Cytovene

Generic Name: Ganciclovir Sodium
Class: Nucleosides and Nucleotides
VA Class: AM800
Chemical Name: 2-Amino-1,9-dihydro-9-[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-6H-purin-6-one sodium salt
CAS Number: 84245-13-6

• 
  

  Clinical toxicity of oral and IV ganciclovir includes granulocytopenia, anemia, and thrombocytopenia.¹

  
  


• 
  

  In animal studies, ganciclovir was carcinogenic, teratogenic, and caused aspermatogenesis.¹

  
  


• 
  

  The only FDA-approved indications for IV ganciclovir are treatment of CMV retinitis in immunocompromised patients and prevention of CMV disease in transplant recipients at risk.¹

  
  


• 
  

  The only FDA-approved indications for oral ganciclovir are prevention of CMV disease in patients with advanced HIV infection, maintenance treatment of CMV retinitis in immunocompromised patients, and prevention of CMV disease in solid organ transplant recipients.¹

  
  


• 
  

  Because oral ganciclovir is associated with a risk of more rapid progression of CMV retinitis, it should be used as maintenance treatment only in those for whom this risk is balanced by the benefits associated with avoiding daily IV infusions.¹

  
  

Introduction

Antiviral; purine nucleoside analog of guanine.^{1 2 3 8 9 10 11 12}

Uses for Cytovene

Cytomegalovirus (CMV) Infections

Treatment of CMV retinitis in immunocompromised patients, including HIV-infected patients.^{1 5 11 21 28 100 103 104 105 117 118 126 127 139 164 174 175 187 207 225 243 268} ganciclovir is not curative; stabilization or improvement of ocular manifestations may occur, but progression of retinitis is possible during or following treatment.^{1 4 5 8 9 11 13 21 27 28 63 65 77 94 100 120 126 128 139 167 168}

Drugs of choice for initial induction and maintenance therapy of CMV retinitis are IV ganciclovir, IV foscarnet, IV cidofovir, oral valganciclovir, or intravitreal fomivirsen.^{268 319 322 331} A regimen of both ganciclovir and foscarnet is used for treatment of CMV retinitis in patients who have relapsed following monotherapy with either drug.^{268 319 322 331}

Primary prevention (primary prophylaxis) of CMV disease in HIV-infected patients at risk for the disease, including adults, adolescents, and children who are positive for CMV antibody and have CD4⁺ T-cell counts <50/mm³.^{317 320 321 322} USPHS/IDSA recommends oral ganciclovir as the drug of choice for primary CMV prophylaxis in these patients.³¹⁷

Long-term suppressive or maintenance therapy (secondary prophylaxis) of recurrent CMV disease in HIV-infected adults, adolescents, or children.³¹⁷ USPHS/IDSA recommends IV ganciclovir or IV foscarnet as drugs of choice for such prophylaxis.³¹⁷

Prevention of CMV disease in solid organ transplant recipients and bone marrow transplant (BMT) recipients at risk for the disease.^{1 268 271 283 284 286 287 304 305 307 313 324}

Has been used in immunocompromised patients for parenteral treatment of extraocular CMV infections, including GI infections†,^{3 4 5 6 8 11 16 20 21 26 68 69 70 76 77 92 102 108 110 122 134 146 166 193 194 207} pneumonitis†,^{3 4 5 8 10 11 15 16 17 18 19 20 21 33 43 64 72 73 74 106 107 108 109 110 111 121 122 137 140 145 146 147 149 151 154 159 180 188 193 198 199 200 201 202 207 219 220 225} nervous system†,^{4 5 8 11 21 110 165 207 231} hepatobiliary†,^{4 5 8 20 21 68 106 108 146 166 219} or cardiac†^{110 171 220} CMV infections.^{3 5 8 15 19 108 140} Safety and efficacy have not been established for extraocular CMV infections;^{1 2} use in these infections should be limited to severe and/or potentially life-threatening infections when potential benefits outweigh risks.^{3 6 15 16 72 106 107 110 134 146 219 262}

Safety and efficacy not established for treatment of congenital or neonatal CMV disease or for treatment of CMV infections in immunocompetent patients.¹

Cytovene Dosage and Administration

General

• 
  

  Frequent monitoring of neutrophil and platelet counts is necessary during ganciclovir induction and maintenance therapy.^{1 2 20 191}

  
  


• 
  

  Dosage adjustment and/or interruption of ganciclovir therapy may be necessary if hematologic abnormalities occur.^{1 2}

  
  


• 
  

  Ganciclovir should be withheld if the ANC declines to <500/mm³ or the platelet count declines to <25,000/mm³ and should not be resumed until there is evidence of bone marrow recovery.^{1 2}

  
  

Administration

Administer orally or by slow IV infusion.^{1 2}

Do not administer by rapid IV infusion or direct IV injection since potentially toxic plasma ganciclovir concentrations may result.^{1 2} In addition, do not administer by IM or sub-Q injection.^{1 2}

Can be administered via a commercially available intravitreal implant for treatment of CMV retinitis.^{323 340} Although ganciclovir has been administered by intravitreal injection† for the treatment of ocular infections,^{4 5 8 67 84 117 129 135 170 209} safety and efficacy of intravitreal injection of solutions made from the powder for IV infusion have not been established.^{4 5 8 67 170}

Oral Administration

Administer orally with food.¹

Oral ganciclovir should be used only for prevention of CMV disease in HIV-infected patients or transplant recipients at risk for the disease or for maintenance treatment of CMV retinitis in patients in whom the disease is stable following initial IV induction therapy.¹

IV Infusion

For solution and drug compatibility information see Compatibility under Stability.

Handle the powder and reconstituted and diluted solutions cautiously because of the high pH of the solutions and because of the mutagenic and/or carcinogenic potential of the drug.^{1 2} Use protective equipment (e.g., latex gloves, protective eyewear).^{1 2}

Since ganciclovir shares some of the properties of cytotoxic drugs, consider consulting specialized references for procedures for proper handling and disposal of antineoplastics, although there is no general agreement that all of the procedures recommended in such guidelines are necessary or appropriate.^{1 2}

Because of the high pH of ganciclovir solutions, a vein with adequate blood flow should be used to allow for rapid dilution and distribution of the drug, which may minimize risk of phlebitis.^{1 2}

Reconstitution and Dilution

For intermittent IV infusion, reconstitute 500-mg vial by adding 10 mL of sterile water for injection to provide a solution containing 50 mg/mL.^{1 2} Bacteriostatic water for injection containing parabens should not be used.^{1 2} Shake vial well to ensure complete dissolution of the drug.^{1 2}

The appropriate dose of reconstituted solution should then be withdrawn from the vial and diluted in 50–250 (usually 100) mL of a compatible IV infusion solution.^{1 2 8} For use in fluid-restricted patients, the appropriate dose of reconstituted solution may be diluted to a concentration ≤10 mg/mL; use of more concentrated solutions is not recommended.^{1 2 8 191}

Rate of Administration

Administer by slow IV infusion over 1 hour, either via a large peripheral or central vein,^{4 190} at a constant rate of administration.^{1 2}

For highly concentrated solutions (e.g., 5–10 mg/mL), a controlled-infusion device (e.g., pump) is recommended.^{8 262}

Dosage

Available as ganciclovir and ganciclovir sodium; dosage expressed in terms of ganciclovir.^{1 2}

Because the risk of toxicity may be increased with higher doses and/or more rapid infusion,^{1 2} recommended doses, frequencies of administration, and rate of IV infusion should not be exceeded.^{1 2}

Pediatric Patients

Cytomegalovirus (CMV) Infections

Treatment of CMV Retinitis

Oral

Maintenance therapy in children >3 months of age†: after an initial IV induction regimen, 1 g 3 times daily.^{1 191} Alternatively, 500 mg 6 times daily (every 3 hours while awake).^{1 191}

IV

Initial induction therapy in children >3 months of age†: 5 mg/kg every 12 hours for 14–21 days.^{1 191}

Maintenance treatment in children >3 months of age†: 5 mg/kg once daily.^{1 2 5 20 191 216 268} Alternatively, 6 mg/kg once daily 5 days weekly.^{1 2 71 106 191 262 268}

Primary Prevention (Primary Prophylaxis) of CMV in HIV-infected Children and Adolescents

Oral

Infants and children†: 30 mg/kg 3 times daily.³¹⁷

Adolescents: 1 g 3 times daily.³¹⁷

Prevention of Recurrence (Secondary Prophylaxis) of CMV in HIV-infected Children and Adolescents

Oral

1 g 3 times daily.³¹⁷ Initiate secondary prophylaxis after initial induction treatment.³¹⁷

IV

Infants and children†: 5 mg/kg daily.³¹⁷

Adolescents: 5–6 mg/kg once daily 5–7 days each week.³¹⁷

Consideration can be given to discontinuing secondary CMV prophylaxis in adolescents with sustained (e.g., for ≥6 months) increase in CD4⁺ T-cell counts to >100–150/mm³ in response to potent antiretroviral therapy.³¹⁷ This decision should be made in consultation with an ophthalmologist and factors such as the magnitude and duration of CD4⁺ T-cell increase, anatomic location of the retinal lesion, vision in the contralateral eye, and feasibility of regular ophthalmic monitoring should be considered.³¹⁷ Relapse of CMV retinitis could occur following discontinuance of secondary prophylaxis, especially in those whose CD4⁺ T-cell count decreases to <50/mm³; relapse has been reported rarely in those with CD4⁺ T-cell counts >100/mm³.³¹⁷

Reinitiate secondary CMV prophylaxis if CD4⁺ T-cell count decreases to <100–150/mm³.³¹⁷

Adults

Cytomegalovirus (CMV) Infections

Treatment of CMV Retinitis

Oral

Maintenance therapy after an initial IV induction regimen: 1 g 3 times daily.¹ Alternatively, 500 mg 6 times daily (every 3 hours while awake).¹

IV

Initial induction therapy: 5 mg/kg every 12 hours for 14–21 days.^{1 191}

Maintenance therapy: 5 mg/kg once daily.^{1 2 5 20 191 216 268} Alternatively, 6 mg/kg once daily 5 days weekly.^{1 2 71 106 191 262 268}

Primary Prevention (Primary Prophylaxis) of CMV in HIV-infected Adults

Oral

1 g 3 times daily.^{1 317}

Prevention of Recurrence (Secondary Prophylaxis) of CMV in HIV-infected Adults

Oral

1 g 3 times daily.³¹⁷ Initiate secondary prophylaxis after initial induction treatment.³¹⁷

IV

5–6 mg/kg once daily 5–7 days each week.³¹⁷

Consideration can be given to discontinuing secondary CMV prophylaxis in adults with sustained (e.g., for ≥6 months) increase in CD4⁺ T-cell counts to >100–150/mm³ in response to potent antiretroviral therapy.³¹⁷ This decision should be made in consultation with an ophthalmologist and factors such as the magnitude and duration of CD4⁺ T-cell increase, anatomic location of the retinal lesion, vision in the contralateral eye, and feasibility of regular ophthalmic monitoring should be considered.³¹⁷ Relapse of CMV retinitis could occur following discontinuance of secondary prophylaxis, especially in those whose CD4⁺ T-cell count decreases to <50/mm³; relapse has been reported rarely in those with CD4⁺ T-cell counts >100/mm³.³¹⁷

Reinitiate secondary CMV prophylaxis if CD4⁺ T-cell count decreases to <100–150/mm³.³¹⁷

Prevention of CMV Disease in Transplant Recipients

Oral

1 g 3 times daily.¹

IV

Initially, 5 mg/kg every 12 hours for 7–14 days, then 5 mg/kg once daily 7 days per week or 6 mg/kg once daily 5 days per week.¹

Duration of ganciclovir maintenance in organ transplant recipients depends on several factors including the duration and degree of immunosuppression.^{1 283 302 303} Bone marrow allograft recipients have received IV ganciclovir for up to 100–120 days following transplantation.^{1 271 284} In cardiac allograft recipients, ganciclovir should be continued for >28 days in patients to prevent late development of CMV disease.^{1 283} Liver transplant recipients have received oral ganciclovir for up to 98 days following transplantation.^{1 325}

Special Populations

Renal Impairment

In patients with impaired renal function, doses and/or frequency of administration of oral or IV ganciclovir must be modified in response to the degree of impairment.^{1 2 5 6 9 11 28 33 191 346} Dosage should be based on the patient’s measured or estimated Cl_cr.^{1 2}

IV Dosage for Adults with Renal Impairment1

Clcr (mL/min)	Induction Dosage	Maintenance Dosage
50–69	2.5 mg/kg every 12 h	2.5 mg/kg every 24 h
25–49	2.5 mg/kg every 24 h	1.25 mg/kg every 24 h
10–24	1.25 mg/kg every 24 h	0.625 mg/kg every 24
<10	1.25 mg/kg 3 times weekly, following hemodialysis	0.625 mg/kg 3 times weekly, following hemodialysis

Oral Dosage for Adults with Renal Impairment1

Clcr (mL/min)	Dosage
50–69	1.5 g once daily or 500 mg 3 times daily
25–49	1 g once daily or 500 mg 2 times daily
10–24	500 mg once daily
<10	500 mg 3 times weekly, following hemodialysis

Geriatric Patients

Select dosage with caution because of age-related decreases in renal function.^{1 2} (See Renal Impairment under Dosage and Administration.)

Cautions for Cytovene

Contraindications

• 
  

  Known hypersensitivity to ganciclovir or acyclovir.^{1 2}

  
  

Warnings/Precautions

Warnings

Hematologic Effects

Hematologic toxicity, principally neutropenia (ANC <1000/mm³) and/or thrombocytopenia (platelet count <50,000/mm³) frequently occurs.^{1 2 3 4 8 11 21 33 75 109 110 122 133 149 172 215 248 264 265} Anemia also reported.¹

Neutropenia usually develops early in treatment (e.g., during the first or second week of induction therapy),^{1 2 3 5 20 23 74 122} but can occur at any time.^{1 2 5 20 23 74}

In most cases, interruption of ganciclovir therapy^{1 2 3 4 8 23 74 92 122 149 190 248} or a decrease in dosage^{2 4 6 8 140 149 190 248} will result in increased neutrophil counts, usually evident within 3–7 days; however, prolonged or irreversible neutropenia has occurred.^{1 2 3 4 74 92 122 174} Bacterial or fungal sepsis and subsequent death have been reported occasionally in patients with ganciclovir-induced neutropenia.^{1 2 3 4 74 122 174} In addition, neutropenia has recurred following reinitiation of ganciclovir therapy,^{1 2 3 33} occasionally even at reduced dosage.³

CBCs should be monitored frequently.^{1 2 20 191 279} Neutrophil and platelet counts should be performed several times weekly (every other day or 2 or 3 times weekly) during IV induction therapy and at least weekly thereafter during maintenance therapy.^{1 2 279} More frequent monitoring is recommended for patients who have previously experienced leukopenia with ganciclovir or another nucleoside analog or in whom neutrophil counts are <1000/mm³ prior to initiating therapy with the drug.^{1 2} Manufacturer suggests that daily monitoring of neutrophil counts be considered in such patients;² others suggest that less frequent monitoring (e.g., twice weekly) may be sufficient during maintenance therapy.²⁶² Manufacturer also recommended that neutrophil and platelet counts be monitored daily in patients undergoing hemodialysis.^{1 2}

If neutropenia and/or thrombocytopenia occur, dosage adjustment and/or interruption of ganciclovir therapy may be necessary.^{1 2 3 4 5 6 8 100 102 104 105 106 122 140 149 164 189 190 191 248}

Do not use if ANC is <500/mm³ or if platelet count is <25,000/mm³.¹

Use with caution in patients with preexisting cytopenias or a history of cytopenic reactions to other drugs, chemicals, or radiation therapy.^{1 2}

Mutagenic, Carcinogenic, and Teratogenic Potential

Ganciclovir has mutagenic and teratogenic potential that should be considered when weighing the benefits and risks of therapy.¹

Women of childbearing potential should use effective contraception during treatment.¹ In addition, men should practice barrier contraception during and for ≥90 days after treatment.¹

Potential carcinogen in humans.¹

Effects on Fertility

Animal studies indicate ganciclovir causes inhibition of spermatogenesis and subsequent infertility; effects were reversible at lower doses and irreversible at higher doses.¹ Suppression of fertility in female animals also noted.¹

Human data not available; possibility that ganciclovir at recommended doses may cause temporary or permanent inhibition of spermatogenesis.¹

General Precautions

Local Reactions

Initially reconstituted ganciclovir solutions have a high pH (pH 11).¹ Despite further dilution in IV fluids, phlebitis and/or pain may occur at site of IV infusion.¹

To avoid local irritation, care must be taken to infuse only into veins with adequate blood flow to permit rapid dilution and distribution of the drug.¹

Sodium Content

Ganciclovir sodium contains approximately 4 mEq of sodium per gram of ganciclovir.^{1 2 191}

Specific Populations

Pregnancy

Category C.¹ (See Mutagenic, Carcinogenic, and Teratogenic Potential under Cautions.)

Lactation

Distributed into milk in animals;^{1 3} not known whether distributed into milk in humans.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy of oral or IV ganciclovir not established in children.¹

Only limited experience with IV ganciclovir in children younger than 12 years of age.^{1 2 157 217} Safety and efficacy in treatment of congenital or neonatal CMV infections, including retinitis, not established.^{1 2}

Because of the drug’s potential for long-term carcinogenic and adverse reproductive effects, manufacturer warns that oral or IV ganciclovir should be used in children with extreme caution and only when potential benefits outweigh possible risks.^{1 2}

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.¹

Renal Impairment

Use with caution in patients with impaired renal function.¹

Dosage adjustments necessary based on degree of renal impairment.¹

Common Adverse Effects

Hematologic effects (neutropenia, thrombocytopenia, anemia);^{1 2 5 75 131 172 174} nervous system effects (headache, confusion);^{1 2 3 8} injection site reactions (inflammation, phlebitis, pain.^{1 2 21 122 133 215}

Interactions for Cytovene

Nephrotoxic Drugs

Possible increased risk of adverse effects; use concomitantly with caution and closely monitor renal function.¹

Specific Drugs

Drug	Interaction	Comments
Amphotericin B	Possible additive toxicity, including nephrotoxicity1	Use concomitantly only if potential benefits outweigh risks.1 Consider risk of nephrotoxicity in renal transplant patients.1
Antineoplastic agents (adriamycin, vinblastine, vincristine)	Possible additive toxicity1	Use concomitantly only if potential benefits outweigh risks1
Co-trimoxazole	Possible additive toxicity1	Use concomitantly only if potential benefits outweigh risks1
Dapsone	Possible additive toxicity1	Use concomitantly only if potential benefits outweigh risks1
Didanosine	Increased AUC of didanosine; no effect on ganciclovir pharmacokinetics1 347 b	Appropriate dosages for concomitant use with respect to safety and efficacy not established.b If used concomitantly, monitor closely for didanosine toxicity.347
Flucytosine	Possible additive toxicity1	Use concomitantly only if potential benefits outweigh risks1
Foscarnet	In vitro evidence of additive or synergistic antiviral activity against CMV and HSV-2274 275 276 277 278
Imipenem	Seizures reported with concomitant use1 2 3 258	Use concomitantly only when potential benefits outweigh possible risks1 2 258
Immunosuppressive agents (azathioprine, corticosteroids, cyclosporine)	Possible increased risk of bone marrow suppression or increased risk of nephrotoxicity. No effect on cyclosporine clearance.15 19 140 188 193 202 219 262	Consider need for decreased dosage or temporary withdrawal of the immunosuppressive agent15 19 140 188 193 202 219 262
Interferons	In vitro evidence of synergistic antiviral effects against CMV, HSV-1 or -2, and varicella-zoster virus with interferons alfa and beta and, to a lesser extent, interferon gamma180 181 182 183 184 221
Pentamidine	Possible additive toxicity1	Use concomitantly only if potential benefits outweigh risks1
Probenecid	Possible increase in AUC and decrease in renal clearance of ganciclovir 1
Zidovudine	Possible pharmacokinetic interaction.1 Increased risk of hematologic toxicity.1 2 83 84 295	Concomitant use not recommended1 18 83 84 87 96 126 129 133 135 170 187 191 293 295

Cytovene Pharmacokinetics

Absorption

Bioavailability

Poorly absorbed from GI tract;^{3 4 8 26 58 235} peak plasma concentrations attained within 1 hour after a dose.⁵⁸

Absolute bioavailability of oral ganciclovir is only 5 or 6–9% under fasting or nonfasting conditions, respectively.¹

Distribution

Extent

Distribution into human body tissues and fluids has not been fully elucidated.^{5 9 64 262} Autopsy findings in patients who received IV ganciclovir suggest that the drug concentrates in the kidney, with substantially lower concentrations occurring in lung, liver, brain, and testes.^{5 9 64}

Appears to have good ocular distribution following IV administration;^{2 5 93 104 117} distributed into aqueous and vitreous humor.^{3 104}

Distributed into CSF following IV administration.^{1 2 3 4 5 9 28 59 64 68}

Crosses the placenta in animals.³ Distributed into milk in animals;^{1 3} not known whether distributed into milk in humans.¹

Plasma Protein Binding

1–2%.¹

Elimination

Metabolism

With the exception of intracellular phosphorylation of the drug, ganciclovir does not appear to be metabolized appreciably in humans.^{1 2 4 5 11 28 59 61 64 124}

Elimination Route

Following oral administration, 86% of the dose is recovered in feces and 5% is recovered in urine.¹

Following IV administration, approximately 90–99% of the dose is excreted unchanged in urine.^{1 2 3 4 5 11 28 59 61 64 124} Renal excretion appears to occur principally via glomerular filtration,^{1 2 3 5 11 59 124} although limited renal tubular secretion also may occur.^{1 2 5 59}

Removed by hemodialysis.^{1 2 3 5 60 108 124 151}

Half-life

In adults with normal renal function: half-life in the initial distribution phase averages 0.23–0.76 hours and half-life in the terminal elimination phase averages 2.53–3.6 hours.^{1 2 3 4 5 8 9 11 59 61 64 124 132 205} Half-life following oral administration is 4.8 hours.¹

Special Populations

Plasma concentrations may be higher and elimination half-life prolonged in patients with impaired renal function.^{1 2 3 5}