VA Class:AM800
Valganciclovir, a prodrug of ganciclovir, is an antiviral agent; after in vivo conversion to an active metabolite, the drug is active against herpes viruses.1, 85
Treatment of Cytomegalovirus Infection and Disease
Valganciclovir hydrochloride is used for initial treatment (induction therapy) and maintenance therapy (secondary prophylaxis) of cytomegalovirus (CMV) retinitis in adults with human immunodeficiency virus (HIV) infection, including those with acquired immunodeficiency syndrome (AIDS).1, 3, 8, 85, 155 The drug also is used for the management of CMV retinitis in certain HIV-infected pediatric patients†.156
Like others antivirals, valganciclovir is not a cure for CMV retinitis;1 the retinitis may relapse and/or progress during or after discontinuance of the drug.1
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 the 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 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
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 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 the 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
In a randomized, open-label, comparative study (study WV15376) in HIV-infected adults with AIDS (median age 39 years, baseline plasma HIV-1 RNA levels of 4.9 log10, median CD4+ T-cell count of 23/mm3, 91% male, 53% white, 31% Hispanic, 11% black) with previously untreated CMV retinitis, oral valganciclovir (900 mg twice daily for 21 days followed by 900 mg once daily for 7 days) was as effective as IV ganciclovir (5 mg/kg twice daily for 21 days followed by 5 mg/kg once daily for 7 days) in delaying CMV retinitis progression based on a masked evaluation of retinal photographs at week 4 of the study (the primary outcome measure).1, 3
All patients enrolled in study WV15376 received maintenance therapy with open-label valganciclovir after week 4;1 the median time to photographically determined first CMV retinitis progression in patients who had received initial treatment (induction therapy) with oral valganciclovir or IV ganciclovir was 180 days (mean: 226) or 126 days (mean: 219), respectively.7
Extraocular Cytomegalovirus Infections
Safety and efficacy of valganciclovir have not been established for the management of extraocular CMV infections.1
CDC, NIH, and IDSA state that IV ganciclovir usually is the preferred antiviral for initial management of CMV GI disease (e.g., colitis, esophagitis) 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 also state that oral valganciclovir can be considered for initial management of CMV esophagitis† or colitis† in patients with GI symptoms that do not interfere with oral absorption.155
Congenital Cytomegalovirus Disease
Although safety and efficacy of valganciclovir have not been established in neonates or infants with congenital CMV infection,1 the drug has been used for the management of symptomatic congenital CMV disease† when an antiviral was indicated.83, 85, 156, 292
Transmission of CMV from infected mothers to their fetuses occurs as a result of maternal viremia and transplacental infection.1 Perinatal infection also can occur from exposure of the neonate to CMV shedding in the mother's genital tract.1 Approximately 10% of children with congenital CMV infection are symptomatic at birth;1 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 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
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
A 6-month regimen of oral valganciclovir has been used in neonates with symptomatic congenital CMV disease (with or without CNS involvement), and there is some evidence that this regimen is associated with some improvement in audiologic and neurodevelopmental outcomes at 12 and 24 months compared with a 6-week regimen of oral valganciclovir.83, 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 in HIV-exposed or HIV-infected infants with symptomatic congenital CMV disease with CNS involvement.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
Valganciclovir hydrochloride is used for prophylaxis to prevent CMV infection and disease in certain adult and pediatric solid organ transplant recipients at high risk for the disease.1, 76, 79, 80, 81, 82, 85 The drug also has been used for prophylaxis or preemptive treatment of CMV infection and disease in hematopoietic stem cell transplant (HSCT) recipients† at risk for the disease.74, 76, 78, 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, 78, 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, 78, 81, 82, 86 These antiviral strategies each have certain advantages and disadvantages.74, 76, 78, 81, 82
Specialized references should be consulted for specific information regarding prevention and management of CMV infections in HSCT or solid organ transplant recipients.74, 76, 78, 81, 82
Solid Organ Transplant Recipients
Valganciclovir hydrochloride is used for prophylaxis to prevent CMV infection and disease in adult kidney, heart, and kidney-pancreas transplant recipients considered at high risk (CMV-seronegative recipient of an organ from a CMV-seropositive donor).1, 76, 79, 80, 81, 82, 85 The drug also is used for prophylaxis to prevent CMV infection and disease in pediatric kidney transplant recipients 4 months to 16 years of age and pediatric heart transplant recipients 1 month to 16 years of age considered at high risk (CMV-seronegative recipient of an organ from a CMV-seropositive donor).1
Valganciclovir also has been used for preemptive treatment of CMV infection in solid organ transplant recipients† (e.g., kidney, heart, pancreas);76, 80, 81, 85 however, safety and efficacy of the drug have not been established for preemptive treatment of CMV infections in transplant recipients.1
Although safety and efficacy of valganciclovir have not been established in adult or pediatric liver transplant recipients and low efficacy was reported in one study in adult patients (see Clinical Experience under Prevention of Cytomegalovirus Infection and Disease: Solid Organ Transplant Recipients, in Uses), 1, 9 the drug has been used and is recommended by some clinicians for prophylaxis or preemptive treatment of CMV infection in liver transplant recipients†.76, 80, 81, 82
Safety and efficacy of valganciclovir for prevention of CMV disease in 372 solid organ transplant recipients were evaluated in a double-blind, double-dummy, active comparator study (study PV16000) in heart, liver, kidney, and kidney-pancreas transplant patients at high risk (CMV-seronegative recipient of an organ from a CMV-seropositive donor).1 Patients were randomized to receive oral valganciclovir (900 mg once daily) or oral ganciclovir (1 g 3 times daily; not commercially available in the US) initiated within 10 days of transplantation and continued until 100 days after transplantation.1 During the first 6 months following transplantation, 12% of those receiving valganciclovir and 15% of those receiving ganciclovir developed CMV disease (CMV syndrome and/or tissue-invasive disease).1 However, in liver transplant recipients, the incidence of CMV disease was greater in those receiving valganciclovir (19%) than in those receiving ganciclovir (12%); tissue-invasive CMV disease was reported most frequently.1 Mortality at 6 months was 3.7% in the oral valganciclovir group and 1.6% in the oral ganciclovir group.1
Safety and efficacy of a longer duration (200 days) of valganciclovir prophylaxis against CMV disease in kidney transplant recipients were established in a double-blind, placebo-controlled trial that included 326 adult kidney transplant patients at high risk (CMV-seronegative recipient of an organ from a CMV-seropositive donor).1, 12 Patients were randomized to receive valganciclovir prophylaxis (900 mg once daily) starting within 10 days of transplantation and continued for either 200 days posttransplantation or for 100 days posttransplantation followed by placebo for 100 days.1, 12 At 1 year posttransplantation, the incidence of CMV disease was about 17% in those who received 200 days of valganciclovir prophylaxis compared with 37% in those who received only 100 days of such prophylaxis.1, 12 There was no overall difference in the safety profile between the 2 groups.12
Safety and pharmacokinetics of oral valganciclovir for prevention of CMV disease in pediatric patients were established in an open-label study of 63 solid organ transplant (i.e., kidney, liver, heart, kidney-liver) recipients 4 months to 16 years of age.1, 10 These pediatric patients received once-daily valganciclovir (tablets or oral solution) given in a dose calculated based on body surface area (BSA) and estimated creatinine clearance (modified Schwartz formula) and limited to a maximum dosage of 900 mg daily.1, 10 Valganciclovir treatment was initiated within 10 days posttransplantation and continued for a maximum of 100 days (median duration was approximately 92 days).1, 10 Systemic ganciclovir exposures in these pediatric solid organ transplant patients were somewhat higher compared with exposures reported in adult solid organ transplant patients receiving the drug at a dosage of 900 mg once daily.1, 10 Although CMV viremia was reported in 11% of patients in this study, CMV disease was not reported in any pediatric patient up to 26 weeks posttransplantation.1, 10 Use of valganciclovir for the prevention of CMV disease in pediatric kidney or heart transplant recipients 4 months to 16 years of age at high risk for the disease is based on pharmacokinetic, safety, and efficacy data from this open-label study and efficacy extrapolated from a study in adults.1
Valganciclovir in pediatric patients also was evaluated in an open-label tolerability study that included 57 renal transplant recipients 1 month to 16 years of age who were at risk for developing CMV disease.1 All patients received once-daily valganciclovir (tablets or oral solution) given in a dose calculated based on BSA and modified creatinine clearance.1 Valganciclovir treatment was initiated within 10 days posttransplantation and continued for a maximum of 200 days.1 No cases of CMV syndrome or tissue-invasive CMV disease were reported within the first 12 months posttransplantation.1
Hematopoietic Stem Cell Transplant Recipients
Valganciclovir has been used for prophylaxis or preemptive treatment of CMV infection and disease in HSCT recipients†.74, 76, 78, 85
Valganciclovir hydrochloride is administered orally as tablets or an oral solution and should be given with food.1
Adults should receive valganciclovir tablets (not the oral solution).1 Valganciclovir tablets should not be broken or crushed.1
Valganciclovir oral solution is the preferred dosage form for pediatric patients.1 Valganciclovir tablets should be used in pediatric patients only if the calculated dose is within 10% of the tablet strength (i.e., a single 450-mg tablet may be used if the calculated dose is 405-495 mg).1 (See Pediatric Dosage under Dosage and Administration: Dosage.)
Patients receiving valganciclovir should be adequately hydrated.1
Females of childbearing potential should be tested for pregnancy prior to initiation of valganciclovir.1 (See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)
Because of the mutagenic and/or carcinogenic potential of valganciclovir, the tablets, powder for oral solution, and reconstituted oral solutions of the drug should be handled carefully according to guidelines issued for cytotoxic drugs.1 (See Handling and Disposal under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)
Valganciclovir hydrochloride powder for oral solution should be reconstituted at the time of dispensing by adding 91 mL of purified water to provide a solution containing 250 mg of valganciclovir per 5 mL.1 After tapping the bottle to loosen the powder, the water should be added in 2 approximately equal portions and the bottle should be shaken for about 1 minute after each addition.1 Following reconstitution, the solution is colorless to brownish yellow.1
The reconstituted oral solution should be stored at 2-8°C for up to 49 days and should not be frozen.1
Just prior to each dose, the oral solution should be shaken for about 5 seconds.1
The appropriate dose of the reconstituted oral solution should be administered using the bottle adapter and dosing dispenser provided by the manufacturer.1
Dosage of valganciclovir hydrochloride is expressed in terms of valganciclovir.1
For initial treatment (induction therapy) of cytomegalovirus (CMV) retinitis in adults with normal renal function (creatinine clearance 60 mL/minute or greater), the recommended dosage of valganciclovir tablets is 900 mg orally twice daily for 21 days.1, 8, 155 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 (induction therapy) be continued for 14-21 days in adults with human immunodeficiency virus (HIV) infection.155 In patients with immediate sight-threatening CMV retinal lesions (i.e., within 1.5 mm of the fovea), these experts 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 or in patients with inactive CMV retinitis, the recommended dosage of valganciclovir tablets for maintenance therapy (secondary prophylaxis) in adults with normal renal function is 900 mg orally once daily.1, 8, 155
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
If oral valganciclovir is used for the management of CMV esophagitis† or colitis† in HIV-infected adults, CDC, NIH, and IDSA recommend a dosage of 900 mg every 12 hours 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
Prevention of Cytomegalovirus Infection and Disease in Transplant Recipients
For prophylaxis to prevent CMV infection and disease in adult heart or kidney-pancreas transplant recipients, the usual dosage of valganciclovir tablets is 900 mg once daily initiated within 10 days of transplantation and continued until 100 days posttransplantation.1 Some experts recommend that antiviral prophylaxis be continued for 3-6 months in CMV-seronegative recipients of heart, liver†, or pancreas transplants from CMV-seropositive donors.81, 82
For prophylaxis to prevent CMV infection and disease in adult kidney transplant recipients, the usual dosage of valganciclovir tablets is 900 mg once daily initiated within 10 days of transplantation and continued until 200 days posttransplantation.1 Some experts recommend that antiviral prophylaxis be continued for 6 months in CMV-seronegative recipients of kidney transplants from CMV-seropositive donors.81, 82
If oral valganciclovir is used for preemptive treatment of CMV infection in solid organ transplant recipients†, a dosage of 900 mg twice daily is recommended in those with normal renal function.82
If oral valganciclovir is used for initial treatment (induction therapy) of CMV retinitis in HIV-infected older children† and adolescents† who can receive adult dosage, CDC, NIH, IDSA, and others recommend a dosage of 900 mg twice daily for 14-21 days.155, 156
If oral valganciclovir is used for maintenance therapy (secondary prophylaxis) of CMV retinitis in HIV-infected older children† and adolescents† who can receive adult dosage, CDC, NIH, IDSA, and others recommend a dosage of 900 mg once daily.155, 156
Decisions regarding discontinuance of maintenance therapy of CMV retinitis in HIV-infected individuals who have been treated 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, 156 (See Cytomegalovirus Retinitis under Uses: Treatment of Cytomegalovirus Infection and Disease.)
Congenital Cytomegalovirus Disease
If oral valganciclovir 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 16 mg/kg twice daily.84, 292
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 heart transplant patients 1 month to 16 years of age, oral valganciclovir should be given once daily initiated within 10 days of transplantation and continued until 100 days posttransplantation.1
For prophylaxis to prevent CMV infection and disease in pediatric kidney transplant patients 4 months to 16 years of age, oral valganciclovir should be given once daily initiated within 10 days of transplantation and continued until 200 days posttransplantation.1
The pediatric dose of oral valganciclovir for prevention of CMV infection and disease should be individualized based on body surface area (BSA) and estimated creatinine clearance (Clcr, modified Schwartz formula), and is calculated using the following pediatric dosage equation:1
Pediatric dose (in mg) = 7 × BSA (in m2) × Clcr (modified Schwartz formula)
Modified Schwartz Clcr (in mL/minute per 1.73 m2) = [k × height (in cm)]/ serum creatinine (in mg/dL)
k = 0.33 for infants less than 1 year of age with low birthweight for gestational age
k = 0.45 for infants less than 1 year of age with birthweight appropriate for gestational age
k = 0.45 for children 1 to less than 2 years of age
k = 0.55 for girls 2 to less than 16 years of age
k = 0.55 for boys 2 to less than 13 years of age
k = 0.7 for boys 13-16 years of age
To prevent overdosage in pediatric patients, the estimated creatinine clearance used to calculate the pediatric dose should not exceed 150 mL/minute per 1.73 m2, regardless of the value calculated using the modified Schwartz formula.1, 11 If the estimated creatinine clearance exceeds 150 mL/minute per 1.73 m2, the value of 150 mL/minute per 1.73 m2 should be used to calculate the dose for that patient.1, 11 The calculated dose should be rounded to the nearest 10-mg increment.1 The maximum dose in pediatric patients is 900 mg.1
In patients with impaired renal function, dosage and/or frequency of administration of valganciclovir must be modified in response to the degree of impairment.1
Dosage for adults with renal impairment should be based on the patient's creatinine clearance, which can be estimated using the following formula:1
Ccr male = [(140 - age in years) × weight (in kg)] / [72 × serum creatinine (in mg/dL)]
Ccr female = 0.85 × Ccr male
Dosage for pediatric patients with renal impairment can be calculated using the usually recommended pediatric dosage equation since this is based on both BSA and estimated creatinine clearance.1 (See Pediatric Dosage under Dosage and Administration: Dosage.)
Valganciclovir should not be used in adults undergoing hemodialysis (creatinine clearance less than 10 mL/minute).1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
When valganciclovir is used for initial treatment (induction therapy) and maintenance therapy (secondary prophylaxis) of CMV retinitis in adults with renal impairment, dosage should be based on the patient's creatinine clearance.1 (See Table 1.)
Creatinine Clearance (mL/minute) | Initial Treatment (Induction) Dosage | Maintenance Dosage |
|---|---|---|
40-59 | 450 mg twice daily | 450 mg once daily |
25-39 | 450 mg once daily | 450 mg once every 2 days |
10-24 | 450 mg once every 2 days | 450 mg twice weekly |
Less than 10 (hemodialysis patients) | Not recommended | Not recommended |
Dosage of valganciclovir for geriatric patients should be selected with caution, usually starting at the low end of the dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function.1 Renal function should be assessed before and during valganciclovir therapy and appropriate dosage adjustments made as necessary.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
Valganciclovir is contraindicated in patients who have had a clinically important hypersensitivity reaction (e.g., anaphylaxis) to valganciclovir, ganciclovir, or any ingredient in the formulation.1
Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure (including aplastic anemia) have been reported in patients receiving valganciclovir or ganciclovir.1 Cytopenia may occur at any time during valganciclovir therapy and the degree of cytopenia may increase with continued therapy with the drug.1 Cell counts usually begin to return to baseline within 3-7 days after valganciclovir is discontinued.1
Complete blood cell counts (CBCs) with differential and platelet counts should be performed frequently, especially in infants and in patients with baseline neutrophil counts less than 1000/mm3, in those who previously experienced leukopenia while receiving ganciclovir or other nucleoside analogs, and in those with renal impairment.1 Because oral valganciclovir results in comparatively increased plasma ganciclovir concentrations compared with oral ganciclovir (not commercially available in the US), more frequent monitoring for cytopenias may be warranted if therapy is changed from oral ganciclovir to valganciclovir.1
Valganciclovir should be avoided 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
Valganciclovir should be used with caution in patients with preexisting cytopenias and in those who have received or are receiving concomitant myelosuppressive drugs or irradiation.1
In patients experiencing severe leukopenia, neutropenia, anemia, and/or thrombocytopenia, treatment with hematopoietic growth factors may be considered.1
Animal data from studies using ganciclovir and limited data from patients receiving valganciclovir indicate that valganciclovir may cause temporary or permanent inhibition of spermatogenesis in males and may cause suppression of fertility in females.1
In a small, open-label, nonrandomized clinical study, adult male renal transplant patients receiving cytomegalovirus (CMV) prophylaxis with oral valganciclovir 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 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 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
Patients receiving valganciclovir should be advised that the drug may be associated with infertility.1
Animal data from studies using ganciclovir indicate that valganciclovir may cause fetal toxicity and has the potential to cause birth defects if administered to pregnant women.1
In studies in pregnant mice and rabbits receiving ganciclovir at dosages resulting in 2 times the human exposure, maternal toxicity and embryofetal toxicity (e.g., fetal resorptions, embryofetal mortality) was observed.1 In addition, teratogenic effects (cleft palate, anophthalmia/microphthalmia, hydrocephalus, brachygnathia, aplastic organs [kidney, pancreas]) were reported in rabbits.1
Females of childbearing potential should undergo pregnancy testing before valganciclovir is initiated.1
Females of childbearing potential should be advised to use an effective method of contraception during and for at least 30 days after valganciclovir is discontinued.1 Male patients should be advised to use a reliable method of barrier contraception during and for at least 90 days after valganciclovir is discontinued.1
Mutagenicity and Carcinogenicity
Animal studies using ganciclovir indicate the drug is mutagenic and carcinogenic.1
Valganciclovir should be considered a potential carcinogen in humans.1
Acute renal failure may occur in geriatric patients (with or without renal impairment), patients receiving potentially nephrotoxic drugs, and inadequately hydrated patients.1
Adequate hydration should be maintained in all patients.1
Valganciclovir should be used with caution in geriatric patients and in patients receiving concomitant therapy with potentially nephrotoxic drugs.1
Dosage adjustment of valganciclovir is recommended in patients with renal impairment.1 (See Renal Impairment under Dosage and Administration: Special Populations.)
Because valganciclovir is considered a potential teratogen and carcinogen, caution should be exercised when handling the drug.1 Valganciclovir tablets should not be broken or crushed.1 Direct contact of broken or crushed tablets, powder for oral solution, or reconstituted oral solution with skin or mucous membranes should be avoided.1 If such contact occurs, skin should be washed thoroughly with soap and water; eyes should be rinsed thoroughly with water.1 For further information on handling of cytotoxic drugs, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
In animal studies, ganciclovir caused maternal and fetal toxicity, embryofetal mortality, and teratogenicity.1 Valganciclovir is expected to have reproductive toxicity similar to ganciclovir.1 (See Teratogenesis under Warnings/Precautions: Warnings, in Cautions.)
Data are not available regarding use of valganciclovir in pregnant women to establish the presence or absence of drug-associated risk.1 An ex vivo placental model indicates that ganciclovir crosses the human placenta by passive diffusion and is not saturable over a concentration range of 1-10 mg/mL.1
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., those with human immunodeficiency virus [HIV] infection and acquired immunodeficiency syndrome [AIDS], transplant recipients) may be symptomatic and result in substantial maternal morbidity and mortality.1 Perinatal transmission of CMV from infected mothers to their neonates can occur resulting in congenital CMV infection and disease.1 (See Congenital Cytomegalovirus Disease under Uses: Treatment of Cytomegalovirus Infection and Disease.)
Females of childbearing potential should undergo pregnancy testing before initiation of valganciclovir.1 In addition, pregnancy should be avoided in female patients receiving valganciclovir and in females with male partners receiving valganciclovir.1
Females of childbearing potential should be advised to use an effective method of contraception during and for at least 30 days after valganciclovir therapy and male patients should be advised to use a reliable method of barrier contraception during and for at least 90 days after valganciclovir therapy.1
It is not known whether valganciclovir or ganciclovir is distributed into human milk, affects the breast-fed infant, or affects milk production.1 Animal data from studies using ganciclovir indicate that the drug is distributed into milk of lactating rats.1
Because of the potential for serious adverse effects in nursing infants, valganciclovir is not recommended in breast-feeding women.1 HIV-infected mothers should be instructed not to breast-feed their infants because of the risk of transmission of HIV.1
Safety and efficacy of valganciclovir have not been established in pediatric patients younger than 1 month of age.1
Use of valganciclovir for the prevention of CMV disease in pediatric heart transplant recipients 1 month to 16 years of age is based on safety and pharmacokinetic data from 2 studies in pediatric solid organ transplant recipients and is supported by efficacy data from studies in adult solid organ transplant recipients.1
Use of valganciclovir for the prevention of CMV disease in pediatric kidney transplant recipients 4 months to 16 years of age is based on safety, tolerability, and pharmacokinetic data from 2 open-label studies in solid organ transplant recipients in this age group and is supported by efficacy data from studies in adult solid organ transplant recipients.1
Safety and efficacy of valganciclovir have not been established for prevention of CMV disease in pediatric heart transplant recipients younger than 1 month of age, pediatric kidney transplant recipients younger than 4 months of age, or pediatric liver transplant recipients of any age.1
The safety profile of valganciclovir in pediatric patients generally is similar to that observed in adults.1 However, upper respiratory tract infection, pyrexia, nasopharyngitis, anemia, abdominal pain, and neutropenia have been reported more frequently in pediatric patients than in adults.1
Safety and efficacy of valganciclovir have not been specifically evaluated in geriatric patients 65 years of age or older and there were insufficient numbers of individuals in this age group in clinical studies to determine whether they respond differently than younger adults.1 Pharmacokinetics of the drug have been not studied in geriatric patients.1
Because geriatric individuals frequently have decreased renal function and because valganciclovir is substantially excreted by the kidneys, particular attention should be paid to assessing renal function before and during valganciclovir therapy in this age group.1 If evidence of renal impairment exists or develops, appropriate dosage adjustments should be made.1 In general, dosage should be selected carefully, usually starting at the low end of the dosage range, taking into account the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.1
Safety and efficacy of valganciclovir have not been evaluated in patients with hepatic impairment.1
The major route of elimination of valganciclovir is renal excretion as ganciclovir.1 If renal function is impaired, dosage of valganciclovir must be adjusted based on measured or estimated creatinine clearance.1 (See Renal Impairment under Dosage and Administration: Special Populations.)
Hemodialysis reduces plasma concentrations of ganciclovir by approximately 50%.1 Valganciclovir should not be used in adults undergoing hemodialysis (creatinine clearance less than 10 mL/minute) because the appropriate daily dose for such patients is lower than 450 mg (i.e., would require breaking a tablet);1 such patients should receive ganciclovir instead.1
Adverse effects occurring in 20% or more of adults receiving valganciclovir include diarrhea, pyrexia, fatigue, nausea, tremor, neutropenia, anemia, leukopenia, thrombocytopenia, headache, insomnia, urinary tract infection, and vomiting.1
Adverse effects occurring in 20% or more of pediatric patients receiving valganciclovir include diarrhea, pyrexia, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache.1
No formal drug interaction studies have been performed using valganciclovir.1 However, valganciclovir is rapidly and extensively converted to ganciclovir and interactions reported with ganciclovir are expected to occur in patients receiving valganciclovir.1
Drug interaction studies with ganciclovir were performed in patients with normal renal function.1 In patients with renal impairment, concomitant use of valganciclovir 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
Imipenem and Cilastatin Sodium
Generalized seizures have been reported in patients who received ganciclovir concomitantly with the fixed combination of imipenem and cilastatin sodium (imipenem/cilastatin).1
Concomitant use of valganciclovir and imipenem/cilastatin is not recommended.1
Concomitant use of ganciclovir and trimethoprim does not affect the pharmacokinetics of either drug.1
Because of the potential for increased toxicity (e.g., nephrotoxicity), concomitant use of valganciclovir and trimethoprim should be considered only if potential benefits outweigh potential risks.1
Because of the potential for increased toxicity (e.g., myelosuppression, nephrotoxicity) if valganciclovir is used with certain anti-infectives (e.g., co-trimoxazole, dapsone, pentamidine), concomitant use of valganciclovir and such anti-infectives should be considered only if potential benefits outweigh potential risks.1
If valganciclovir and amphotericin B are used concomitantly, renal function should be monitored since there is a potential for increased serum creatinine concentrations.1
Because of the potential for increased toxicity (e.g., myelosuppression, nephrotoxicity), concomitant use of valganciclovir and flucytosine should be considered only if potential benefits outweigh potential risks.1
Because of the potential for increased toxicity (e.g., myelosuppression, nephrotoxicity), concomitant use of valganciclovir and certain antineoplastic agents (e.g., doxorubicin, hydroxyurea, vinblastine, vincristine) should be considered only if potential benefits outweigh potential risks.1
Concomitant use of ganciclovir and didanosine increases peak plasma concentrations and area under the plasma concentration-time curve (AUC) of didanosine, but does not affect the pharmacokinetics of ganciclovir.1
If valganciclovir and didanosine are used concomitantly, the patient should be closely monitored for didanosine toxicity (e.g., pancreatitis).1
Concomitant use of valganciclovir and tenofovir alafenamide or tenofovir disoproxil fumarate may result in increased serum concentrations of ganciclovir and/or tenofovir; patients receiving such concomitant therapy should be monitored for dose-related toxicities.200
Concomitant use of ganciclovir and zidovudine has resulted in additive or synergistic bone marrow toxicity.85
If valganciclovir and zidovudine are used concomitantly, there is an increased risk of hematologic toxicity.1, 200 Concomitant use of valganciclovir and zidovudine should be considered only if potential benefits outweigh potential risks.1
Concomitant use of ganciclovir and cyclosporine does not appear to affect cyclosporine whole blood concentrations.1
If valganciclovir and cyclosporine are used concomitantly, renal function should be monitored since there is potential for increased serum creatinine concentrations.1
Concomitant use of ganciclovir and mycophenolate mofetil in patients with normal renal function does not affect the pharmacokinetics of either drug.1
If valganciclovir and mycophenolate mofetil are used concomitantly, the patient should be monitored for hematologic and renal toxicity because of increased risk.1
Because of the potential for increased toxicity (e.g., nephrotoxicity) if valganciclovir is used with tacrolimus, concomitant use should be considered only if potential benefits outweigh potential risks.1
Concomitant use of ganciclovir and probenecid decreases renal clearance and increases the AUC of ganciclovir.1
If valganciclovir and probenecid are used concomitantly, dosage of valganciclovir may need to be reduced and the patient should be monitored for evidence of ganciclovir toxicity.1
Valganciclovir, a prodrug of ganciclovir, is well absorbed from the GI tract2, 3 and rapidly metabolized by intestinal and hepatic esterases to ganciclovir.1, 85 Systemic exposure to the prodrug is transient and low.1, 3
Following an oral dose of valganciclovir given with food, absolute bioavailability of ganciclovir is approximately 60%2 and the median time to peak ganciclovir concentrations is 2.2 hours.1 The area under the plasma concentration-time curve (AUC) of ganciclovir is proportional to the valganciclovir dose when given under fed conditions.1
Administration of valganciclovir with a high-fat meal (approximately 600 calories, 31 g fat) increases the AUC and peak plasma concentrations of ganciclovir at steady state by 30 and 14%, respectively.1
Results from pharmacokinetic studies in adults indicate that oral valganciclovir (900 mg once daily with food) results in a ganciclovir AUC similar to that reported following IV ganciclovir (5 mg/kg once daily).1, 2, 3, 85
It is not known whether valganciclovir is distributed into CSF;1 ganciclovir is distributed into CSF.1
Ganciclovir crosses the placenta (based on an ex vivo human placental model).1
It is not known whether valganciclovir or ganciclovir is distributed into human milk;1 animal data indicate that ganciclovir is distributed into milk of lactating rats.1
Ganciclovir is 1-2% bound to plasma proteins;1 protein binding of valganciclovir has not been determined because of rapid conversion to ganciclovir.1
Valganciclovir is rapidly hydrolyzed to ganciclovir.1 Ganciclovir is then phosphorylated by viral protein kinase (pUL97) to ganciclovir monophosphate within cytomegalovirus (CMV)-infected cells.1 Ganciclovir monophosphate is further phosphorylated by cellular kinases to ganciclovir triphosphate, which is slowly metabolized intracellularly.1
The major route of elimination of valganciclovir is renal excretion as ganciclovir by glomerular filtration and active tubular secretion.1
The mean half-life of ganciclovir after administration of oral valganciclovir (900 mg once daily with food) is approximately 4 hours in healthy adults, adults with human immunodeficiency virus (HIV) infection, or HIV-positive/CMV-positive adults (with or without retinitis).1
The mean half-life of ganciclovir after administration of oral valganciclovir (900 mg once daily with food) in adult heart, kidney, and kidney-pancreas transplant recipients is 6.6-6.8 hours.1
In pediatric solid organ transplant recipients, the mean half-life of ganciclovir after administration of oral valganciclovir is 2.8-4.8 hours in those 4 months to less than 12 years of age and 4.4-6 hours in those 12 years of age or older.1 Clearance is influenced by body surface area (BSA) and renal function.1
The intracellular half-life of ganciclovir in CMV-infected cells is 18 hours.1
In patients with renal impairment, the half-life of ganciclovir after administration of oral valganciclovir is increased and renal clearance is decreased.1, 2 Data from otherwise healthy adults with renal impairment indicate that the mean half-life of ganciclovir following a single 900-mg dose of oral valganciclovir is about 10, 22, or 68 hours in those with creatinine clearances of 21-50, 11-20, or up to 10 mL/minute, respectively.1
Following administration of oral valganciclovir, hemodialysis reduces plasma concentrations of ganciclovir by approximately 50%.1
Valganciclovir, the l-valyl ester of ganciclovir, is an antiviral agent.1, 85 Valganciclovir is a prodrug and exhibits no antiviral activity until converted by intestinal and hepatic esterases to ganciclovir and subsequently to the active form ganciclovir triphosphate.1, 85
Valganciclovir is commercially available as the hydrochloride salt and differs structurally from ganciclovir by the presence of the l-amino acid, valine, attached to the 2-hydroxyl group of the nucleoside and by the presence of the monohydrochloride salt.1, 7 These structural modifications result in substantially increased GI absorption of valganciclovir relative to oral ganciclovir (no longer commercially available in the US), resulting in plasma ganciclovir concentrations comparable to those achieved with IV ganciclovir.2, 4, 6
Valganciclovir is rapidly converted to ganciclovir in vivo and subsequently phosphorylated within cytomegalovirus (CMV)-infected cells to ganciclovir triphosphate.1, 85 Since initial phosphorylation of ganciclovir depends largely on the presence of a viral kinase (pUL97), phosphorylation occurs preferentially in virus-infected cells.1 Ganciclovir triphosphate is a viral DNA polymerase inhibitor and exerts its antiviral activity on CMV by inhibiting the viral DNA polymerase.1, 85, 86 Other mechanisms also are involved.85 For additional information, see Mechanism of Action in Ganciclovir 8:18.32.
The absolute bioavailability of ganciclovir following oral administration of valganciclovir is about 60%.1 Results from pharmacokinetic studies in adults indicate that oral administration of valganciclovir 900 mg once daily with food provides a mean area under the plasma concentration-time curve0-24 hour (AUC0-24 hour) for ganciclovir comparable to that following IV ganciclovir 5 mg/kg once daily.1, 2, 3 However, at these dosages, oral valganciclovir produces lower peak plasma ganciclovir concentrations than IV ganciclovir.1
Following conversion of valganciclovir to the pharmacologically active ganciclovir triphosphate, the drug is active against human herpes viruses, including CMV,1, 85 herpes simplex virus types 1 and 2 (HSV-1 and HSV-2),85 and varicella-zoster virus (VZV).85 Although the clinical importance is unclear, ganciclovir has some in vitro activity against Epstein-Barr virus (EBV)85 and human herpes viruses types 6 and 8 (HHV-6 and HHV-8).85 Ganciclovir is not active against human immunodeficiency virus type 1 (HIV-1).85
CMV isolates with reduced susceptibility or resistance to ganciclovir have been selected in vitro in the presence of the drug.1, 85 CMV resistant to ganciclovir may emerge after prolonged treatment or prophylaxis with the drug, and the possibility of ganciclovir-resistant CMV should be considered in patients who show poor clinical response or relapse or experience persistent viral shedding during valganciclovir therapy.1, 85
Resistance can occur as 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
Importance of reading the patient information and instructions for use provided by the manufacturer.1
Importance of taking valganciclovir with food.1 Inform adults that they should receive valganciclovir tablets, not valganciclovir oral solution.1
Inform patients that valganciclovir may cause granulocytopenia (neutropenia), anemia, thrombocytopenia, and elevated creatinine concentrations and that dosage modification or discontinuance of the drug may be required.1 Necessity of frequent monitoring of blood cell counts, platelet counts, and serum creatinine concentrations.1
Advise patients that valganciclovir may cause seizures, dizziness, and/or confusion, which may affect tasks requiring alertness (e.g., ability to drive or operate machinery).1
When valganciclovir is used for the management of cytomegalovirus (CMV) retinitis, advise patients that the drug is not a cure for CMV retinitis; progression of retinitis may occur during or after treatment with valganciclovir.1 Advise patients that regular ophthalmologic examinations during valganciclovir therapy (at least every 4-6 weeks) are necessary and some patients require more frequent follow-up.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Advise patients that valganciclovir is a potential carcinogen.1
Advise patients that valganciclovir may cause temporary or permanent female and male infertility.1
Advise females of reproductive potential that the drug causes birth defects in animals.1
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise women to avoid pregnancy and to not breast-feed infants.1
Importance of both women and men using effective contraception during valganciclovir therapy.1 Advise females of reproductive potential to use effective contraception during and for at least 30 days after valganciclovir therapy.1 Advise male patients to use effective barrier contraception during and for at least 90 days after valganciclovir therapy.1
Importance of advising patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | For solution | 250 mg (of valganciclovir) per 5 mL* | ||
Valganciclovir for Oral Solution | ||||
Tablets, film-coated | 450 mg (of valganciclovir)* | Valcyte® | Roche | |
Valganciclovir Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Genentech. Valcyte® (valganciclovir hydrochloride) tablets and for oral solution prescribing information. South San Francisco, CA; 2018 Aug.
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4. Jung D, Dorr A. Single-dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects. J Clin Pharmacol . 1999; 39:800-4. [PubMed 10434231]
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7. Roche, Nutley, NJ: Personal communication.
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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]
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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]
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83. Kimberlin DW, Jester PM, Sánchez PJ et al. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med . 2015; 372:933-43. [PubMed 25738669]
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; 2015:1738-53.
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]
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