region of the stomach.1,2,14

Although most maternal CMV infections are asymptomatic or may be associated with a self-limited mononucleosis-like syndrome, CMV infections in pregnant immunocompromised patients (e.g., HIV-infected patients with AIDS, transplant recipients) may be symptomatic and result in substantial maternal morbidity and mortality.1,2,14 Perinatal transmission of CMV from an infected mother to her fetus can occur resulting in congenital CMV infection and disease.1,2,14 (See Congenital Cytomegalovirus Disease under Uses: Treatment of Cytomegalovirus Infection and Disease.)

Females of childbearing potential should undergo pregnancy testing before initiation of ganciclovir.1,2,14

Females of childbearing potential should use effective contraception during and for at least 30 days after ganciclovir therapy and male patients should use effective barrier contraceptive methods during and for at least 90 days after ganciclovir therapy.1,2,14

Fertility

Based on animal data and limited human data, ganciclovir at the usually recommended dosages may cause temporary or permanent inhibition of spermatogenesis in men and may cause suppression of fertility in women.1,2,14

In female mice, ganciclovir caused decreased mating behavior, decreased fertility, and increased incidence of embryolethality at exposures approximately 1.7 times those attained in humans at the recommended human dose.1,2,14 Ganciclovir caused decreased fertility in male mice and hypospermatogenesis in male mice and dogs following oral or IV doses ranging from 0.2-10 mg/kg.1,2 Systemic exposures at the lowest dose associated with toxicity in each species ranged from 0.03-0.1 times the human exposures attained with the recommended human dose.1,2

In a small, open-label, nonrandomized clinical study, adult male renal transplant patients receiving CMV prophylaxis with valganciclovir (prodrug of ganciclovir) for up to 200 days posttransplantation were followed for 6 months after the drug was discontinued and data compared with an untreated control group.1,2 Among 24 evaluable patients in the valganciclovir group, the mean sperm density at the end-of-treatment visit was decreased by 11 million/mL from baseline; whereas, among 14 evaluable patients in the control group, the mean sperm density at the end-of-treatment visit had increased by 33 million/mL.1,2 However, at the final follow-up visit, the mean sperm density among 20 evaluable patients in the valganciclovir group was comparable to that observed among 10 evaluable patients in the untreated control group (mean sperm density increased by 41 or 43 million/mL from baseline, respectively).1,2

Patients receiving ganciclovir should be advised that the drug may be associated with infertility.1,2,14

Lactation

It is not known whether ganciclovir is distributed into human milk, affects the breast-fed infant, or affects milk production.1,2,14 The drug is distributed into milk in lactating rats;1,2,14 the milk-to-serum ratio at steady state is approximately 1.6 in rats.1,2,14

Because of the potential for serious adverse reactions to ganciclovir in breast-fed infants, nursing women should be instructed not to breast-feed while they are receiving the drug.1,2,14 HIV-infected mothers should be instructed not to breast-feed their infants because of the risk of transmission of HIV.1,2,14

Drug interaction studies with ganciclovir were performed in patients with normal renal function.1 In patients with renal impairment, concomitant use of ganciclovir and other drugs eliminated by renal excretion may result in increased concentrations of ganciclovir and the concomitant drug and such patients should be closely monitored for toxicity associated with ganciclovir and the concomitant drug.1

Antibacterial Agents

Imipenem and Cilastatin Sodium

Generalized seizures have occurred in several patients who received concomitant therapy with the fixed combination of imipenem and cilastatin sodium (imipenem/cilastatin) and ganciclovir.1,3 While the mechanism of this potential interaction is not known, the seizures resolved in all but one patient when both imipenem/cilastatin and ganciclovir or just imipenem/cilastatin was discontinued.3 In the patient whose seizures failed to resolve following discontinuance of imipenem/cilastatin, continued seizures were attributed to encephalitis rather than the drugs.3

Because of the risk of seizures, concomitant use of imipenem/cilastatin and ganciclovir is not recommended.1

Trimethoprim

Concomitant use of trimethoprim and oral ganciclovir (no longer commercially available in the US) did not affect the pharmacokinetics of either drug.1

Because of possible increased toxicity, concomitant use of trimethoprim and ganciclovir should be considered only if potential benefits outweigh risks.1

Other Antibacterials

Because of possible increased toxicity if ganciclovir is used with certain anti-infectives (e.g., co-trimoxazole, dapsone, pentamidine, sulfamethoxazole), concomitant use of ganciclovir and such anti-infectives should be considered only if potential benefits outweigh risks.1

Antifungal Agents

Amphotericin B

Concomitant use of amphotericin B and ganciclovir may result in increased serum creatinine concentrations.1

Renal function should be monitored if amphotericin B and ganciclovir are used concomitantly.1

Flucytosine

Because of possible increased toxicity, concomitant use of flucytosine and ganciclovir should be considered only if potential benefits outweigh risks.1

Antiretroviral Agents

Didanosine

Although the clinical importance is unclear, there is some in vitro evidence that ganciclovir may antagonize the antiretroviral activity of didanosine against human immunodeficiency virus (HIV).85,294

Concomitant use of didanosine (200 mg every 12 hours) with IV ganciclovir (5 mg/kg twice daily) has resulted in a 70% increase in the area under the plasma concentration-time curve (AUC_0-12) and 49% increase in peak plasma concentrations of didanosine, but did not affect the pharmacokinetics of ganciclovir.1

Patients receiving didanosine and ganciclovir concomitantly should be monitored closely for didanosine toxicity (e.g., pancreatitis).1,347

Tenofovir

Concomitant use of ganciclovir and tenofovir alafenamide or tenofovir disoproxil fumarate may result in increased serum concentrations of ganciclovir and/or tenofovir and patients should be monitored for dose-related tenofovir toxicities.200

Zidovudine

Although the clinical importance is unclear, there is some in vitro evidence that ganciclovir may antagonize the antiretroviral activity of zidovudine against HIV.85,294

Concomitant use of zidovudine with ganciclovir can increase the risk of hematologic toxicity.1,25,83,200,295 Both zidovudine and ganciclovir alone produce direct, dose-dependent inhibitory effects on myeloid and erythroid progenitor cells,96 and combined use of the drugs may result in additive or synergistic myelotoxic effects.25,83,135,170,295 In several studies in patients with acquired immunodeficiency syndrome (AIDS) and cytomegalovirus (CMV) infection, profound, intolerable myelosuppression, evidenced principally as severe neutropenia, occurred in all patients receiving oral zidovudine (200 mg every 4 hours) concomitantly with IV ganciclovir (5 mg/kg 1-4 times daily);18,267 anemia also occurred in many of these patients.18,267 Severe hematologic toxicity, which required a reduction in zidovudine dosage, also occurred in more than 80% of patients receiving oral zidovudine (100 mg every 4 hours) concomitantly with IV ganciclovir (5 mg/kg 1-2 times daily).267 Several other patients with initially stable hematologic findings on ganciclovir alone, developed prolonged pancytopenia during concomitant therapy with oral zidovudine and IV ganciclovir.83,126 The increased risk of hematologic toxicity does not appear to be related to a pharmacokinetic interaction between ganciclovir and zidovudine.83,267

Because of the risk of hematologic toxicity, concomitant use of zidovudine and ganciclovir should be considered only if potential benefits outweigh risks.1,18,25,83,87,96,126,129,133,135,170,187,293,295 If combined therapy is considered necessary, the drugs should be used with extreme caution and careful monitoring of hematologic function.83,293

Antiviral Agents

Foscarnet

Concomitant use of ganciclovir and foscarnet does not affect the pharmacokinetics of either drug.352 However, ganciclovir and foscarnet are physically incompatible and must not be admixed.352

Foscarnet has exhibited additive or synergistic antiviral activity with ganciclovir in vitro against CMV and herpes simplex virus type 2 (HSV-2).85,274,275,276,277,278 There was no in vitro evidence of antagonistic antiviral effects between ganciclovir and foscarnet. 352

In addition, combined therapy with the drugs may be effective in the treatment of CMV infection resistant to either drug alone.277,278,310,312 In several AIDS patients with CMV retinitis and/or GI infections that progressed during therapy with either ganciclovir or foscarnet alone, concomitant use of the drugs appeared to effectively reduce the symptoms and halt progression of the disease.310,312 Concomitant therapy was effective in some patients who previously had received monotherapy with both drugs.310 Although the incidence of anemia during concomitant therapy was higher than that reported during use of ganciclovir alone, adverse effects were not severe enough to require discontinuance of concomitant therapy.310,312

Letermovir

In vitro, there was no evidence of antagonistic anti-CMV effects between letermovir and ganciclovir.351

Immunosuppressive Agents

Patients receiving immunosuppressive agents (e.g., azathioprine, cyclosporine, corticosteroids) may require decreased dosages or temporary withdrawal of these drugs during ganciclovir therapy to prevent excessive suppression of bone marrow or the immune system.15,19,140,188,193,202,219,262

Cyclosporine

When oral cyclosporine at therapeutic doses was used concomitantly with IV ganciclovir (5 mg/kg every 12 hours) in liver allograft recipients, there was no evidence of any change in cyclosporine whole blood concentrations.1 However, concomitant use of these drugs may increase serum creatinine concentrations.1

If ganciclovir is used concomitantly with cyclosporine, renal function should be monitored.1

Mycophenolate Mofetil

Concomitant use of mycophenolate mofetil and ganciclovir in patients with normal renal function does not affect the pharmacokinetics of either drug.1

Because of possible increased risk, the patient should be monitored for hematologic and renal toxicity if mycophenolate mofetil and ganciclovir are used concomitantly.1

Tacrolimus

Because of possible increased toxicity, concomitant use of tacrolimus and ganciclovir should be considered only if potential benefits outweigh risks.1

Myelosuppressive Drugs

Concomitant use of ganciclovir and myelosuppressive drugs may have additive toxicity.1 Such drugs include dapsone,1,122 pentamidine,1,122 pyrimethamine,141 flucytosine,1,122,187 cytotoxic antineoplastic agents (e.g., vincristine,1,122,187 vinblastine,1,122,187 doxorubicin,1,122,187 hydroxyurea1 ), amphotericin B,1,122,187 co-trimoxazole,1,21,105,122,187,244 or other nucleoside analogs.122,187 These drugs should be used concomitantly with ganciclovir only when the potential benefits of such therapy are thought to outweigh the possible risks.1 In addition, the possibility that AIDS patients may be at particular risk for potential toxicity during combined therapy should be considered,21,105,122,244 since such patients appear to be at increased risk of hematologic toxicity with some of these drugs alone (e.g., co-trimoxazole).192

Probenecid

Concomitant use of probenecid (500 mg every 6 hours) with oral ganciclovir (no longer commercially available in the US) has resulted in a 53% increase in the AUC of ganciclovir and a 22% decrease in renal clearance of ganciclovir.1

If probenecid and ganciclovir are used concomitantly, reduced ganciclovir dosage may be required and the patient should be monitored for ganciclovir toxicity.1

Acute Toxicity

The acute lethal dose of ganciclovir in humans is not known.262

Overdosages of IV ganciclovir, including some fatalities, have been reported during clinical trials and postmarketing experience.1 In general, overdosage may be expected to produce toxicities that are extensions of the drug's pharmacologic and adverse effects.1 Ganciclovir overdosage has resulted in hematologic toxicity (pancytopenia, leukopenia, neutropenia, granulocytopenia, thrombocytopenia, bone marrow failure), hepatotoxicity (hepatitis, liver function disorder), renal toxicity (worsening of hematuria, acute kidney injury, elevated creatinine concentration), GI toxicity (abdominal pain, diarrhea, vomiting), and neurotoxicity (seizure).1

Management of ganciclovir overdosage generally involves symptomatic and supportive care.262 Because the drug is removed by dialysis (see Pharmacokinetics: Elimination), hemodialysis or peritoneal dialysis might be useful in the management of overdosage.1,85 Adequate hydration should be maintained.1 Protective measures for neutropenia may be necessary until bone marrow function returns;262 use of hematopoietic growth factors should be considered in patients with cytopenias.1

Mechanism of Action

Ganciclovir exerts its antiviral effect on human cytomegalovirus (CMV) and other human herpesviruses1,3,152,209 by interfering with DNA synthesis via competition with deoxyguanosine for incorporation into viral DNA and thereby inhibiting viral DNA polymerase as well as being incorporated into growing viral DNA chains.1,8,9,57,58,85,99,113,133,206,209

Ganciclovir is a prodrug and exhibits no antiviral activity until converted intracellularly to the active metabolite, ganciclovir triphosphate.1,36,85,98,112,113 In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase pUL97.1,85 Further phosphorylation occurs by cellular kinases to produce the pharmacologically active ganciclovir triphosphate.1,85 Ganciclovir triphosphate is a viral DNA polymerase inhibitor that competitively inhibits viral DNA polymerase pUL54.1,85 The drug also is incorporated into growing DNA chains as a false nucleotide, thus interfering with chain elongation (prematurely terminating DNA synthesis) and/or resulting in formation of a mutant DNA chain and thereby inhibiting viral replication.1,5,9,11,36,44,45,52,99,113,115,119,133,195,206,209

Because conversion of ganciclovir to the pharmacologically active triphosphate is largely dependent on viral kinase, phosphorylation of the drug occurs preferentially in virus-infected cells.1,85 The formation of ganciclovir monophosphate appears to be the rate-limiting step in the formation of ganciclovir triphosphate.39,113 In vitro in herpesviruses, ganciclovir triphosphate functions both as substrate for, and a preferential inhibitor of, viral DNA polymerase and as a false nucleotide base.9,11,65,133,209 In cells infected with herpes simplex virus type 1 or 2 (HSV-1 or HSV-2) or varicella-zoster virus (VZV), ganciclovir is converted to ganciclovir monophosphate via virus-coded thymidine kinase.8,22,42,44,45,55,113 The pathway for conversion to the monophosphate in cells infected with CMV or Epstein-Barr virus (EBV) differs since these viruses do not code for thymidine kinase.8,22,44,57,108,113 A cellular deoxyguanosine kinase, found in the cytosol and in mitochondria, may be involved.3,21,39,113,138,224 In CMV-infected cells, increased concentrations of deoxyguanosine kinase (mitochondrial origin) have been detected,138 suggesting that the virus may induce production of the enzyme.1,3,39,41,49,113,138,224

Ganciclovir is virustatic in action.9,27,37,85,99,113,139,209 Following removal of the drug from the culture medium in vitro, viral DNA synthesis (which previously was inhibited) resumes, resulting in restored viral replication.9,27,37,99,113,139,209 In addition, clinical evidence of reactivated disease63,65,94,128,167,168,184,187,203 suggests that ganciclovir acts principally to suppress virus activity and that eradication of the virus does not occur.1,3,4,5,8,9,11,13,21,23,27,28,37,63,65,94,99,100,104,108,113,120,126,128,129,139,167,168,184,187,206

During the course of an acute or asymptomatic herpesvirus infection, the virus usually leaves the initial site of infection and invades other cells and tissues where it establishes a latent infection.8,174,226,241 HSV-1, HSV-2, and VZV are thought to establish latent infections principally within the ganglia.226,227,229 CMV and Epstein-Barr virus are thought to establish latent infections within leukocytes and B cells, respectively.204,228 CMV also may establish a site of latent infection in solid organ tissue (e.g., lung, kidney).228 The exact nature of the virus in the latent state is not well understood;229 however, evidence suggests that the virus is not actively replicating and, therefore, would not be susceptible to the action of antiviral agents such as ganciclovir.218,222,226,227 Despite the host's immunity, herpesvirus latency usually persists for life and the viruses can be reactivated periodically by various stimuli, including immunosuppression.226,229,230 Reactivation of latent CMV has been specifically linked to pregnancy and to decreases in host immunocompetence, either iatrogenic or via disease process (i.e., acquired immunodeficiency syndrome).4,5,8,100,174,204,218,228,241 Once reactivated, the virus usually reinfects the site of initial infection.229 Ganciclovir, like other antivirals, is unable to eliminate an established latent infection, as demonstrated in animal tests.213,218

Spectrum

Following intracellular conversion of ganciclovir to the pharmacologically active ganciclovir triphosphate, the drug is active against human herpesviruses,3,21,85,152,209,221,232 including cytomegalovirus (CMV),1,3,11,12,37,85 herpes simplex virus types 1 and 2 (HSV-1 and HSV-2),3,11,12,46,78,79,80,85,97,161,163,222 and varicella-zoster virus (VZV).3,11,12,37,97,221 Although the clinical importance is unclear, ganciclovir has some in vitro activity against Epstein-Barr virus (EBV)3,11,12,85,89,97,169,222 and human herpesvirus type 685,232 and type 8.85 Ganciclovir is not active against human immunodeficiency virus (HIV).85

Resistance

Cytomegalovirus (CMV) isolates resistant to ganciclovir have been selected in vitro in the presence of increasing concentrations of the drug.1,85 Ganciclovir-resistant CMV have been reported in ganciclovir-naive patients1 and may emerge in patients receiving prolonged treatment or prophylaxis with the drug.1,85 The possibility of ganciclovir-resistant CMV should be considered in patients who show poor clinical response or relapse or experience persistent viral shedding during ganciclovir therapy.1,85

Several mechanisms of resistance to ganciclovir apparently exist.1,3,36,53,55,89,98,112,113,194,262,290 Since the antiviral activity of ganciclovir depends on phosphorylation of the drug to ganciclovir triphosphate (see Mechanism of Action),1,3,36,98,112,113,290 resistance to the drug may result from decreased phosphorylation.5,53,194,290 In some viruses, such as herpes simplex virus (HSV) and varicella-zoster virus (VZV), resistance to ganciclovir might result from low or absent concentrations of virus-coded thymidine kinase40,41,53,55,322 or from alterations in substrate specificity of the enzyme.262 However, other mechanisms also appear to be involved since some thymidine-kinase deficient or mutant strains of acyclovir-resistant HSV are susceptible to ganciclovir.55,89

Ganciclovir resistance usually is the result of amino acid substitutions in the viral protein kinase pUL97 and/or the viral DNA polymerase pUL54.1,85 Certain pUL97 ganciclovir resistance-associated substitutions (e.g., M460V/I, H520Q, C529G, A594V, L595S, C603W) have been reported most frequently in clinical isolates.1 Numerous other pUL97 and pUL54 ganciclovir resistance-associated mutations also have been reported.1,85

Cross-resistance can occur between ganciclovir and some other antivirals (e.g., acyclovir, cidofovir, foscarnet).1,85 Certain amino acid substitutions selected in vitro in cell culture following exposure of CMV to ganciclovir, cidofovir, or foscarnet have resulted in cross-resistance.1,85 Amino acid substitutions in pUL54 that confer cross-resistance between ganciclovir and cidofovir generally have involved the exonuclease domains and region V of the viral DNA polymerase.1 A variety of amino acid substitutions have conferred cross-resistance between ganciclovir and foscarnet, but concentrate at and between regions II and III of viral DNA polymerase.1

Pharmacokinetics

Dosages and concentrations of ganciclovir sodium are expressed in terms of ganciclovir.1 A concentration of 1 mcg of ganciclovir per mL is approximately equivalent to 3.92 µmol/L.263

Absorption

Following IV administration of ganciclovir given in a dosage of 5 mg/kg every 12 hours by IV infusion over 1 hour, peak plasma concentrations of the drug ranged from 8.3-9 mcg/mL.1 In immunocompromised patients with cytomegalovirus (CMV) infection and normal renal function who received 2.5 mg/kg of ganciclovir every 8 hours by IV infusion over 1 hour, peak and trough plasma concentrations of the drug averaged 4.09-5.36 (range: 1.66-7.78 mcg/mL) and 0.33-1.07 mcg/mL (range: 0.2-1.66 mcg/mL), respectively.11,20,59,64,117 In a limited number of such patients receiving 5 mg/kg every 8 hours by IV infusion over 1 hour, peak and trough plasma concentrations averaged 6.53-11.41 and 1.13-2.23 mcg/mL, respectively.11,64,117 Following IV administration, ganciclovir exhibits linear pharmacokinetics over the dosage range of 1.6-5 mg/kg.1 Accumulation of the drug does not appear to occur in patients with normal renal function receiving IV dosages of 3-15 mg/kg daily in divided doses.3,11,59,124

Studies have not been performed to specifically evaluate the pharmacokinetics of IV ganciclovir in geriatric adults 65 years of age and older.1

In a limited number of neonates 2-49 days of age†, IV administration of a ganciclovir dose of 4 or 6 mg/kg resulted in peak plasma concentrations of 5.5 or 7 mcg/mL, respectively.1 In pediatric patients 9 months to 12 years of age† who received IV ganciclovir (single or multiple doses of 5 mg/kg every 12 hours), peak plasma concentrations of the drug were 7.9 mcg/mL.1

Limited data regarding intravitreal injection† of ganciclovir suggest that minimal systemic absorption of the drug occurs,4,25,67 although adequate intravitreal ganciclovir concentrations appear to be achievable with this route.4,5,67,253 In a patient with CMV retinitis receiving five 200-mcg intravitreal doses of ganciclovir over 15 days, plasma concentrations of the drug were less than 0.1 mcg/mL.67 A vitreous humor concentration of 1.17 mcg/mL and an aqueous humor concentration of 0.66 mcg/mL were achieved 51.4 hours after the initial dose in this patient, and a vitreous humor concentration of 0.1 mcg/mL was achieved 97.3 hours after the fourth dose.67 Data from rabbits also indicate that antiviral intravitreal concentrations of the drug are achievable with small intravitreal but not subconjunctival doses of ganciclovir.253 Following intravitreal injection of a single 400-mcg dose in rabbits, vitreous humor ganciclovir concentrations averaged 543, 423, 57.7, 16, 2.02, and 1.2 mcg/mL at 2, 5, 12, 24, 48, and 60 hours after injection.253 Following subconjunctival injection of a single 1.25-mg dose in rabbits, ganciclovir concentrations at 1, 2, 3, and 8 hours after injection averaged 0.09, 0.31, 0.16, and 0.02 mcg/mL, respectively, in vitreous humor and 2.18, 3.27, 2.22, and 0.07 mcg/mL, respectively, in aqueous humor.253

Distribution

Following IV administration, ganciclovir is widely distributed.85 Autopsy findings in several patients who had been receiving IV ganciclovir suggest that the drug concentrates in the kidneys, with substantially lower concentrations occurring in lung, liver, brain, and testes.5,9,64 While efficacy of ganciclovir in CMV pneumonitis has been reported to be substantially less than in some other CMV infections (e.g., retinitis),4,5,8,11,20,21,64,108,151 lung ganciclovir concentrations that exceed the ID₅₀ for CMV appear to be achievable with usual IV dosages of the drug.5,11,64,108,151,262 Concentrations attained in lung and liver were 99 and 92%, respectively, of those attained concurrently in heart/blood in several adults receiving the drug IV.64 Following IV administration in mice, ganciclovir was distributed widely, achieving highest concentrations in the kidney and lowest concentrations in the brain.3 Substantial distribution of ganciclovir into lung, liver, heart, spleen, stomach, intestines, muscle, and testes also occur, exceeding concurrent blood concentrations in these tissues; concentrations achieved in brain, eyes, and fat were lower than concurrent blood concentrations.3 Accumulation of the drug did not appear to occur, although measurable concentrations persisted for at least 30 hours in stomach, liver, and intestines in these animals.3 In addition, there was no evidence of testicular ganciclovir accumulation in several men receiving 15 mg/kg IV daily for 8-13 days.64

The volume of distribution of ganciclovir at steady state following IV administration is 0.74 L/kg.1 The volume of distribution appears to be reduced in patients with renal impairment.124

Data on intraocular concentrations of ganciclovir following IV administration are limited, but it appears that the drug has good ocular distribution following administration by this route.5,85,93,104,117 In one adult patient, subretinal ganciclovir concentrations were 0.87 and 2 times concurrent plasma concentrations at 5.5 and 8 hours after IV administration, respectively.3,93 In another adult patient, aqueous and vitreous humor ganciclovir concentrations were 0.4 and 0.6 times simultaneous plasma concentrations, respectively, at 2.5 hours after IV infusion of the drug; at 21 hours after IV infusion, plasma concentrations were undetectable, while the vitreous humor concentration was still 0.2 mcg/mL.3,104 Following intravitreal injection† of ganciclovir in an adult with CMV retinitis, the apparent volume of distribution in vitreous humor was 11.7 mL, suggesting that the drug may distribute into the retina.67

Ganciclovir crosses the blood-brain barrier.3,4,5,9,28,59,64,68 Following IV administration in several adult patients, ganciclovir concentrations in CSF at 0.25-5.7 hours after a dose ranged from 0.31-0.68 mcg/mL and averaged 41% (range: 24-70%) of corresponding plasma concentration of the drug.1,28,59 Autopsy findings revealed similar evidence of CNS distribution of the drug in several other patients, with brain tissue concentrations of ganciclovir averaging 38% of corresponding blood concentrations.64

Ganciclovir appears to cross the placenta based on ex vivo experiments with human placenta and at least one case report in a pregnant woman.1

It is not known whether ganciclovir is distributed into milk in humans,1 but the drug is distributed into milk following IV administration in rats.1

Ganciclovir is 1-2% bound to plasma proteins at drug concentrations of 0.5-51 mcg/mL.1

Elimination

Following IV administration in adults with normal renal function, the half-life of ganciclovir is 3.5 hours.1 Plasma concentrations of the drug may be higher and the elimination half-life prolonged in patients with impaired renal function.1,3,5,9,11,20,59,60,61,64,124 In a limited number of immunocompromised patients with renal impairment who received IV ganciclovir doses ranging from 1.25-5 mg/kg, mean plasma half-life of the drug was 4.4 hours in those with creatinine clearances of 25-59 mL/minute and 10.7 hours in those with creatinine clearances less than 25 mL/minute.1 In adults with moderate to severe renal impairment (creatinine clearances less than 50 mL/minute per 1.73 m²), the terminal half-life (t_½β) of IV ganciclovir ranged from 4.4-30 hours, depending on the degree of impairment.3,11,60,61,64,124

Although the pharmacokinetics of ganciclovir have not been specifically evaluated in geriatric patients, renal clearance decreases with age and decreased ganciclovir total body clearance and prolonged half-life of the drug are expected in adults 65 years of age and older.1

In a limited number of neonates 2-49 days of age† who received IV ganciclovir, the plasma half-life of the drug was 2.4 hours.1 In pediatric patients 9 months to 12 years of age† who received IV ganciclovir, the plasma half-life of the drug also was approximately 2.4 hours.1

Following intravitreal injection† of ganciclovir in a patient with CMV retinitis, the elimination half-life of the drug from the vitreous humor was estimated to be 13.3 hours.67 In this patient, intravitreal ganciclovir concentrations were estimated to exceed the ID₅₀ (0.66 mcg/mL) of the virus for about 62 hours after a single 200-mcg intravitreal dose.67 In rabbits, the elimination half-life from vitreous humor after intravitreal injection of a single 400-mcg dose was 8.6 hours, and intravitreal ganciclovir concentrations exceeded the ID₅₀ (range: 0.24-1.5 mcg/mL) of many strains of CMV for at least 60 hours.253

With the exception of intracellular phosphorylation of the drug (see Mechanism of Action), ganciclovir does not appear to be metabolized appreciably in humans.4,5,11,28,59,61,64,124 The drug appears to undergo little, if any, extrarenal elimination, and approximately 90-99% of an IV dose is excreted unchanged in urine.1,3,4,5,11,28,59,61,64,124 Renal excretion of ganciclovir appears to occur principally via glomerular filtration and active tubular secretion.1,3,5,11,59,124

Total body clearance of ganciclovir from plasma reportedly averages 170-203 mL/minute per 1.73 m² in adults with normal renal function.3,5,11,59,61 Total body clearance of the drug is decreased in adults with renal impairment1,3,124 and appears to correlate positively with creatinine clearance.1,3,5,11,59,61,124 In a limited number of patients, total body clearance from plasma averaged 128, 57, or 30 mL/minute in adults with creatinine clearances of 50-79, 25-49, or less than 25 mL/minute, respectively.1

Ganciclovir is removed by hemodialysis.1,3,5,60,108,124,151 The amount of ganciclovir removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow rate); however, in several patients, a 4-hour period of hemodialysis removed into the dialysate approximately 40-50% of a dose.1,3,5,60,108,124,151

Chemistry and Stability

Chemistry

Ganciclovir, a synthetic nucleoside analog of guanine, is an antiviral agent.1,2,14,85,86 Ganciclovir is structurally and pharmacologically related to acyclovir, differing from acyclovir only by the addition of a second terminal hydroxymethyl group at C-2 of the acyclic side chain on the ribose ring.3,5,23,52,54,112 Compared with acyclovir, this structural difference results in substantially increased antiviral activity against cytomegalovirus (CMV)3,34,40,42,52,54,56,97,133 and less selectivity for viral DNA.3,42,52,54,56

Ganciclovir occurs as a white to off-white powder and has an aqueous solubility of 2.6 mg/mL at 25°C.1,2,14 Aqueous solubility of the drug is relatively constant over a pH range of 3.5-8.5, but increases substantially in strongly acidic or basic solutions.3 The drug has pK_as of 2.2 and 9.4.1,2,14

Ganciclovir is commercially available for IV use as the monosodium salt,1,2 which is formed in situ by the addition of sodium hydroxide during the manufacturing process.263 At physiologic pH, ganciclovir sodium exists as the unionized form with a solubility of approximately 6 mg/mL at 37°C.1,2 Potency of ganciclovir sodium is expressed in terms of ganciclovir.1,2

Commercially available ganciclovir sodium sterile powder for IV use provided in single-use vials containing 500 mg of ganciclovir occurs as a white to off-white lyophilized powder.1 The lyophilized powder has an aqueous solubility that is greater than 50 mg/mL at 25°C.1 Following reconstitution of the powder with preservative-free sterile water for injection, ganciclovir sodium solutions containing 50 mg of ganciclovir per mL are alkaline with a pH of 111 and are colorless.263

Commercially available sterile ganciclovir sodium concentrate for IV use provided in single-use vials containing 500 mg of ganciclovir (50 mg/mL) should appear as a clear solution.2

Commercially available premixed injection for IV use containing 500 mg of ganciclovir in 250 mL of 0.8% sodium chloride (2 mg/mL) is provided in single-use polymeric IV bags.14 The premixed solution has a pH of 7.5 and does not contain any preservatives.14

Stability

Ganciclovir sodium lyophilized powder for IV use provided in single-use vials should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.1 Following reconstitution with sterile water for injection, ganciclovir sodium solutions containing 50 mg of ganciclovir per mL are stable for 12 hours at 25°C and should not be refrigerated or frozen.1 Bacteriostatic water for injection containing parabens should not be used for reconstitution of ganciclovir sodium since a precipitate may form.1 The manufacturer states that reconstituted ganciclovir sodium that has been further diluted in 0.9% sodium chloride or other compatible IV infusion solution should be stored under refrigeration at 2-8°C and used within 24 hours.1 The solution should not be frozen.1

Ganciclovir sodium concentrate for IV use containing 500 mg of ganciclovir (50 mg/mL) provided in single-use vials should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.2 Following dilution in 0.9% sodium chloride or other compatible IV infusion solution, the manufacturer states that the solution should be stored under refrigeration at 2-8°C and used within 24 hours.2 The solution should not be frozen.2

The premixed injection for IV use containing 500 mg of ganciclovir in 250 mL of 0.8% sodium chloride (2 mg/mL) provided in single-use IV bags should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°C.14 Crystals may form in the premixed solution if it is exposed during transportation or storage to temperatures lower than recommended;14 the crystals should redissolve if the bag is gently shaken.14

At a concentration of 10 mg or less of ganciclovir per mL, ganciclovir sodium is physically and chemically stable in the following IV solutions: 0.9% sodium chloride, 5% dextrose, Ringer's, or lactated Ringer's.1,2 Solutions containing approximately 2.5 mg of ganciclovir per mL reportedly are physically and chemically stable for at least 5 days at 4-25°C in 0.9% sodium chloride injection or 5% dextrose injection.7,263 Although sterility of the solutions was not assessed, results of one study indicate that ganciclovir is stable for up to 35 days when diluted in 0.9% sodium chloride or 5% dextrose to a concentration of 1 or 5 mg/mL and stored in polyvinyl chloride (PVC) containers at 5°C or 25°C.296 In another study, ganciclovir was stable for up to 28 days when diluted in 0.9% sodium chloride or 5% dextrose to a concentration of 5 or 10 mg/mL and stored in PVC containers at 4°C or -20°C or stored in ADFuse syringes (Healthtek) at 4°C.297 Protection of diluted ganciclovir sodium solutions from usual room light is not necessary.7 The drug does not appear to adsorb appreciably to PVC containers.7

1. Genentech. Cytovene^®-IV (ganciclovir sodium for injection) prescribing information. South San Francisco, CA; 2018 Aug.

2. Pharmascience Inc. Ganciclovir sodium injection, solution prescribing information. Candiac Canada; 2018 Nov.

3. Syntex Research. Investigator's monograph: ganciclovir. 5th ed. Palo Alto, CA: 1987 Dec. (Syntex Document No. RS-21592)

4. Jacobson MA, Mills J. Serious cytomegalovirus disease in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med . 1988; 108:585-94. [PubMed 2831765]

5. Fletcher CV, Balfour HH Jr. Evaluation of ganciclovir for cytomegalovirus disease. DICP . 1989; 23:5-12. [PubMed 2541566]

6. Chachoua A, Dieterich D, Krasinski K et al. 9-(1,3-Dihydroxy-2-propoxymethyl)guanine (ganciclovir) in the treatment of cytomegalovirus gastrointestinal disease with the acquired immunodeficiency syndrome. Ann Intern Med . 1987; 107:133-7. [PubMed 3037960]

7. Visor GC, Lin LH, Jackson SE et al. Stability of ganciclovir sodium (DHPG sodium) in 5% dextrose or 0.9% sodium chloride injections. Am J Hosp Pharm . 1986; 43:2810-2. [PubMed 3492139]

8. Drew WL. Cytomegalovirus infection in patients with AIDS. J Infect Dis . 1988; 158:449-56. [PubMed 2841381]

9. Weintraub M, Standish R. Ganciclovir: an antiviral agent for AIDS and other immunocompromised patients. Hosp Formul . 1987; 22:1011-6.

10. Weller IVD. ABC of AIDS: treatment of infections and antiviral agents. BMJ . 1987; 295:200-3. [PubMed 3115376][PubMedCentral]

11. Laskin OL, Cederberg DM, Mills J et al. Ganciclovir for the treatment and suppression of serious infections caused by cytomegalovirus. Am J Med . 1987; 83:201-7. [PubMed 3039841]

12. Tuazon CU, Labriola AM. Management of infectious and immunological complications of acquired immunodeficiency syndrome (AIDS)—current and future prospects. Drugs . 1987; 33:66-84. [PubMed 3545766]

13. Bach MC, Bagwell SP, Knapp NP et al. 9-(1, 3-Dihydroxy-2-propoxymethyl)guanine for cytomegalovirus infections in patients with the acquired immunodeficiency syndrome. Ann Intern Med . 1985; 103:381-2. [PubMed 2992335]

14. Exela Pharma Sciences, LLC. Ganciclovir injection solution prescribing information. Lenoir, NC; 2017 Sep.

15. Nicholson ML, Flower AJE, Simpson A et al. Ganciclovir for severe cytomegalovirus infection in transplant recipients. Lancet . 1988; 2:1501-2. [PubMed 2904627]

16. Rostoker G, Ben Maadi A, Buisson C et al. Ganciclovir for severe cytomegalovirus infection in transplant recipients. Lancet . 1988; 2:1137-8. [PubMed 2903346]

17. Frank I, Friedman HM. Progress in the treatment of cytomegalovirus pneumonia. Ann Intern Med . 1988; 109:769-71. [PubMed 2847608]

18. Tindall B, Swanson C, Whyte BM et al. Fourth international conference on the acquired immunodeficiency syndrome. Med J Aust . 1989; 150: 87-92.

19. Hiesse C, Farquet C, Dussaix E et al. Ganciclovir for cytomegalovirus infection in renal transplant recipients. Lancet . 1989; 1:216-7.

20. Erice A, Jordan MC, Chace BA et al. Ganciclovir treatment of cytomegalovirus disease in transplant recipients and other immunocompromised hosts. JAMA . 1987; 257:3082-7. [PubMed 3035246]

21. Collaborative DHPG Treatment Study Group. Treatment of serious cytomegalovirus infections with 9-(1,3-dihydroxy-2-propoxymethyl)guanine in patients with AIDS and other immunodeficiencies. N Engl J Med . 1986; 314:801-5. [PubMed 3005861]

22. Meyers JD. Management of cytomegalovirus infection. Am J Med . 1988; 85(Suppl 2A):102-6. [PubMed 2841853]

23. Masur H, Lane HC, Palestine A et al. Effect of 9-(1,3-dihydroxy-2-propoxymethyl) guanine on serious cytomegalovirus disease in eight immunosuppressed homosexual men. Ann Intern Med . 1986; 104:41-4. [PubMed 3000248]

25. Henry K, Cantrill H, Kish MA. Intravitreous ganciclovir for patients receiving zidovudine. JAMA . 1987; 257:3066. [PubMed 3035245]

26. Mau S, Salamone FR, Muller RJ et al. Trimetrexate, ganciclovir, foscarnet, fluconazole—investigational drugs used in the management of AIDS. Hosp Pharm . 1989; 24:209-14.

27. Jordan MC. Ganciclovir for treatment of cytomegalovirus disease. DICP . 1989; 23:85-6. [PubMed 2541567]

28. Laskin OL, Stahl-Bayliss CM, Kalman CM et al. Use of ganciclovir to treat serious cytomegalovirus infections in patients with AIDS. J Infect Dis . 1987; 155:323-7. [PubMed 3027195]

29. Wood MJ, Geddes AM. Antiviral therapy. Lancet . 1987; 2:1189-93. [PubMed 2890817]

30. Nahata MC. Clinical use of antiviral drugs. Drug Intell Clin Pharm . 1987; 21:399-405. [PubMed 3556126]

31. Devita VT, Broder S, Fauci AS et al. Developmental therapeutics and the acquired immunodeficiency syndrome. Ann Intern Med . 1987; 106:568-81. [PubMed 2435201]

32. Deeter RG, Khanderia U. Recent advances in antiviral therapy. Clin Pharm . 1986; 5:961-76. [PubMed 3542344]

33. Keay S, Bissett J, Merigan TC. Ganciclovir treatment of cytomegalovirus infections in iatrogenically immunocompromised patients. J Infect Dis . 1987; 156:1016-21. [PubMed 2824621]

34. Martin JC, Dvorak CA, Smee DF et al. 9-[(1, 3-dihydroxy-2-propoxy)methyl] guanine: a new potent and selective antiherpes agent. J Med Chem . 1983; 26:759-61. [PubMed 6302255]

35. Tyms AS, Davis JM, Jeffries DJ et al. BWB759U and an analogue of acyclovir, inhibits human cytomegalovirus in vitro. Lancet . 1984; 2:924-5. [PubMed 6148640]

36. St. Clair MH, Miller WH, Miller RL et al. Inhibition of cellular α DNA polymerase and herpes simplex virus-induced DNA polymerases by the triphosphate of BW759U. Antimicrob Agents Chemother . 1984; 25:191-4. [PubMed 6324666] [PubMedCentral]

37. Mar EC, Cheng YC, Huang ES. Effect of 9-(1, 3-dihydroxy-2-propoxymethyl) guanine on human cytomegalovirus replication in vitro. Antimicrob Agents Chemother . 1983; 24:518-21. [PubMed 6316844][PubMedCentral]

38. Goring DR, DuBow MS. A cytotoxic effect associated with 9-(1,3-dihydroxy-2-propoxymethyl) guanine is observed during the selection for drug resistant human cells containing a single herpesvirus thymidine kinase gene. Biochem Biophys Res Commun . 1985; 133:195-201. [PubMed 3878145]

39. Smee DF. Interaction of 9-(1,3-dihydroxy-2 -propoxymethyl) guanine with cytosol and mitochondrial deoxyguanosine kinases: possible role in anti-cytomegalovirus activity. Mol Cell Biochem . 1985; 69:75-81. [PubMed 3001505]

40. Smee DF, Martin JC, Verheyden JPH et al. Anti-herpesvirus activity of the acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl) guanine. Antimicrob Agents Chemother . 1983; 23:676-82. [PubMed 6307132][PubMedCentral]

41. Biron KK, Stanat SC, Sorrell JB et al. Metabolic activation of the nucleoside analog 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine in human diploid fibroblasts infected with human cytomegalovirus. Proc Natl Acad Sci USA . 1985; 82:2473-7. [PubMed 2986118][PubMedCentral]

42. Field AK, Davies ME, DeWitt C et al. 9-[2-Hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine: a selective inhibitor of herpes group virus replication. Proc Natl Acad Sci USA . 1983; 80:4139-43. [PubMed 6306664][PubMedCentral]

43. Cheng YC, Huang ES, Lin JC et al. Unique spectrum of activity of 9-[(1,3-dihydroxy-2 -propoxy)methyl]guanine against herpesviruses in vitro and its mode of action against herpes simplex virus type 1. Proc Natl Acad Sci, USA . 1983; 80: 2767-70.

44. Oberg B, Johansson NG. The relative merits and drawbacks of new nucleoside analogues with clinical potential. J Antimicrob Chemother . 1984; 14(Suppl A):5-26. [PubMed 6436227]

45. Cheng YC, Grill SP, Dutschman GE et al. Metabolism of 9-(1,3-dihydroxy-2-propoxymethyl) guanine and a new anti-herpes virus compound, in herpes simplex virus infected cells. J Biol Chem . 1983; 258:12460-4. [PubMed 6313660]

46. Smith KO, Galloway KS, Kennell WL et al. A new nucleoside analog, 9-[2-hydroxy-1 -(hydroxymethyl)ethoxy]methyl]guanine, highly active in vitro against herpes simplex virus types 1 and 2. Antimicrob Agents Chemother . 1982; 22:55-61. [PubMed 6289741][PubMedCentral]

47. Ashton WT, Karkas JD, Field AK et al. Activation by thymidine kinase and potent antiherpetic activity of 2'-nor-2'-deoxyguanosine (2'NDG). Biochem Biophys Res Commun . 1982; 108:1716-21. [PubMed 6295389]

48. Bowden RA, Digel J, Reed EC et al. Immunosuppressive effects of ganciclovir on in vitro lymphocyte responses. J Infect Dis . 1987; 156: 899-903. [PubMedCentral]

49. Freitas VR, Smee DF, Chernow M et al. Activity of 9-(1,3-dihydroxy-2-propoxymethyl)guanine compared with that of acyclovir against human and monkey, and rodent cytomegaloviruses. Antimicrob Agents Chemother . 1985; 28:240-5. [PubMed 3010840][PubMedCentral]

50. Plotkin SA, Drew WL, Felsenstein D et al. Sensitivity of clinical isolates of human cytomegalovirus to 9-(1,3-dihydroxy-2 -propoxymethyl)guanine. J Infect Dis . 1985; 152: 833-4. [PubMedCentral]

51. Cheng YC, Grill SP, Dutschman GE et al. Effects of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, a new antiherpesvirus compound, on synthesis of macromolecules in herpes simplex virus-infected cells. Antimicrob Agents Chemother . 1984; 26:283-8. [PubMed 6095751][PubMedCentral]

52. St. Clair MH, Lambe CU, Furman PA. Inhibition by ganciclovir of cell growth and DNA synthesis of cells biochemically transformed with herpesvirus genetic information. Antimicrob Agents Chemother . 1987; 31:844-9. [PubMed 3039910][PubMedCentral]

53. Erice A, Chou S, Biron KK et al. Progressive disease due to ganciclovir-resistant cytomegalovirus in immunocompromised patients. N Engl J Med . 1989; 320:289-293. [PubMed 2536135]

54. Germershausen J, Bostedor R, Field AK et al. A comparison of the antiviral agents 2'-nor-2 '-deoxyguanosine and acyclovir: uptake and phosphorylation in tissue culture and kinetics of in vitro inhibition of viral and cellular DNA polymerases by their respective triphosphates. Biochem Biophys Res Commun . 1983; 116:360-7. [PubMed 6316950]

55. Collins P, Oliver NM. Comparison of the in vitro and in vivo antiherpes virus activities of the acyclic nucleosides and acyclovir (Zovirax), 9-[(2-hydroxy-1-hydroxymethyl-ethoxy)methyl]guanine (BWB759U). Antiviral Res . 1985; 5:145-56. [PubMed 2992369]

56. Smee DF, Boehme R, Chernow M et al. Intracellular metabolism and enzymatic phosphorylation of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and acyclovir in herpes simplex virus-infected and uninfected cells. Biochem Pharmacol . 1985; 34: 1049-56. [PubMed 3872662]

57. Tocci MJ, Livelli TJ, Perry HC et al. Effects of the nucleoside analog 2'-nor-2'-deoxyguanosine on human cytomegalovirus replication. Antimicrob Agents Chemother . 1984; 25:247-52. [PubMed 6324669][PubMedCentral]

58. Jacobson MA, de Miranda P, Cederberg DM et al. Human pharmacokinetics and tolerance of oral ganciclovir. Antimicrob Agents Chemother . 1987; 31:1251-4. [PubMed 2820301][PubMedCentral]

59. Fletcher C, Sawchuk R, Chinnock B et al. Human pharmacokinetics of the antiviral drug DHPG. Clin Pharmacol Ther . 1986; 40:281-6. [PubMed 3017630]

60. Lake KD, Fletcher CV, Love KR et al. Ganciclovir pharmacokinetics during renal impairment. Antimicrob Agents Chemother . 1988; 32:1899-1900. [PubMed 2854457][PubMedCentral]

61. Weller S, Liao SHT, Cederberg DM et al. The pharmacokinetics of ganciclovir in patients with cytomegalovirus (CMV) infections. J Pharm Sci . 1987; 76:S120.

62. O'Donnell JJ, Jacobson MA, Mills J. Development of cytomegalovirus (CMV) retinitis in a patient with AIDS during ganciclovir therapy for CMV colitis. New Engl J Med . 1987; 316:1607-8. [PubMed 3035374]

63. Felsenstein D, D'Amico DJ, Hirsch MS et al. Treatment of cytomegalovirus retinitis with 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl)]guanine. Ann Intern Med . 1985; 103:377-80. [PubMed 2992334]

64. Shepp DH, Dandliker PS, de Miranda P et al. Activity of 9-[2-hydroxy-1- (hydroxymethyl)ethoxymethyl]guanine in the treatment of cytomegalovirus pneumonia. Ann Intern Med . 1985; 103:368-73. [PubMed 2992333]

65. Harris ML, Mathalone MBR. Dihydroxypropoxymethyl guanine in the treatment of AIDS related retinitis due to cytomegalovirus. BMJ . 1987; 294:92. [PubMed 3032325][PubMedCentral]

66. Emanuel D, Cunningham I, Jules-Elysee K et al. Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin. Ann Intern Med . 1988; 109:777-82. [PubMed 2847609]

67. Henry K, Cantrill H, Fletcher C et al. Use of intravitreal ganciclovir (dihydroxy propoxymethyl guanine) for cytomegalovirus retinitis in a patient with AIDS. Am J Ophthalmol . 1987; 103:17-23. [PubMed 3026186]

68. Stein DS, Verano AS, Levandowski RA. Successful treatment with ganciclovir of disseminated cytomegalovirus infection after liver transplantation. Am J Gastroenterol . 1988; 83:684-6. [PubMed 2837082]

69. Kotler DP, Tierney AR, Altilio D et al. Body mass repletion during ganciclovir treatment of cytomegalovirus infections in patients with acquired immunodeficiency syndrome. Arch Intern Med . 1989; 149:901-5. [PubMed 2539791]

70. Jacobson MA, Cello JP, Sande MA. Cholestasis and disseminated cytomegalovirus disease in patients with the acquired immunodeficiency syndrome. Am J Med . 1988; 84:218-24. [PubMed 2841850]

71. Jabs DA, Enger C, Bartlett JG. Cytomegalovirus retinitis and acquired immunodeficiency syndrome. Arch Ophthalmol . 1989; 107:75-80. [PubMed 2535932]

72. Hecht DW, Snydman DR, Crumpacker CS et al. Ganciclovir for treatment of renal transplant-associated primary cytomegalovirus pneumonia. J Infect Dis . 1988; 157:187-90. [PubMed 2826608]

73. Reed EC, Bowden RA, Dandliker PS et al. Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med . 1988; 109:783-8. [PubMed 2847610]

74. Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in hematopoietic stem cell transplant recipients. Hematol Oncol Clin North Am . 2011; 25:151-69. [PubMed 21236396]

75. Hermans PE, Cockerill FR III. Antiviral agents. Mayo Clin Proc . 1987; 62:1108-15. [PubMed 3500376]

76. Meesing A, Razonable RR. Pharmacologic and immunologic management of cytomegalovirus infection after solid organ and hematopoietic stem cell transplantation. Expert Rev Clin Pharmacol . 2018; 11:773-788. [PubMed 30009675]

78. Klein RJ, Friedman-Kien AE. Effect of 9-(1, 3-dihydroxy-2-propoxymethyl)guanine on the acute local phase of herpes simplex virus-induced skin infections in mice and the establishment of latency. Antimicrob Agents Chemother . 1985; 27:763-8. [PubMed 3874596][PubMedCentral]

79. Smith KO, Hodges SL, Kennell WL et al. Experimental ocular herpetic infections in rabbits: treatment with 9-([2-hydroxy-1- (hydroxymethyl)ethoxy methyl)]guanine. Arch Ophthalmol . 1984; 102:778-81. [PubMed 6326720]

80. Field HJ, Anderson JR, Efstathiou S. A quantitative study of the effects of several nucleoside analogues on established herpes encephalitis in mice. J Gen Virol . 1984; 65:707-19. [PubMed 6323620]

81. Kotton CN, Kumar D, Caliendo AM et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation . 2018; 102:900-931. [PubMed 29596116]

82. Razonable RR, Humar A. Cytomegalovirus in Solid Organ Transplant Recipients - Guidelines of the American Society of Transplantation Infectious Disease Community of Practice. Clin Transplant . 2019; :e13512. [PubMed 30817026]

83. Jacobson MA, de Miranda P, Gordon SM et al. Prolonged pancytopenia due to combined ganciclovir and zidovudine therapy. J Infect Dis . 1988; 158:489-90. [PubMed 3261316]

84. Lim Y, Lyall H. Congenital cytomegalovirus - who, when, what-with and why to treat?. J Infect . 2017; 74 Suppl 1:S89-S94. [PubMed 28646968]

85. Beauduy CE, Jacobson MA. Ganciclovir and valganciclovir. In: Grayson ML, ed. Kucers' the use of antibiotics: a clinical review of antibacterial, antifungal, antiparasitic, and antiviral drugs. 7th ed. Boca Raton, FL: CRC Press; 2018:3502-30.

86. Crumpacker CS. Cytomegalovirus (CMV). In: Bennett JE, Dolin R, Blaser MJ eds. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015: pp. 1738-53.

87. Pulido J, Peyman GA, Lesar T et al. Intravitreal toxicity of hydroxyacyclovir (BW-B759U) and a new antiviral agent. Arch Ophthalmol . 1985; 103:840-1. [PubMed 3873931]

88. Debs RJ, Montgomery AB, Brunette EN et al. Aerosol administration of antiviral agents to treat lung infection due to murine cytomegalovirus. J Infect Dis . 1988; 157:327-31. [PubMed 2826613]

89. Lin JC, Smith MC, Pagano JS. Prolonged inhibitory effect of 9-(1,3-dihydroxy -2-propoxymethyl)guanine against replication of Epstein-Barr virus. J Virol . 1984; 50:50-5. [PubMed 6321799][PubMedCentral]

90. Bach MC. Breakthrough of cytomegalovirus infection despite 9-(1,3-dihydroxy -2-propoxymethyl)guanine therapy. Ann Intern Med . 1986; 104:587. [PubMed 3006573]

91. Meyers JD. Prevention and treatment of cytomegalovirus infection after marrow transplantation. Bone Marrow Transplant . 1988; 3:95-104. [PubMed 2844342]

92. Reed EC, Shepp DH, Dandliker PS et al. Ganciclovir treatment of cytomegalovirus infection of the gastrointestinal tract after marrow transplantation. Bone Marrow Transplant . 1988; 3: 199-206. [PubMed 2844343]

93. Jabs DA, Wingard JR, de Bustros S et al. BW B759U for cytomegalovirus retinitis: intraocular drug penetration. Arch Ophthalmol . 1986; 104:1436-7. [PubMed 3021090]

94. Holland GN, Sakamoto MJ, Hardy D et al. Treatment of cytomegalovirus retinopathy in patients with acquired immunodeficiency syndrome: use of the experimental drug 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine. Arch Ophthalmol . 1986; 104:1794-800. [PubMed 3024606]

95. Jacobson MA, Mills J, Rush J et al. Failure of antiviral therapy for acquired immunodeficiency syndrome-related cytomegalovirus myelitis. Arch Neurol . 1988; 45:1090-2. [PubMed 2845899]

96. Sommadossi JP, Carlisle R. Toxicity of 3'-azido-3'-deoxythymidine and 9-(1,3-dihydroxy -2-propoxymethyl)guanine for normal human hematopoietic progenitor cells in vitro. Antimicrob Agents Chemother . 1987; 31:452-4. [PubMed 3495235][PubMedCentral]

97. Smee DF, Campbell NL, Matthews TR. Comparative anti-herpesvirus activities of 9-(1,3-dihydroxy -2-propoxymethyl)guanine and acyclovir, and two 2'-fluoropyrimidine nucleosides. Antiviral Res . 1985; 5:259-67. [PubMed 2998275]

98. Duke AE, Smee DF, Chernow M et al. In vitro and in vivo activities of phosphate derivatives of 9-(1, 3-dihydroxy-2-propoxymethyl)guanine against cytomegalovirus. Antiviral Res . 1986; 6:299-308. [PubMed 3021055]

99. Fong CKY, Cohen SD, McCormick S et al. Antiviral effect of 9-(1,3-dihydroxy-2-propoxymethyl) guanine against cytomegalovirus infection in a guinea pig model. Antiviral Res . 1987; 7:11-23. [PubMed 3026243]

100. Rosecan LR, Stahl-Bayliss CM, Kalman CM et al. Antiviral therapy for cytomegalovirus retinitis in AIDS with dihydroxy propoxymethyl guanine. Am J Ophthalmol . 1986; 101:405-18. [PubMed 3008560]

101. Small PM, McPhaul LW, Sooy CD et al. Cytomegalovirus infection of the laryngeal nerve presenting as hoarseness in patients with acquired immunodeficiency syndrome. Am J Med . 1989; 86:108-10. [PubMed 2535917]

102. Kotler DP, Culpepper-Morgan JA, Tierney AR et al. Treatment of disseminated cytomegalovirus infection with 9-(1,3-dihydroxy-2-propoxymethyl) guanine: evidence of prolonged survival in patients with the acquired immunodeficiency syndrome. AIDS Res . 1986; 2:299-308. [PubMed 3028443]

103. Orellana J, Teich SA, Friedman AH et al. Combined short- and long-term therapy for the treatment of cytomegalovirus retinitis using ganciclovir (BW B759U). Ophthalmology . 1987; 94:831-8. [PubMed 2821466]

104. Jabs DA, Newman C, de Bustros S et al. Treatment of cytomegalovirus retinitis with ganciclovir. Ophthalmology . 1987; 94:824-30. [PubMed 2821465]

105. Holland GN, Sidikaro Y, Kreiger AE et al. Treatment of cytomegalovirus retinopathy with ganciclovir. Ophthalmology . 1987; 94:815-23. [PubMed 2821464]

106. Dieterich DT, Chachoua A, Lafleur F et al. Ganciclovir treatment of gastrointestinal infections caused by cytomegalovirus in patients with AIDS. Rev Infect Dis . 1988; 10(Suppl 3):S532-7. [PubMed 2847290]

107. Crumpacker C, Marlowe S, Zhang JL et al. Treatment of cytomegalovirus pneumonia. Rev Infect Dis . 1988; 10(Suppl 3):S538-46. [PubMed 2847291]

108. Winston DJ, Ho WG, Bartoni K et al. Ganciclovir therapy for cytomegalovirus infections in recipients of bone marrow transplants and other immunosuppressed patients. Rev Infect Dis . 1988; 10(Suppl 3):S547-53. [PubMed 2847292]

109. Snydman DR. Ganciclovir therapy for cytomegalovirus disease associated with renal transplants. Rev Infect Dis . 1988; 10(Suppl 3): S554-62. [PubMed 2847293]

110. Keay S, Petersen E, Icenogle T et al. Ganciclovir treatment of serious cytomegalovirus infection in heart and heart-lung transplant recipients. Rev Infect Dis . 1988; 10(Suppl 3): S563-72. [PubMed 2847294]

111. Gianello P, Stoffel M, Squifflet JP et al. Ganciclovir for cytomegalovirus infections in renal transplant recipients. Lancet . 1989; 1:217.

112. Crumpacker CS II. Molecular targets of antiviral therapy. N Engl J Med . 1989; 321:163-72. [PubMed 2546077]

113. Matthews T, Boehme R. Antiviral activity and mechanism of action of ganciclovir. Rev Infect Dis . 1988; 10(Suppl 3):S490-4. [PubMed 2847285]

114. Raufman JP. Odynophagia/dysphagia in AIDS. Gastroenterol Clin North Am . 1988; 17:599-614. [PubMed 3049365]

115. Crowe S, Mills J. The future of antiviral chemotherapy. Dermatol Clin . 1988; 6:521-37. [PubMed 3067915]

116. Montgomery P, Lopez JR. DHPG in cytomegalovirus infections. Drug Intell Clin Pharm . 1986; 20:854-5.

117. Daikos GL, Pulido J, Kathpalia SB et al. Intravenous and intraocular ganciclovir for CMV retinitis in patients with AIDS or chemotherapeutic immunosuppression. Br J Ophthalmol . 1988; 72:521-4. [PubMed 2843218][PubMedCentral]

118. Orellana J, Teich SA, Winterkorn JS et al. Treatment of cytomegalovirus retinitis with ganciclovir (9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine (BW B759U)). Br J Ophthalmol . 1988; 72:525-9. [PubMed 2843219][PubMedCentral]

119. Furman PA. Chemotherapy of herpesvirus infections. Curr Eye Res . 1987; 6:213-9. [PubMed 3493884]

120. Teich SA, Castle J, Friedman AH et al. Active cytomegalovirus particles in the eyes of an AIDS patient being treated with 9-[2-hydroxy -1-(hydroxymethyl)ethoxymethyl]guanine (ganciclovir). Br J Ophthalmol. 1988; 72 293-8.

121. Hutter JA, Scott J, Wreghitt T et al. The importance of cytomegalovirus in heart-lung transplant recipients. Chest . 1989; 95:627-31. [PubMed 2537711]

122. Buhles Jr WC, Mastre BJ, Tinker AJ et al. Ganciclovir treatment of life- or sight-threatening cytomegalovirus infection: experience in 314 immunocompromised patients. Rev Infect Dis . 1988; 10(Suppl 3):S495-506. [PubMed 2847286]

123. Winston DJ, Ho WG, Gale RP et al. Prophylaxis of infection in bone marrow transplants. Eur J Cancer Clin Oncol . 1988; 24(Suppl 1):S15-23. [PubMed 3127217]

124. Sommadossi JP, Bevan R, Ling T et al. Clinical pharmacokinetics of ganciclovir in patients with normal and impaired renal function. Rev Infect Dis . 1988; 10(Suppl 3):S507-14. [PubMed 2847287]

125. Palestine AG. Clinical aspects of cytomegalovirus retinitis. Rev Infect Dis . 1988; 10(Suppl 3):S515-21. [PubMed 2847288]

126. Mills J, Jacobson MA, O'Donnell JJ et al. Treatment of cytomegalovirus retinitis in patients with AIDS. Rev Infect Dis . 1988; 10(Suppl 3):S522-31.

127. Henderly DE, Freeman WR, Causey DM et al. Cytomegalovirus retinitis and response to therapy with ganciclovir. Ophthalmology . 1987; 94:425-434. [PubMed 3035453]

128. Pepose JS, Newman C, Bach MC. Pathologic features of cytomegalovirus retinopathy after treatment with the antiviral agent ganciclovir. Ophthalmology . 1987; 94:414-24. [PubMed 3035452]

129. Cantrill HL, Henry K, Melroe NH et al. Treatment of cytomegalovirus retinitis with intravitreal ganciclovir—long-term results. Ophthalmology . 1989; 96:367-74. [PubMed 2540470]

130. Sacks SL. Therapeutic use of newer antiviral agents. Int J Cell Cloning . 1986; 4(Suppl 1):155-73. [PubMed 3018100]

131. Jacobson MA, O'Donnell JJ, Brodie HR et al. Randomized prospective trial of ganciclovir maintenance therapy for cytomegalovirus retinitis. J Med Virol . 1988; 25:339-49. [PubMed 2844981]

132. Sommadossi JP, Bevan R. High-performance liquid chromatographic method for the determination of 9-(1,3-dihydroxy-2-propoxymethyl)guanine in human plasma. J Chromatogr . 1987; 414:429-33. [PubMed 3494740]

133. Tyms AS, Taylor DL, Parkin JM. Cytomegalovirus, the acquired immunodeficiency syndrome. J Antimicrob Ther . 1989; 23(Suppl A): 89-105.

134. Ong ELC, Ellis ME, Tweedle DEF et al. Cytomegalovirus cholecystitis and colitis associated with the acquired immunodeficiency syndrome. J Infect . 1989; 18:73-5. [PubMed 2536775]

135. Ussery FM III, Gibson SR, Conklin RH et al. Intravitreal ganciclovir in the treatment of AIDS-associated cytomegalovirus retinitis. Ophthalmology . 1988; 95:640-8. [PubMed 2845321]

136. Pollard RB, Matzke DS, Ramsey KM et al. Therapy of disseminated cytomegalovirus (CMV) infections in immunosuppressed individuals using dihydroxy propoxymethyl guanine (DHPG). Clin Res . 1985; 33:416A.

137. Shepp DH, Dandliker PS, Burnette TC et al. 9-[(2-Hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine: antiviral activity in cytomegalovirus pneumonia. Clin Res . 1985; 33:419A.

138. Lewis RA, Watkins L, St. Jeor S. Enhancement of deoxyguanosine kinase activity in human lung fibroblast cells infected with human cytomegalovirus. Mol Cell Biochem . 1985; 65:67-71.

139. Palestine AG, Stevens G Jr, Lane HC. Treatment of cytomegalovirus retinitis with dihydroxy propoxymethyl guanine. Am J Ophthalmol . 1986; 101: 95-101. [PubMed 3002177]

140. Cantarovich M, Hiesse C, Lantz O et al. Treatment of cytomegalovirus infections in renal transplant recipients with 9-(1,3-dihydroxy -2-propoxymethyl) guanine. Transplantation . 1988; 45:1139-41. [PubMed 2837848]

141. Culbertson WW. Infections of the retina in AIDS. Int Ophthalmol Clin . 1989; 29:108-18. [PubMed 2541096]

142. O'Donnell JJ, Jacobson MA. Cotton-wool spots and cytomegalovirus retinitis in AIDS. Int Ophthalmol Clin . 1989; 29:105-7. [PubMed 2541095]

143. Gaub J, Poulsen AG, Pedersen C et al. Efficacy and safety of two different dose levels of ganciclovir for the treatment of cytomegalovirus chorioretinitis in AIDS patients. Scand Infect Dis . 1988; 20:479-82.

144. Shea BF, Hoffman S, Sesin GP et al. Ganciclovir hepatotoxicity. Pharmacotherapy . 1987; 7:223-6. [PubMed 2832836]

145. Stoffel M, Gianello P, Squifflet JP et al. Effect of 9-(2-hydroxy -1-[hydroxymethyl]ethoxymethyl)guanine (DHPG) on cytomegalovirus pneumonitis after renal transplantation. Transplantation . 1988; 46:594-5. [PubMed 2845613]

146. Harbison MA, DeGirolami PC, Jenkins RL et al. Ganciclovir therapy of severe cytomegalovirus infections in solid-organ transplant recipients. Transplantation . 1988; 46:82-8. [PubMed 2839916]

148. Rook AH. Interactions of cytomegalovirus with the human immune system. Rev Infect Dis . 1988; 10(Suppl 3):S460-7. [PubMed 2847282]

149. Milliken S, Powles R, Ettinger N et al. Ganciclovir in the treatment of cytomegalovirus pneumonitis in bone marrow transplant recipients. Transplant Proc . 1989; 21:3110-1. [PubMed 2539692]

150. Drew WL. Diagnosis of cytomegalovirus infection. Rev Infect Dis . 1988; 10(Suppl 3):S468-76. [PubMed 2847283]

151. Ho WG, Winston DJ, Champlin RE. Tolerance and efficacy of ganciclovir in the treatment of cytomegalovirus infections in immunosuppressed patients. Transplant Proc . 1989; 21:3103-6. [PubMed 2539690]

152. Verheyden JPH. Evolution of therapy for cytomegalovirus infection. Rev Infect Dis . 1988; 10(Suppl 3):S477-89.

153. Rubin RH, Tolkoff-Rubin NE. Infection: the new problems. Transplant Proc . 1989; 21:1440-5. [PubMed 2652463]

154. Mai M, Nery J, Sutker W et al. DHPG (gancyclovir) improves survival in CMV pneumonia. Transplant Proc . 1989; 21:2263-5. [PubMed 2540565]

155. Panel on Opportunistic Infection in HIV-infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America (Accessed February 6, 2019). Updates may be available at HHS AIDS Information (AIDSinfo) website [Web]

156. Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for the prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected children: recommendations from the National Institutes of Health, Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, and the Pediatric Infectious Diseases Society (Accessed February 6, 2019). Updates may be available at HHS AIDS Information (AIDSinfo) website [Web]

157. Lim W, Kahn E, Gupta A et al. Treatment of cytomegalovirus enterocolitis with ganciclovir in an infant with acquired immunodeficiency syndrome. Pediatr Infect Dis J . 1988; 7:354-7. [PubMed 2837718]

158. Shelby J, Saffle JR, Kern ER. Delayed type hypersensitivity (DTH) response and skin graft survival in 9-(1,3-dihydroxy-2-propoxymethyl) guanine (DHPG) treated mice. Transplant Proc . 1989; 21:1150-1. [PubMed 2650083]

159. Lang P, Buisson C, Rostoker G et al. DHPG treatment of kidney transplant recipients with severe CMV infection. Transplant Proc . 1989; 21:2084-6. [PubMed 2540560]

160. Akula SK, Mansell PWA, Ruiz R. Treatment of cytomegalovirus retinitis with dihydroxy propoxymethyl guanine. Am J Ophthalmol . 1986; 101:622. [PubMed 3010726]

161. Pulliam L, Panitch HS, Baringer JR et al. Effect of antiviral agents on replication of herpes simplex virus type 1 in brain cultures. Antimicrob Agents Chemother . 1986; 30:840-6. [PubMed 3028250][PubMedCentral]

162. Shanley JD, Morningstar J, Jordan MC. Inhibition of murine cytomegalovirus lung infection and interstitial pneumonitis by acyclovir and 9-(1, 3-dihydroxy-2-propoxymethyl) guanine. Antimicrob Agents Chemother . 1985; 28:172-5. [PubMed 3010835][PubMedCentral]

163. Davies MEM, Bondi JV, Grabowski L et al. 2'-Nor-2'-deoxyguanosine is an effective therapeutic agent for treatment of experimental herpes keratitis. Antiviral Res . 1987; 7:119-25. [PubMed 3495237]

164. Bach MC, Hedstrom PS. CMV retinitis treated with ganciclovir [9-(1,3-dihydroxy -2-propoxymethyl)guanine] in patients with AIDS. Ann Ophthalmol . 1987; 19:369-75. [PubMed 2825580]

165. Masdeu JC, Small CB, Weiss L et al. Multifocal cytomegalovirus encephalitis in AIDS. Ann Neurol . 1988; 23:97-99. [PubMed 2830836]

166. Topiel MS, Kutscher JJ, Pilipshen SJ et al. Cytomegalovirus infection and 9-(1,3-dihydroxy -2-propoxymethyl)guanine, and Crohn's disease. Ann Intern Med . 1986; 105:302-3. [PubMed 3014944]

167. D'Amico DJ, Talamo JH, Felsenstein D et al. Ophthalmoscopic and histologic findings in cytomegalovirus retinitis treated with BW-B759U. Arch Ophthalmol . 1986; 104:1788-93. [PubMed 3024605]

168. Acheson JF, Shah SM, Spalton DJ et al. Treatment of CMV retinitis in an AIDS patient. Br J Ophthalmol . 1987; 71:810-6. [PubMed 2825756][PubMedCentral]

169. Pirsch JD, Stratta RJ, Sollinger HW et al. Treatment of severe Epstein-Barr virus-induced lymphoproliferative syndrome with ganciclovir: two cases after solid organ transplantation. Am J Med . 1989; 86:241-4. [PubMed 2536518]

170. Büchi ER, Fitting PL, Michel AE. Long-term intravitreal ganciclovir for cytomegalovirus retinitis in a patient with AIDS. Arch Ophthalmol . 1988; 106:1349-50. [PubMed 2845902]

171. Gonwa TA, Capehart JE, Pilcher JW et al. Cytomegalovirus myocarditis as a cause of cardiac dysfunction in a heart transplant recipient. Transplantation . 1989; 47:197-9. [PubMed 2536201]

172. Robinson MR, Teitelbaum C, Taylor-Findlay C. Thrombocytopenia and vitreous hemorrhage complicating ganciclovir treatment. Am J Ophthalmol . 1989; 107:560-1. [PubMed 2540661]

173. De Clercq E. Recent trends and development in antiviral chemotherapy. Antiviral Res . 1985; 5(Suppl 1):11-9.

174. Jacobson MA, Mills J. Cytomegalovirus infection. Clin Chest Med . 1988; 9:443-8. [PubMed 2842110]

175. Reed EC, Meyers JD. Treatment of cytomegalovirus infection. Clin Lab Med . 1987; 7: 831-52. [PubMed 2446819]

176. Henderly DE, Freeman WR, Smith RE et al. Cytomegalovirus retinitis as the initial manifestation of the acquired immune deficiency syndrome. Am J Ophthalmol . 1987; 103:316-20. [PubMed 3030112]

177. Teich SA, Orellana J, Friedman AH. Prevalence and pathophysiology, and treatment of rhegmatogenous retinal detachment in treated cytomegalovirus retinitis. Am J Ophthalmol . 1987; 104:312-4. [PubMed 2820231]

178. Reed EC, Dandliker PS, Meyers JD. Treatment of cytomegalovirus pneumonia with 9-[2-hydroxy-1- (hydroxymethyl)ethoxymethyl]guanine and high-dose corticosteroids. Ann Intern Med . 1986; 105:214-5. [PubMed 3014941]

179. Verdonck LF, de Gast GC, Dekker AW et al. Treatment of cytomegalovirus pneumonia after bone marrow transplantation with cytomegalovirus immunoglobulin combined with ganciclovir. Bone Marrow Transplant . 1989; 4:187-9. [PubMed 2539877]

180. Morris DJ. Ganciclovir and immune globulin in cytomegalovirus pneumonia. Ann Intern Med . 1989; 110:575. [PubMed 2538100]

181. Rasmussen L, Chen PT, Mullenax JG et al. Inhibition of human cytomegalovirus replication by 9-(1,3-dihydroxy-2-propoxymethyl)guanine alone and in combination with human interferons. Antimicrob Agents Chemother . 1984; 26:441-5. [PubMed 6097163][PubMedCentral]

182. Fraser-Smith EB, Eppstein DA, Marsh YV et al. Enhanced efficacy of the acyclic nucleoside 9-(1, 3-dihydroxy-2-propoxymethyl)guanine in combination with alpha-interferon against herpes simplex virus type 2 in mice. Antimicrob Agents Chemother . 1984; 26:937-8. [PubMed 6335382][PubMedCentral]

183. Moran DM, Kern ER, Overall JC Jr. Synergism between recombinant human interferon and nucleoside antiviral agents against herpes simplex virus: examination with an automated microtiter plate assay. J Infect Dis . 1985; 151:1116-22. [PubMed 2987369]

184. Eppstein DA, Marsh YV. Potent synergistic inhibition of herpes simplex virus-2 by [9-(1, 3-dihydroxy-2-propoxy)methyl]guanine in combination with recombinant interferons. Biochem Biophys Res Commun . 1984; 120:66-73. [PubMed 6201172]

185. Schmidt GM, Kovacs A, Zaia JA et al. Ganciclovir/immunoglobulin combination therapy for the treatment of human cytomegalovirus-associated interstitial pneumonia in bone marrow allograft recipients. Transplantation . 1988; 48:905-7.

186. Dolin R. Antiviral chemotherapy and chemoprophylaxis. Science . 1985; 227:1296-303. [PubMed 2983421]

187. Schulman JA, Peyman GA. Management of viral retinitis. Ophthalmic Surg . 1988; 19:876-84. [PubMed 2852786]

188. Watson FS, O'Connell JB, Amber IJ et al. Treatment of cytomegalovirus pneumonia in heart transplant recipients with 9-(1,3-dihydroxy -2-propoxymethyl)guanine (DHPG). J Heart Transplant . 1988; 7:102-5. [PubMed 2835468]

192. Gordin FM, Simon GL, Wofsy CB et al. Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med . 1984; 100:495-9. [PubMed 6230976]

193. Icenogle TB, Peterson E, Ray G. DHPG effectively treats CMV infection in heart and heart-lung transplant patients: a preliminary report. J Heart Transplant . 1987; 6:199-203. [PubMed 2822880]

194. Biron KK, Fyfe JA, Stanat SC et al. A human cytomegalovirus mutant resistant to the nucleoside analog 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine (BW B759U) induces reduced levels of BW B759U triphosphate. Proc Natl Acad Sci USA . 1986; 83:8769-73. [PubMed 3022304][PubMedCentral]

195. Reid R, Mar EC, Huang ES et al. Insertion and extension of acyclic and dideoxy, and ara nucleotides by Herpesviridae and human α and human β polymerases. J Biol Chem . 1988; 263:3898-904. [PubMed 2831212]

196. Boehme RE. Phosphorylation of the antiviral precursor 9-(1,3-dihydroxy-2-propoxymethyl) guanine monophosphate by guanylate kinase isoenzymes. J Biol Chem . 1984; 259:12346-9. [PubMed 6092331]

197. Murray JF, Felton CP, Garay SM et al. Pulmonary complications of the acquired immunodeficiency syndrome: report of a National Heart, Lung, and Blood Institute workshop. N Engl J Med . 1984; 310:1682-8. [PubMed 6328301]

198. Bratanow N, Ash RC, Turner P et al. The use of 9(1,3-dihydroxy-2-propoxymethyl)guanine (ganciclovir, DHPG) and intravenous immunoglobulin (IVIG) in the treatment of serious cytomegalovirus (CMV) infections in thirty-one allogeneic bone marrow transplant (BMT) patients. Blood . 1987; 70(Suppl 1):302.

199. Bratanow NC, Ash RC, Turner PA et al. Successful treatment of serious cytomegalovirus disease with 9(1,3-dihydroxy-2-propoxymethyl) guanine in bone marrow transplant (BMT) patients. Blood . 1986; 68:280a.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV (Accessed March 14, 2019). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]

201. Selby P, Powles RL, Jameson B et al. Treatment of cytomegalovirus pneumonitis after bone marrow transplantation with 9-[2-hydroxy -1-(hydroxymethyl)ethoxymethyl]guanine. Lancet . 1986; 1:1377-8. [PubMed 2872484]

202. Creasy TS, Flower AJE, Veitch PS. Life-threatening cytomegalovirus infection treated with dihydropropoxymethylguanine. Lancet . 1986; 1:675. [PubMed 2869359]

203. Freeman WR, Henderly DE, Wan WL et al. Prevalence and pathophysiology, and treatment of rhegmatogenous retinal detachment in treated cytomegalovirus retinitis. Am J Ophthalmol . 1987; 103:527-36. [PubMed 3031984]

204. Montplaisir S. Latency and activation of cytomegalovirus in man and in mice. Can J Microbiol . 1979; 25:261-6. [PubMed 222415]

205. Reed EC, Bowden RA, Dandliker PS et al. Treatment of cytomegalovirus (CMV) pneumonia in bone marrow transplant (BMT) patients (pts) with ganciclovir (GCV) and CMV immunoglobulin (CMV-IG). Blood . 1987; 70(Suppl 1):313.

206. Hooymans JMM, Sprenger HG, Weits J. Treatment of cytomegalovirus retinitis with DHPG in a patient with AIDS. Doc Ophthalmol . 1987; 67:5-12. [PubMed 2827978]

207. Chachoua A, Dieterich DT. 9-(1,3-Dihydroxy -2-propoxymethyl)guanine in patients with AIDS and CMV infections. Clin Res . 1986; 34:514A.

208. Kenley RA, Jackson SE, Winterle JS et al. Water soluble complexes of the antiviral drugs 9-[(1,3-dihydroxy-2-propoxy)methyl)]guanine and acyclovir: the role of hydrophobicity in complex formation. J Pharm Sci . 1986; 75:648-53. [PubMed 3489833]

209. Visser OHE, Bos PJM. Kaposi's sarcoma of the conjunctiva and CMV-retinitis in AIDS. Doc Ophthalmol . 1986; 64:77-85. [PubMed 3034535]

210. Cole NL, Balfour HH Jr. In vitro susceptibility of cytomegalovirus isolates from immunocompromised patients to acyclovir and ganciclovir. Diag Microbiol Infect Dis . 1987; 6:255- 61.

211. Shiota H, Naito T, Mimura Y. Anti-herpes simplex virus (HSV) effect of 9-(1,3-dihydroxy -2-propoxymethyl)guanine (DHPG) in rabbit cornea. Curr Eye Res . 1987; 6:241-5. [PubMed 3030645]

212. D'Alessandro AM, Pirsch JD, Stratta RJ et al. Successful treatment of severe cytomegalovirus infections with ganciclovir and CMV hyperimmune globulin in liver transplant recipients. Transplant Proc . 1989; 21:3560-1. [PubMed 2545018]

213. Wilson EJ, Medearis DN Jr, Hansen LA et al. 9-(1,3-Dihydroxy-2-propoxymethyl)guanine prevents death but not immunity in murine cytomegalovirus-infected normal and immunosuppressed BALB/c mice. Antimicrob Agents Chemother . 1987; 31:1017-20. [PubMed 2821884][PubMedCentral]

214. Taylor DL, Jeffries DJ, Taylor-Robinson D et al. The susceptibility of adenovirus infection to the anti-cytomegalovirus drug and ganciclovir (DHPG). FEMS Microbiol Lett . 1988; 49:337-41.

216. Anon. Ganciclovir. Med Lett Drugs Ther . 1989; 31:79-80. [PubMed 2549352]

217. Rosecan LR, Laskin OL, Kalman CM et al. Antiviral therapy with ganciclovir for cytomegalovirus retinitis and bilateral exudative retinal detachments in an immunocompromised child. Ophthalmology . 1986; 93:1401-7. [PubMed 3027642]

218. Katzenstein DA, Crane RT, Jordan MC. Successful treatment of murine cytomegalovirus disease does not prevent latent virus infection. J Lab Clin Med . 1986; 108:155-60. [PubMed 3016127]

219. de Hemptinne B, Lamy ME, Salizzoni M et al. Successful treatment of cytomegalovirus disease with 9-(1,3-dihydroxy-2-propoxymethyl)guanine. Transplant Proc . 1988; 20(Suppl 1):652-5. [PubMed 2831645]

220. Shabtai M, Luft B, Waltzer WC et al. Massive cytomegalovirus pneumonia and myocarditis in a renal transplant recipient: successful treatment with DHPG. Transplant Proc . 1988; 20:562-3. [PubMed 2837853]

221. Baba M, Konno K, Shigeta S et al. Inhibitory effects of selected antiviral compounds on newly isolated clinical varicella-zoster virus strains. Tohoku J Exp Med . 1986; 148:275-83. [PubMed 3010502]

222. van der Horst CM, Lin JC, Raab-Traub N et al. Differential effects of acyclovir and 9-(1, 3-dihydroxy-2-propoxymethyl)guanine on herpes simplex virus and Epstein-Barr virus in a dually infected human lymphoblastoid cell line. J Virol . 1987; 61:607-10. [PubMed 3027389][PubMedCentral]

223. Woolf NK, Ochi JW, Silva EJ et al. Ganciclovir prophylaxis for cochlear pathophysiology during experimental guinea pig cytomegalovirus labyrinthitis. Antimicrob Agents Chemother . 1988; 32:865-72. [PubMed 2843084][PubMedCentral]

224. Meijer H, Bruggeman CA, Dormans PHJ et al. Human cytomegalovirus induces a cellular deoxyguanosine kinase and also interacting with acyclovir. FEMS Microbiol Lett . 1984; 25:283-7.

225. Drew WL, Buhles W, Erlich KS. Herpesvirus infections (cytomegalovirus and herpes simplex virus, varicella-zoster virus): how to use ganciclovir (DHPG) and acyclovir. Infect Dis Clin North Am . 1988; 2: 495-509. [PubMed 2849621]

226. Corey L. The diagnosis and treatment of genital herpes. JAMA . 1982; 248:1041-9. [PubMed 7109193]

227. Pavan-Langston D, Park NH, Hettinger M. Ganglionic herpes simplex and systemic acyclovir. Arch Ophthalmol . 1981; 99:1417-9. [PubMed 6266375]

228. Fiala M, Payne JE, Berne TV et al. Epidemiology of cytomegalovirus infection after transplantation and immunosuppression. J Infect Dis . 1975; 132:421-33. [PubMed 171315]

229. Pavan-Langston D, Park NH, Lass JH. Herpetic ganglionic latency—aciclovir and vidarabine therapy. Arch Ophthalmol . 1979; 97:1508-10. [PubMed 223531]

230. Bader C, Crumpacker CS, Schnipper LE et al. The natural history of recurrent facial-oral infection with herpes simplex virus. J Infect Dis . 1978; 138:897-905. [PubMed 216753]

231. Graveleau P, Perol R, Chapman A. Regression of cauda equina syndrome in AIDS patient being treated with ganciclovir. Lancet . 1989; 2:511-2. [PubMed 2570224]

232. Russler SK, Tapper MA, Carrigan DR. Susceptibility of human herpesvirus 6 to acyclovir and ganciclovir. Lancet . 1989; 2:382. [PubMed 2569565]

233. Yamanishi K, Okuno T, Shiraki K et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet . 1988; 1:1065-7. [PubMed 2896909]

234. Agut H, Huraux JM, Collandre H et al. Susceptibility of human herpesvirus 6 to acyclovir and ganciclovir. Lancet . 1989; 2:626. [PubMed 2570323]

236. Lorian V, ed. Antibiotics in laboratory medicine. 2nd ed. Baltimore: Williams & Wilkins; 1986:365-8.

238. Holland GN, Pepose JS, Petit TH et al. Acquired immune deficiency syndrome: ocular manifestations. Ophthalmology . 1983; 90:859-73. [PubMed 6314219]

241. Pass RF. Epidemiology and transmission of cytomegalovirus. J Infect Dis . 1985; 152:243-8. [PubMed 2993429]

243. Jacobson MA, O'Donnell JJ, Porteous D et al. Retinal and gastrointestinal disease due to cytomegalovirus in patients with the acquired immunodeficiency syndrome: prevalence and natural history, and response to ganciclovir therapy. Q J Med . 1988; 67:473-86. [PubMed 2854894]

244. Palestine AG. Clinical aspects of cytomegalovirus retinitis. Rev Infect Dis . 1988; 10:S520-1. [PubMed 2847288]

245. Crawford SW, Bowden RA, Hackman RC et al. Rapid detection of cytomegalovirus pulmonary infection by bronchoalveolar lavage and centrifugation culture. Ann Intern Med . 1988; 108:180-5. [PubMed 2829672]

246. Margulis SJ, Honig CL, Soave R et al. Biliary tract obstruction in the acquired immunodeficiency syndrome. Ann Intern Med . 1986; 105:207-10. [PubMed 3014940]

247. Schneiderman DJ, Cello JP, Laing FC et al. Papillary stenosis and sclerosing cholangitis in the acquired immunodeficiency syndrome. Ann Intern Med . 1987; 106:546-9. [PubMed 3548523]

248. Ettinger NA, Selby P, Powles R et al. Cytomegalovirus pneumonia: the use of ganciclovir in marrow transplant recipients. J Antimicrob Chemother . 1989; 24:53-62. [PubMed 2550414]

249. Grundy JE, Shanley JD, and Griffiths PD. Is cytomegalovirus interstitial pneumonitis in transplant recipients an immunopathological condition? Lancet. 1987; 2:996-9.

250. Guarda LA, Luna MA, Smith JL Jr et al. Acquired Immune deficiency syndrome: postmortem findings. Am J Clin Pathol . 1984; 81:549-57. [PubMed 6326563]

251. Glasgow BJ, Anders K, Layfield LJ et al. Clinical and pathologic findings of the liver in the acquired immune deficiency syndrome (AIDS). Am J Clin Pathol . 1985; 83:582-8. [PubMed 2986450]

252. Quinnan GV Jr, Masur H, Rook AH et al. Herpesvirus infections in the acquired immunodeficiency syndrome. JAMA . 1984; 252:72-77. [PubMed 6328055]

253. Schulman J, Peyman GA, Horton MB et al. Intraocular 9-([2-hydroxy -1-(hydroxymethyl)ethoxymethyl)]guanine levels after intravitreal and subconjunctival administration. Ophthalmic Surg . 1986; 17:429-32. [PubMed 3014412]

254. Jabs DA, Bolten SG, Dunn JP et al. Discontinuing anticytomegalovirus therapy in patients with immune reconstitution after combination antiretroviral therapy. Am J Ophthalmol . 1998; 126:817-22. [PubMed 9860006]

255. Agut H, Collandre H, Aubin JT et al. In vitro sensitivity of human herpesvirus-6 to antiviral drugs. Res Virol . 1989; 140:219-28. [PubMed 2547238]

256. Jouan M, Saves M, Tubiana R et al. Discontinuation of maintenance therapy for cytomegalovirus retinitis in HIV-infected patients receiving highly active antiretroviral therapy. AIDS . 2001; 15:23-31. [PubMed 11192865]

257. Grossberg HS, Bonnem EM, Buhles Jr WC. GM-CSF with ganciclovir for the treatment of CMV retinitis in AIDS. New Engl J Med . 1989; 320:1560.

259. Pollard RB. Cytomegalovirus infections in renal and heart and heart-lung and liver transplantation. Pediatr Infect Dis J . 1988; 7: S97-102. [PubMed 2456512]

260. Yarchoan R, Mitsuya Y, Myers CE et al. Clinical pharmacology of 3'-azido-2', 3'-dideoxythymidine (zidovudine) and related dideoxynucleosides. N Engl J Med. 1989; 321:726-38.

261. Yarchoan R, Mitsuya H, Thomas RV et al. In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine. Science. 1989; 245:412-5.

262. Reviewers' comments (personal observations).

263. Dorfman J (Syntex Laboratories, Inc, Palo Alto, CA): Personal communication; 1989 Dec.

264. Heinemann MH. Long-term intravitreal ganciclovir therapy for cytomegalovirus retinopathy. Arch Ophthalmol . 1989; 107:1767-72. [PubMed 2556990]

265. Freeman WR. Intraocular antiviral therapy. Arch Ophthalmol . 1989; 107:1737-9. [PubMed 2556988]

266. Davis CL, Springmeyer S, Gmerek BJ. Central nervous system side effects of ganciclovir. New Engl J Med . 1990; 322:933-4. [PubMed 2156162]

267. Hochster H, Dieterich D, Bozzette S et al. Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS: an AIDS clinical trials group study. Ann Intern Med . 1990; 113:111-7. [PubMed 2163228]

270. Sulecki M, Rosenfeld CS, Przepiorka D et al. Treatment of ganciclcovir-induced neutropenia with recombinant human GM-CSF. Am J Med . 1991; 90:401-2. [PubMed 1848397]

271. Schmidt GM, Horak DA, Niland JC et al. A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants. N Engl J Med . 1991; 324:1005-11. [PubMed 1848679]

272. Knox KK, Drobyski WR, Carrigan DR. Cytomegalovirus isolate resistant to ganciclovir and foscarnet from a marrow transplant patient. Lancet . 1991; 337:1292-3. [PubMed 1674092]

273. Henderly DE, Jampol LM. Diagnosis and treatment of cytomegalovirus retinitis. J Acquir Immune Defic Syndr . 1991; 4(Suppl 1):S6-10. [PubMed 1848624]

274. Manischewitz JF, Quinnan GV Jr. Synergistic effect of ganciclovir and foscarnet on cytomegalovirus replication in vitro. Antimicrob Agents Chemother . 1990; 34:373-5. [PubMed 2158278][PubMedCentral]

275. Freitas VR, Fraser-Smith EB, Matthews TR. Increased efficacy of ganciclovir in combination with foscarnet against cytomegalovirus and herpes simplex virus type 2 in vitro and in vivo. Antiviral Res . 1989; 12:205-12. [PubMed 2559657]

276. Jacobson MA, O'Donnell JJ. Approaches to the treatment of cytomegalovirus retinitis: ganciclovir and foscarnet. J Acquir Immune Defic Syndr . 1991; 4(Suppl 1):S11-5.

277. Nelson MR, Barter G, Hawkins D et al. Simultaneous treatment of cytomegalovirus retinitis with ganciclovir and foscarnet. Lancet . 1991; 338:250. [PubMed 1676798]

278. Coker RJ, Tomlinson D, Horner P et al. Treatment of cytomegalovirus retinitis with ganciclovir and foscarnet. Lancet . 1991; 338:574. [PubMed 1678829]

279. Kupfer C, Jabs D, Stein M et al. Clinical alert and HHS News: findings of the Foscarnet-Ganciclovir Cytomegalovirus Trial. Bethesda, MD: National Institutes of Health, National Eye Institute; 1991 Oct 17 and Rockville, MD: US Public Health Service; 1991 Oct 21.

280. Palestine AG, Polis MA, De Smet MD et al. A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med . 1991; 115:665-73. [PubMed 1656826]

281. Hirsch MS. The treatment of cytomegalovirus in AIDS—more than meets the eye. N Engl J Med . 1992; 326:264-6. [PubMed 1309391]

282. Ocular Complications of AIDS Research Group and the AIDS Clinical Trials Group. Mortality in patients with the acquired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis. N Engl J Med . 1992; 326:213-20. [PubMed 1345799]

283. Merigan TC, Renlund DG, Keay S et al. A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation. N Engl J Med . 1992; 326:1182-6. [PubMed 1313549]

284. Goodrich JM, Mori M, Gleaves CA et al. Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. N Engl J Med . 1991; 325:1601-7. [PubMed 1658652]

285. Bailey TC, Trulock EP, Ettinger NA et al. Failure of prophylactic ganciclovir to prevent cytomegalovirus disease in recipients of lung transplants. J Infect Dis . 1992; 165:548-52. [PubMed 1311352]

286. Rubin RH. Preemptive therapy in immunocompromised hosts. N Engl J Med . 1991; 324:1057-8. [PubMed 1848680]

287. Laske A, Gallino A, Mohacsi P et al. Prophylactic treatment with ganciclovir for cytomegalovirus infection in heart transplantation. Transplant Proc . 1991; 23:1170-3. [PubMed 1846456]

288. Bailey TC, Trulock EP, Storch GA et al. Ganciclovir for cytomegalovirus after heart transplantation. N Engl J Med . 1991; 327:891.

289. Winston DJ. Ganciclovir for cytomegalovirus after heart transplantation. N Engl J Med . 1991; 327:891.

290. Stanat SC, Reardon JE, Erice A et al. Ganciclovir-resistant cytomegalovirus clinical isolates: mode of resistance to ganciclovir. Antimicrob Agents Chemother . 1991; 35:2191-7. [PubMed 1666492][PubMedCentral]

291. Jacobson MA, Drew WL, Feinberg J et al. Foscarnet therapy for ganciclovir-resistant cytomegalovirus retinitis in patients with AIDS. J Infect Dis . 1991; 163:1348-51. [PubMed 1645385]

292. American Academy of Pediatrics. Red Book: 2018-2021 Report of the Committee on Infectious Diseases. 31st ed. Itasca, IL: American Academy of Pediatrics; 2018.

293. Pau AK, Pitrak DL. Management of cytomegalovirus infection in patients with acquired immunodeficiency syndrome. Clin Pharm . 1990; 9:613-31. [PubMed 2167189]

294. Medina DJ, Hsiung GD, Mellors JW. Ganciclovir antagonizes the anti-human immunodeficiency virus type 1 activity of zidovudine and didanosine in vitro. Antimicrob Agents Chemother . 1992; 36:1127-30. [PubMed 1510405][PubMedCentral]

295. Prichard MN, Prichard LE, Baguley WA et al. Three-dimensional analysis of the synergistic cytotoxicity of ganciclovir and zidovudine. Antimicrob Agents Chemother . 1991; 35:1060-5. [PubMed 1929243][PubMedCentral]

296. Parasrampuria J, Li LC, Stelmach AH et al. Stability of ganciclovir sodium in 5% dextrose injection and in 0.9% sodium chloride injection over 35 days. Am J Hosp Pharm . 1992; 49:116-8. [PubMed 1570851]

297. Mole L, Oliva C, O'Hanley P. Extended stability of ganciclovir for outpatient parenteral therapy for cytomegalovirus retinitis. J Acquir Immune Defic Syndr . 1992; 5:354-8. [PubMed 1312595]

298. Hartman NR, Yarchoan R, Pluda JM et al. Pharmacokinetics of 2',3'-dideoxyinosine in patients with severe human immunodeficiency infection: II. The effects of different oral formulations and the presence of other medications. Clin Pharmacol Ther . 1991; 50:278-85. [PubMed 1914362]

300. Drew WL. Cytomegalovirus infection in patients with AIDS. Clin Infect Dis . 1992; 14:608-15. [PubMed 1313313]

301. Faulds D, Brogden RN. Didanosine: a review of its antiviral activity, pharmacokinetic properties and therapeutic potential in human immunodeficiency virus infection. Drugs . 1992; 44:94-116. [PubMed 1379914]

302. Laske A, Gallino A, Carrel T et al. Ganciclovir for cytomegalovirus after heart transplantation. N Engl J Med . 1992; 327:892. [PubMed 1324433]

303. Merigan TC, Renlund D, Buhles W et al. N Engl J Med . 1992; 327:892-3. Reply.

304. Yau JC, Dimopoulos MA, Huan SD et al. Prophylaxis of cytomegalovirus infection with ganciclovir in allogeneic marrow transplantation. Eur J Haematol . 1991; 47:371-6. [PubMed 1662140]

305. Atkinson K, Downs K, Golenia M et al. Prophylactic use of ganciclovir in allogeneic bone marrow transplantation: absence of clinical cytomegalovirus infection. Br J Haematol . 1991; 79:57-62. [PubMed 1654994]

306. Goodrich JM, Bowden RA, Fisher L et al. Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann Intern Med . 1993; 118:173-8. [PubMed 8380242]

307. Winston DJ, Ho WG, Bartoni K et al. Ganciclovir prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow transplant recipients. Ann Intern Med . 1993; 118:179-84. [PubMed 8380243]

309. Jacobson MA, Owen W, Campbell J et al. Tolerability of combined ganciclovir and didanosine for the treatment of cytomegalovirus disease associated with AIDS. Clin Infect Dis . 1993; 16(Suppl 1):S69-73. [PubMed 8381032]

310. Dieterich DT, Poles MA, Lew EA et al. Concurrent use of ganciclovir and foscarnet to treat cytomegalovirus infection in AIDS patients. J Infect Dis . 1993; 167:1184-8. [PubMed 8387563]

311. Spector SA, Weingeist T, Pollard RB et al. A randomized, controlled study of intravenous ganciclovir therapy for cytomegalovirus peripheral retinitis in patients with AIDS. J Infect Dis . 1993; 168:557-63. [PubMed 8394858]

312. Peters M, Schurmann D, Pohle HD et al. Combined and alternating ganciclovir/foscarnet in HIV-related cytomegalovirus encephalitis. Lancet . 1992; 340:970. [PubMed 1357363]

313. Rubin RH, Tolkoff-Rubin NE. Antimicrobial strategies in the care of organ transplant recipients. Antimicrob Agents Chemother . 1993; 37:619-24. [PubMed 8494357][PubMedCentral]

314. Zaia JA. Prevention and treatment of cytomegalovirus pneumonia in transplant recipients. Clin Infect Dis . 1993; 17(Suppl 2):S392-9. [PubMed 8274605]

315. Buckner FS, Pomeroy C. Cytomegalovirus disease of the gastrointestinal tract in patients without AIDS. Clin Infect Dis . 1993; 17:644-56. [PubMed 8268345]

316. Dieterich DT, Kotler DP, Busch DF et al. Ganciclovir treatment of cytomegalovirus colitis in AIDS: a randomized, double-blind, placebo-controlled multicenter study. J Infect Dis . 1993; 167:278-82. [PubMed 8380610]

319. Masur H, Whitcup SM, Cartwright C et al. Advances in the management of AIDS-related cytomegalovirus retinitis. Ann Intern Med . 1996; 125:126-36. [PubMed 8678367]

320. Stewart JA, Reef SE, Pellett PE et al. Herpesvirus infections in persons infected with human immunodeficiency virus. Clin Infect Dis . 1995; 21(Suppl 1):S114-20. [PubMed 8547499]

321. Spector SA, McKinley GF, Lalezari JP et al. Oral ganciclovir for the prevention of cytomegalovirus disease in persons with AIDS. N Engl J Med . 1996; 334:1491-7. [PubMed 8618603]

322. Crumpacker CS. Ganciclovir. N Engl J Med . 1996; 335:721-9. [PubMed 8786764]

324. Winston DJ, Wirin D, Shaked A et al. Randomised comparison of ganciclovir and high-dose acyclovir for long-term cytomegalovirus prophylaxis in liver-transplant recipients. Lancet . 1995; 346:69-74. [PubMed 7603215]

325. Gane E, Saliba S, Valdecasas JCG et al. Randomised trial of efficacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in liver-transplant recipients. Lancet . 1997; 350:1729-33. [PubMed 9413463]

326. Goodrich J, Khardori N. Cytomegalovirus: the taming of the beast? Lancet . 1997; 350:1718-19.

327. Patel R, Snydman DR, Rubin RH et al. Cytomegalovirus prophylaxis in solid organ transplant recipients. Transplantation . 1996; 61:1279-89. [PubMed 8629285]

328. Paya CV. Defining an optimal regimen for cytomegalovirus prophylaxis in organ transplant recipients. Transplant Proc . 1996; 28(Suppl 2):9-11. [PubMed 9037269]

329. Griffiths PD. Prophylaxis against CMV infection in transplant patients. J Antimicrob Chemother . 1997; 39:299-301. [PubMed 9096177]

330. Conti DJ, Shen G, Singh T et al. Ganciclovir prophylaxis of cytomegalovirus disease. Transplant Proc . 1997; 29:804-6. [PubMed 9123534]

331. Prentice HG, Kho P. Clinical strategies for the management of cytomegalovirus infection and disease in allogeneic bone marrow transplant. Bone Marrow Transplant . 1997; 19:135-42. [PubMed 9116610]

332. Badas A, Stoukides CA. Guidelines for prophylaxis of cytomegalovirus disease in bone marrow transplant patients. Ann Pharmacother . 1996; 30:1483-6. [PubMed 8968462]

333. Reusser P. The challenge of cytomegalovirus infection after bone arrow transplantation: epidemiology, prophylaxis, and therapy. Bone Marrow Transplant . 1996; 18:107-9. [PubMed 8932809]

334. Hibberd PL, Tolkoff-Rubin NE, Conti D et al. Preemptive ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus antibody-positive renal transplant recipients. Ann Intern Med . 1995; 123:18-26. [PubMed 7762909]

335. Rowe JM, Ciobanu N, Ascensao J et al et al. Recommended guidelines for the management of autologous and allogeneic bone marrow transplantation: a report from the Eastern Cooperative Oncology Group (ECOG). Ann Intern Med . 1994; 120:143-58. [PubMed 8256974]

336. Whitley RS, Jacobson MA, Friedberg DN et al. Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy—recommendations of an international panel. Arch Intern Med . 1998; 158:957-69. [PubMed 9588429]

337. Cunningham ET, Margolis TP. Ocular manifestations of HIV infection. N Engl J Med . 1998; 339:336-44.

339. Balfour HH. Antiviral drugs. N Engl J Med . 1999; 340:1255-68. [PubMed 10210711]

341. Tural C, Romeu J, Sirera G et al. Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virus-infected patients. J Infect Dis . 1998; 177:1080-3. [PubMed 9534987]

342. MacDonald JC, Torriani FJ, Morse LS et al. Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy. J Infect Dis . 1998; 177:1182-7. [PubMed 9593001]

343. Vrabec TR, Baldassano VF, Whitcup SM. Discontinuation of maintenance therapy in patients with quiescent cytomegalovirus retinitis and elevated CD4+ counts. Ophthalmology . 1998; 105:1259-64. [PubMed 9663231]

346. Jayasekara D, Aweeka FT, Rodriguez R et al. Antiviral therapy for HIV patients with renal insufficiency. J Acquir Immune Defic Syndr . 1999; 21:384-95. [PubMed 10458619]

347. Cimoch PJ, Lavelle P, Pollard R et al. Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine, and probenecid in HIV-infected subjects. J Acquir Immun Defic Syndr Hum Retrovirol . 1998; 17:227-34.

350. Engorn B and Flerlage J eds. The Harriet Lane Handbook. 12th ed. Philadelphia, PA: Elsevier; 2015: p. 800.

351. Merck & Co., Inc. Prevymis^® (letermovir) film-coated tablets and injection, for intravenous use prescribing information. Whitehouse Station, NJ; 2019 Mar.

352. Hospira. Foscavir^® (foscarnet sodium) injection prescribing information. Lake Forest, IL; 2017 Nov.