Professional Drug Information > Ganciclovir Sodium

Ganciclovir (Systemic)

VA CLASSIFICATION
Primary: AM890

Commonly used brand name(s): Cytovene; Cytovene-IV.

Another commonly used name is
DHPG
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiviral (systemic)—

Indications

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

Accepted

Cytomegalovirus retinitis (treatment)—Parenteral ganciclovir is indicated for induction and maintenance in the treatment of cytomegalovirus (CMV) retinitis in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS). Oral ganciclovir is indicated only for maintenance treatment of CMV retinitis in patients who have had a complete resolution of active retinitis after an induction course of parenteral ganciclovir ^{{01} {61}}; however, oral ganciclovir has been associated with a shorter time to CMV retinitis progression. ^{{01} {02} {15} {60} {62}} [Intravitreal administration of ganciclovir has also been used in patients who have been unresponsive to intravenous ganciclovir, or in whom serious myelosuppression has precluded the continuation of intravenous therapy.] ^{{29} {31} {34}}

Cytomegalovirus disease (prophylaxis)¹—Parenteral ganciclovir is indicated for the prophylaxis of CMV disease in transplant patients who are at risk for the disease. ^{{01} {49} {50} {51} {52} {53} {54}} Oral ganciclovir is indicated for the prophylaxis of CMV disease in solid organ transplant recipients and in patients with advanced human immunodeficiency virus (HIV) infection who are at risk for developing CMV disease. ^{65}

[Cytomegalovirus disease (treatment) ]¹—Parenteral ganciclovir is used in the treatment of severe CMV disease, including CMV pneumonia, CMV gastrointestinal disease, and disseminated CMV infections, in immunocompromised patients. ^{{03} {06} {11} {15} {20}}

[Polyradiculopathy (treatment)]¹—Parenteral ganciclovir is used in the treatment of polyradiculopathy caused by CMV in patients with AIDS. ^{{38} {39} {40}}

—Resistance to ganciclovir has been reported. One paper described CMV disease refractory to ganciclovir therapy due to infections with a resistant virus, a susceptible virus that became resistant, and an infection first by a susceptible strain, and later by a genetically distinct, resistant one. ^{26} The primary mechanism of resistance to ganciclovir is the decreased ability to form the active triphosphate moiety. ^{01} Recurrence may be more frequent in patients treated with ganciclovir for prolonged periods (> 3 to 6 months). ^{{33} {43}}

Acceptance not established
Ganciclovir has been studied for the treatment of symptomatic congenital CMV infection in neonates. More data are needed to establish the place in therapy for ganciclovir for this indication^{{67}{68}{69}{70}{71}{72}{73}{74}{75}{76}{77}{78}}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
    High pH (11). ^{01}
Molecular weight—
    Ganciclovir: 255.23 ^{04}
    Ganciclovir sodium: 277.22 ^{04}

Mechanism of action/Effect:

Ganciclovir is a prodrug ^{06} that is structurally similar to acyclovir. ^{08} Its antiviral activity results from its intracellular conversion to the triphosphate form. In cytomegalovirus (CMV)-infected cells, ganciclovir is thought to be rapidly phosphorylated to the monophosphate form by a CMV-encoded enzyme ^{63}, then subsequently converted to the diphosphate and triphosphate forms by cellular kinases. Ganciclovir is phosphorylated much more rapidly in infected cells ^{07}; however, uninfected cells can also produce low levels of ganciclovir-triphosphate. ^{03} Ganciclovir-triphosphate competitively inhibits DNA polymerase by acting as a substrate and becoming incorporated into the DNA. ^{05} This inhibits DNA synthesis by suppressing DNA chain elongation. ^{05} The drug inhibits viral DNA polymerases more effectively than it does cellular polymerase. ^{24} Chain elongation resumes when ganciclovir is removed. ^{05}

Absorption:

Ganciclovir is poorly absorbed after oral administration; bioavailability under fasting conditions is approximately 5%, and when administered with food, 6 to 9%. ^{{01} {15} {59}}

Distribution:

Ganciclovir is widely distributed to all tissues and crosses the placenta ^{{15} {58}}; however, there is no marked accumulation in any one type of tissue. Penetration into the cerebrospinal fluid averaged 38% in one study ^{09}, and ranged from 7 to 67% in others. ^{{10} {22}} Ganciclovir also appears to have good intraocular penetration. ^{03} In one patient, the subretinal fluid ganciclovir concentration was 7.2 micromoles per L with a corresponding plasma concentration of 8.2 micromoles per L 5.5 hours after a dose of 5 mg per kg of body weight (mg/kg), and 2.58 micromoles per L with a corresponding plasma concentration of 1.3 micromoles per L 8 hours after a subsequent dose of 5 mg/kg. ^{28}

Vol _D (steady state)—Adults and neonates: Approximately 0.74 L per kg. ^{{01} {57}}

Protein binding:

Low (1 to 2%). ^{01}

Biotransformation:

Little to no metabolism. ^{{03} {06}}

Half-life:


Serum:


Intravenous—

Adults—Normal renal function: 2.5 to 3.6 hours (average, 2.9 hours). ^{{01} {03} {06} {07}}

Adults—Renal function impairment: 9 to 30 hours (creatinine clearance of 20 to 50 mL per minute [0.33 to 0.83 mL per second]). ^{15}

Neonates—Approximately 2.4 hours. ^{{01} {57}}



Oral—

Normal renal function—3.1 to 5.5 hours. ^{59}

Renal function impairment—15.7 to 18.2 hours (creatinine clearance of 10 to 50 mL per minute [0.17 to 0.83 mL per second]). ^{01}




Vitreous fluid:

Approximately 13 hours. ^{34}


Time to peak concentration:


Intravenous:

End of infusion (approximately 1 hour). ^{13}



Oral:

Fasting: Approximately 1.8 hours. ^{01}

With food: Approximately 3 hours. ^{01}


Peak concentrations


Intravenous:

Adults: 5 mg/kg over 1 hour—8.3 to 9 mcg/mL. ^{01}

Neonates: 4 and 6 mg/kg over 1 hour—Approximately 5.5 and 7 mcg/mL, respectively. ^{{01} {57}}



Oral:

3 grams per day: 1 to 1.2 mcg/mL. ^{01}



Intravitreal injection:

1000 mcg administered in five divided doses over 15 days: 16.2 mcg/mL; ganciclovir was not detected in plasma. ^{15}


Elimination:
    Renal; almost 100% excreted unchanged in the urine by glomerular filtration and tubular secretion. ^{{01} {09} {11} {15}}
    In dialysis—Plasma ganciclovir concentrations are reduced by approximately 50% after a single, 4-hour hemodialysis. ^{{01} {12}}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to acyclovir may also be hypersensitive to ganciclovir because of the chemical similarity of the two medications. ^{{01} {02}}

Carcinogenicity/Tumorigenicity

Ganciclovir is carcinogenic in animals and should be considered a potential carcinogen in humans. Ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1000 mg per kg of body weight (mg/kg) per day (approximately 0.1 and 1.4 times, respectively, the mean drug exposure in humans following the recommended intravenous dose of 5 mg/kg, based on the area under the concentration-time curve [AUC]) comparisons. Mice given oral doses of 20 mg/kg per day showed a slightly increased incidence of tumors in the preputial and harderian glands in males, forestomach in males and females, and liver in females. Studies in mice given oral doses of 1000 mg/kg per day showed an increased incidence of tumors of the forestomach in males and females, preputial gland in males, and reproductive tissues and liver in females. All ganciclovir-induced tumors were of epithelial or vascular origin, except for histiocytic sarcoma of the liver. No carcinogenic effect occurred at a dose of 1 mg/kg per day. ^{01}

Mutagenicity

Ganciclovir was mutagenic in mouse lymphoma cells at concentrations between 50 and 500 mcg/mL, and caused chromosomal damage in vitro in human lymphocytes at concentrations between 250 and 2000 mcg/mL. Parenteral ganciclovir was also clastogenic in the mouse micronucleus assay at doses of 150 and 500 mg/kg (2.8 to 10 times the human exposure based on area under the concentration-time curve [AUC] of a single intravenous dose of 5 mg/kg), but not at a dose of 50 mg/kg (exposure approximately comparable to the human dose based on AUC). Ganciclovir was not mutagenic in the Ames Salmonella assay at concentrations of 500 to 5000 mcg/mL. ^{01}

Pregnancy/Reproduction
Fertility—
Although data in humans have not been obtained, temporary or permanent suppression of fertility in women and spermatogenesis in men may occur. ^{01}

In female mice, ganciclovir caused decreased mating behavior, decreased fertility, and increased death in utero at doses approximately 1.7 times the recommended human dose (based on the AUC of a single intravenous dose of 5 mg/kg). Ganciclovir was also found to cause decreased fertility in male mice, and hypospermatogenesis in mice and dogs following daily oral or intravenous administration of doses ranging from 0.2 to 10 mg/kg. ^{01} Inhibition of spermatogenesis and subsequent infertility was reversible at lower doses and irreversible at higher doses in animals. ^{02} Systemic drug exposure (as measured by AUC) at the lowest dose showing toxicity in each species ranged from 0.03 to 0.1 times the AUC of the recommended human intravenous dose. ^{01}

Pregnancy—
Adequate and well-controlled studies in humans have not been done. However, ganciclovir has been found to cross the placenta. ^{{15} {58}} Due to the high toxicity and mutagenic and teratogenic potential of ganciclovir, use during pregnancy should be avoided whenever possible. Women of childbearing age should use effective contraception. Men should use barrier contraception during, and for at least 90 days following, treatment with ganciclovir. ^{01}

Ganciclovir was found to be carcinogenic in animals and teratogenic in rabbits, causing cleft palate, anophthalmia/microphthalmia, aplastic organs (kidneys and pancreas), hydrocephaly, bradygnathia, and fetal growth retardation. It also was found to be embryotoxic in mice, and to cause death in utero and maternal toxicity in both rabbits and mice. Fetal resorptions occurred in at least 85% of rabbits and mice administered 60 mg/kg per day and 108 mg/kg per day (2 times the human exposure based on AUC comparisons), respectively. Daily intravenous doses of 90 mg/kg administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the month-old male offspring, as well as pathologic changes in the nonglandular region of the stomach. The drug exposure in mice as estimated by the AUC was approximately 1.7 times the human AUC. ^{01}

FDA Pregnancy Category C.

Breast-feeding

It is not known whether ganciclovir is distributed into breast milk ^{01}; however, it is likely that some drug will accumulate because of its pharmacokinetic properties. ^{35} Because of the potential for serious adverse effects in nursing infants, breast-feeding should be stopped during ganciclovir therapy. ^{01} Ganciclovir has caused irreversible toxicity in nursing animal pups. ^{14}

Pediatrics

There is little information currently available on the use of ganciclovir in children, especially those up to the age of 12. At this time, the side effects seen in children appear to be similar to those seen in adults, especially granulocytopenia (17%) and thrombocytopenia (10%). However, the probability of long-term carcinogenicity and reproductive toxicity seen in animal studies should also be considered. ^{01}


Geriatrics


No information is available on the relationship of age to the effects of ganciclovir in geriatric patients. However, elderly patients are more likely to have an age-related decrease in renal function, which may require an adjustment of dosage or dosing interval in patients receiving ganciclovir. ^{{01} {02}}


Dental

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

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


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

Blood dyscrasia–causing medications (see Appendix II ) or
» Bone marrow depressants, other (see Appendix II ) or
Radiation therapy^{01}    (concurrent use with ganciclovir may increase the bone marrow–depressant effects of these medications and radiation therapy)


Didanosine    (concurrent and sequential [2 hours apart] administration of didanosine with ganciclovir results in a significant increase in the steady-state area under the concentration-time curve [AUC] of didanosine [range, 72 to 111%] ^{{01} {19} {21}}; when didanosine was administered 2 hours before oral ganciclovir, the steady-state AUC of ganciclovir was decreased by approximately 21% ^{01}; there was no significant change in renal clearance of either medication ^{01})


Imipenem and cilastatin combination^{01}{02}    (generalized seizures have been reported in patients receiving ganciclovir and imipenem and cilastatin combination concurrently)


» Nephrotoxic medications (see Appendix II )^{01}    (concurrent use with ganciclovir may increase serum creatinine; concurrent use with nephrotoxic medications, such as cyclosporine or amphotericin B, may increase the chance of renal function impairment; this may also decrease elimination of ganciclovir and increase the risk of toxicity)


Probenecid    (concurrent use with probenecid increases the AUC of ganciclovir by approximately 53% ^{21} and decreases its renal clearance by approximately 22% ^{01}; concurrent use of ganciclovir with probenecid, or other medications that inhibit renal tubular secretion, may reduce the renal clearance of ganciclovir and lead to toxicity ^{{01} {21}})


» Zidovudine^{{01}{02}{16}{18}}    (concurrent use of ganciclovir with zidovudine has been associated with severe hematologic toxicity in some patients, even when the zidovudine dose was reduced to 300 mg per day ^{37}; concurrent use increases the AUC of zidovudine by approximately 14 to 19% ^{{01} {21}}; in vitro studies found concurrent use of these 2 drugs to be synergistically cytotoxic ^{48}; concurrent administration should be used with caution)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]), serum and
Alkaline phosphatase, serum and
Aspartate aminotransferase (AST [SGOT]), serum and
Bilirubin, serum    (values may be increased ^{{01} {02} {03} {13} {17}})


Blood urea nitrogen (BUN) or
Creatinine, serum    (values may be increased ^{{01} {02}})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Absolute neutrophil count (ANC) < 500 cells/mm ³ or platelet count < 25,000 cells/mm ^3{01}
» Hypersensitivity to acyclovir or ganciclovir^{01}
» Renal function impairment^{01}{03}{06}    (because ganciclovir is excreted through the kidneys, the dose of ganciclovir should be reduced or the dosing interval increased in patients with renal function impairment)



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

» Complete blood counts (CBCs) and
» Platelet counts^{{01}{02}{03}{11}{13}{45}{46}{47}}    (because ganciclovir may cause granulocytopenia and thrombocytopenia, neutrophil and platelet counts should be monitored prior to treatment, every 2 days during induction therapy, then at least weekly thereafter. Neutrophil and platelet counts should be performed daily in patients undergoing hemodialysis, patients with neutrophil counts less than 1000 cells/mm ³ at the beginning of treatment, and those in whom use of ganciclovir or other nucleoside analogs previously resulted in leukopenia. When severe neutropenia [absolute neutrophil count < 500 cells/mm ³] or severe thromboctyopenia [platelet count < 25,000 cells/mm ³] occurs, discontinuation of ganciclovir may be necessary; however, a small number of patients have been successfully treated with concurrent use of sargramostim [GM-CSF; granulocyte-macrophage colony stimulating factor] or filgrastin [G-CSF; granulocyte colony stimulating factor] ^{61})


Liver function tests^{15}{17}    (liver function tests, including serum ALT [SGPT] and AST [SGOT] values, and serum bilirubin concentration, should be monitored periodically since elevations, usually reversible, have occurred during ganciclovir therapy)


» Renal function determinations^{01}    (blood urea nitrogen and serum creatinine determinations should be monitored at least every 2 weeks since patients with renal function impairment will require an adjustment in dosage or dosage interval)


For treatment of cytomegalovirus [CMV] retinitis, in addition to the above
» Ophthalmologic examinations^{30}{61}{64}    (ophthalmologic examinations should be performed weekly during induction and every 4 weeks during maintenance since ganciclovir is not a cure for cytomegalovirus [CMV] retinitis, and progression of retinitis may occur during or following ganciclovir treatment; however, the frequency of examinations may vary, depending on the extent of disease, activity, and proximity to the macula and optic disc)






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

Those indicating need for medical attention
Incidence more frequent
For intravenous and oral administration
    
Granulocytopenia (sore throat and fever)^{{01}{03}{06}{24}{59}}
    
thrombocytopenia (unusual bleeding or bruising)^{{01}{03}{06}{07}{24}{32}{59}}

Note: Granulocytopenia is usually reversible, with an overall incidence of approximately 40% ^{{01} {02} {03} {06}}; the incidence of dose-limiting toxicity is < 20%. ^{24}
Thrombocytopenia is also usually reversible, with an overall incidence of approximately 20% ^{{01} {02} {03} {06} {07}}; the incidence of dose-limiting toxicity is 5 to 10%. ^{{24} {32}}



Incidence less frequent
For intravenous and oral administration
    
Anemia (unusual tiredness and weakness)^{01}{02}{59}
    
central nervous system (CNS) effects (mood or other mental changes; nervousness; tremor)^{{01}{03}{06}{13}{41}}
    
hypersensitivity (fever; skin rash)
^{01}{02}{59}    
phlebitis (pain at site of injection)^{01}{03}{06}

For intravitreal administration ^{35}
    
Bacterial endophthalmitis
    
conjunctival scarring, mild
    
foreign body sensation
    
retinal detachment
    
scleral induration
    
or subconjunctival hemorrhage (decreased vision or any change in vision)




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Gastrointestinal disturbances (abdominal pain; loss of appetite; nausea and vomiting)^{{01}{02}{06}{07}{59}}





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

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

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to acyclovir or ganciclovir

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





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





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






Dental—The neutropenic and thrombocytopenic effects of ganciclovir may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding
Other medications, especially other bone marrow depressants, nephrotoxic medications, or zidovudine
Other medical problems, especially renal function impairment, an absolute neutrophil count (ANC) < 500 cells/mm ³, or platelet count < 25,000 cells/mm ³

Proper use of this medication
» Taking ganciclovir capsules with food

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

» Proper dosing

Precautions while using this medication

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

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

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

Using caution to avoid accidental cuts with use of sharp objects such as a safety razor or fingernail or toenail cutters
» Using contraception since ganciclovir has mutagenic and teratogenic potential; women should use effective contraception during treatment, and men should use barrier contraception during and for at least 90 days following treatment ^{01}

» Regular visits to physician to check blood counts

» For CMV retinitis—Regular visits to ophthalmologist to examine eyes since progression of retinitis and visual loss may occur during ganciclovir therapy


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


General Dosing Information
Ganciclovir is not a cure for cytomegalovirus infections. Maintenance therapy is almost always necessary in AIDS patients to prevent relapse, which is very common once the medication has been withdrawn. ^{01}

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

Ganciclovir sodium should be administered by intravenous infusion only. Intramuscular or subcutaneous injection will result in severe tissue irritation due to ganciclovir's high pH (11). ^{{01} {02}}

Intravenous infusions of ganciclovir should be administered at a constant rate over at least a 1-hour period, and patients must be adequately hydrated, to avoid increased toxicity. The recommended dosage, frequency, and infusion rate should not be exceeded. ^{01}

Severe neutropenia or thrombocytopenia (absolute neutrophil count [ANC] < 500 cells/mm ³ or platelet count < 25,000 cells/mm ³) requires an interruption in therapy until there is evidence of bone marrow recovery (ANC ³ 750 cells/mm ³); however, a small number of patients have been successfully treated with concurrent use of sargramostim (GM-CSF; granulocyte-macrophage colony stimulating factor). ^{{45} {46} {47}}

Ganciclovir capsules should be taken with food for maximum absorption. ^{01}

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

Patients undergoing hemodialysis should not receive a dose in excess of 1.25 mg per kg of body weight (mg/kg) every 24 hours. On dialysis days, the dose of ganciclovir should be administered after hemodialysis has been performed since dialysis will reduce plasma ganciclovir concentrations by approximately 50%. ^{{01} {02}}

Ganciclovir capsules are indicated as an alternative to intravenous ganciclovir for maintenance therapy of CMV retinitis in immunocompromised patients, including those with AIDS. Oral ganciclovir should be used in patients in whom retinitis is stable and quiescent following appropriate induction therapy and for whom the risk of more rapid progression is balanced by the benefit associated with avoiding long-term daily intravenous infusions, usually requiring indwelling intravenous catheters. ^{01}

Intravitreal administration of ganciclovir has been used in patients who have been unresponsive to intravenous ganciclovir, or in whom serious myelosuppression has precluded the continuation of intravenous therapy. Intravitreal doses of 200 micrograms have resulted in improvement or stabilization of retinitis and have been well tolerated. In one report describing a patient who received 28 intravitreal injections, plasma concentrations after intravitreal injections showed no significant systemic absorption. The elimination half-life of ganciclovir from the vitreous fluid was estimated to be 13.3 hours, and the intravitreal concentration remained above the ID _{5 0} of cytomegalovirus for approximately 62 hours after a single injection. ^{{29} {31} {34}}

Safety considerations for handling this medication
Caution should be exercised in the handling and preparation of ganciclovir. Because ganciclovir shares some properties of anti-tumor agents (i.e., carcinogenicity and mutagenicity), it should be handled and disposed of according to guidelines issued for cytotoxic drugs. Ganciclovir solution is alkaline (pH 11). Avoid inhalation, ingestion, or direct contact of ganciclovir with the skin or mucous membranes. If contact does occur, wash area thoroughly with soap and water; rinse eyes thoroughly with plain water. ^{42} Ganciclovir capsules should not be opened or crushed. ^{01}


Oral Dosage Forms

GANCICLOVIR CAPSULES

Usual adult and adolescent dose
Cytomegalovirus retinitis
Induction: Ganciclovir capsules should not be used for induction therapy. See Ganciclovir Sodium for Injection.^{01}

Maintenance: Oral, 1000 mg three times a day with food, or 500 mg six times a day every three hours with food, during waking hours.^{01}

Note: For maintenance, patients with impaired renal function may require a reduction in dose as follows:^{01}{03}{12}

Creatinine Clearance (mL/min)/(mL/sec)	Dose
³ 70/1.17	See Usual adult and adolescent dose
50–69/0.83–1.15	1500 mg once a day, or 500 mg three times a day
25–49/0.42–0.82	1000 mg once a day, or 500 mg twice a day
10–24/0.17–0.40	500 mg once a day
< 10/0.17	500 mg three times a week, following hemodialysis

Cytomegalovirus disease (prophylaxis)^1{65}
Oral, 1000 mg three times a day with food.^{65}

Note: Patients with impaired renal function may require a reduction in dose as follows:^{65}

Creatinine Clearance (mL/min)/(mL/sec)	Dose
³ 70/1.17	See Usual adult and adolescent dose
50–69/0.83–1.15	1500 mg once a day, or 500 mg three times a day
25–49/0.42–0.82	1000 mg once a day, or 500 mg twice a day
10–24/0.17–0.40	500 mg once a day
< 10/0.17	500 mg three times a week, following hemodialysis

Usual pediatric dose
Dosage has not been established.^{01}

Strength(s) usually available
U.S.—


250 mg (Rx) [Cytovene (croscarmellose sodium) ( magnesium stearate) (povidone) ( gelatin) (titanium dioxide) ( yellow iron oxide)^{80}]


500 mg (Rx) [Cytovene (croscarmellose sodium) ( magnesium stearate) (povidone) ( gelatin) (titanium dioxide) ( yellow iron oxide)^{80}]

Canada—


250 mg (Rx) [Cytovene^{66} (croscarmellose sodium ) (gelatin) (indigotine ) (iron oxide) (magnesium stearate) (povidone) ( titanium dioxide)]^{79}


500 mg (Rx) [Cytovene (croscarmellose sodium) ( gelatin) (indigotine) ( iron oxide) (magnesium stearate) ( povidone) (titanium dioxide)]^{79}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Continue medicine for full time of treatment.

Note: Ganciclovir capsules should not be opened or crushed.
Because ganciclovir capsules are associated with a risk of more rapid rate of CMV retinitis progression they should be used as a maintenance treatment only in the patients for whom this risk is balanced by the benefit associated with avoiding daily intravenous infusions.^{80}




Parenteral Dosage Forms

GANCICLOVIR SODIUM FOR INJECTION

Usual adult and adolescent dose
Cytomegalovirus retinitis (treatment)


Induction:
Intravenous infusion, 5 mg per kg of body weight, administered over at least one hour, every twelve hours for fourteen to twenty-one days.^{{01}{02}{03}{06}{08}{20}}

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


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

Note: For induction, patients with impaired renal function may require a reduction in dose as follows^{01}:

Creatinine Clearance (mL/min)/(mL/sec)	Dose
³ 70/1.17	See Usual adult and adolescent dose
50–69/0.83–1.15	2.5 mg per kg every twelve hours
25–49/0.42–0.82	2.5 mg per kg every twenty-four hours
10–24/0.17–0.40	1.25 mg per kg every twenty-four hours
< 10	1.25 mg per kg three times a week, following hemodialysis

Maintenance:
Intravenous infusion, 5 mg per kg of body weight a day, administered over at least one hour, once a day for seven days per week; or 6 mg per kg of body weight, administered over at least one hour, once a day for five days of the week.^{{01}{02}{03}{06}}

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


Intravitreal injection, 200 mcg once a week.^{35}{36}

Note: For maintenance, patients with impaired renal function may require a reduction in dose as follows^{01}:

Creatinine Clearance (mL/min)/(mL/sec)	Dose
³ 70/1.17	See Usual adult and adolescent dose
50–69/0.83–1.15	2.5 mg per kg every twenty-four hours{80}
25–49/0.42–0.82	1.25 mg per kg every twenty-four hours
10–24/0.17–0.40	0.625 mg per kg every twenty-four hours
< 10	0.625 mg per kg three times a week, following hemodialysis

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


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

Size(s) usually available:
U.S.—


500 mg (Rx) [Cytovene-IV (sodium 46 mg)]

Canada—


500 mg (Rx) [Cytovene]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
To prepare initial dilution for intravenous infusion, 10 mL of sterile water for injection (without parabens) should be added to each 500-mg vial to provide 50 mg per mL. To ensure complete dissolution, the vial should be shaken until solution is clear. The resulting solution should be further diluted, usually with 100 mL of 0.9% sodium chloride injection, 5% dextrose injection, Ringer's injection, or lactated Ringer's injection. Final concentrations of 10 mg per mL or less are recommended.^{02}{23}

Note: Caution should be exercised in the handling and preparation of ganciclovir. Because ganciclovir shares some properties of anti-tumor agents (i.e., carcinogenicity and mutagenicity), it should be handled and disposed of according to guidelines issued for cytotoxic drugs. Ganciclovir solution is alkaline (pH 11). Avoid inhalation, ingestion, or direct contact of ganciclovir with the skin or mucous membranes. If contact does occur, wash area thoroughly with soap and water; rinse eyes thoroughly with plain water.^{02}{42}


Stability:
The manufacturer states that after reconstitution, solutions at concentrations of 50 mg per mL retain their potency for 12 hours at room temperature. Refrigeration is not recommended. After further dilution for intravenous infusion, it is recommended that solutions be used within 24 hours since nonbacteriostatic infusion solutions must be used; refrigerate the diluted solution; do not freeze.^{02}{23}

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

Incompatibilities:
Parabens are incompatible with ganciclovir sodium and may cause precipitation.^{{01} {02}}

Revised: 04/04/2001

References

1. Cytovene-IV and Cytovene package insert (Roche—US), Rev 12/94, Rec 2/95.
   

2. Ganciclovir (Cytovene, Syntex). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 320-2.
   

3. Fletcher CV, Balfour HH. Evaluation of ganciclovir for cytomegalovirus disease. Drug Intell Clin Pharm 1989; 23: 5-12.
   

4. Fleeger CA, editor. USP dictionary of USAN and international drug names, 1995. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1994: 309.
   

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

7. Reines ED, Gross PA. Antiviral agents. Med Clin North Am 1988; 72(3): 691-715.
   

8. Jacobson MA, de Miranda P, Cederberg DM, et al. Human pharmacokinetics and tolerance of oral ganciclovir. Antimicrob Agents Chemother 1987; 31(8): 1251-4.
   

9. 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.
   

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11. Laskin OL, Cederberg DM, Mills J, Eron LJ, Mildvan D, Spector SA. Ganciclovir for the treatment and suppression of serious infections caused by cytomegalovirus. Am J Med 1987; 83: 201-7.
    

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17. Shea BF, Hoffman S, Sesin GP, Hammer SM. Ganciclovir hepatotoxicity. Pharmacotherapy 1987; 7(6): 223-6.
    

18. Mills J, Jacobson MA, O"Donnell JJ, Cederberg D, Holland GN. Treatment of cytomegalovirus retinitis in patients with AIDS. Rev Infect Dis 1988; 10(suppl 3): S522-S531.
    

19. Trapnell MD, Cimoch P, Gaines K, Jung D, Hale M, Lavelle J. Altered didanosine pharmacokinetics with concomitant oral ganciclovir [abstract PIII-47]. Clin Pharmacol Ther 1994; 55(2): 193.
    

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21. Gaines K, Wong R, Jung D, Cimoch P, Lavelle J, Pollard R. Pharmacokinetic interactions with oral ganciclovir: zidovudine, didanosine, probenecid [abstract]. Tenth International Conference on AIDS, Yokohama, Japan, August 1994.
    

22. Panel comments, 10/27/89.
    

23. Cytovene package insert (Syntex—US), Rev 6/89, Rec 8/89.
    

24. Panel comments, 11/2/89.
    

25. Levin AV, Zeichner S, Duker JS, et al. Cytomegalovirus retinitis in an infant with acquired immunodeficiency syndrome. Pediatrics 1989; 84(4): 683-7.
    

26. Erice A, Chou S, Biron KK, et al. Progressive disease due to ganciclovir-resistant cytomegalovirus in immunocompromised patients. N Engl J Med 1989; 320(5): 289-93.
    

27. Rosecan LR, Laskin OL, Kalman CM, Haik BG, Ellsworth RM. Antiviral therapy with ganciclovir for cytomegalovirus retinitis and bilateral exudative retinal detachments in an immunocompromised child. Ophthalmology 1986; 93(11): 1401-7.
    

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

29. Ussery FM, Gibson SR, Conklin RH, Piot DF, Stool EW, Conklin AJ. Intravitreal ganciclovir in the treatment of AIDS-associated cytomegalovirus retinitis. Ophthalmology 1988; 95(5): 640-8.
    

30. Panel comments, 12/4/89.
    

31. Panel comments, 11/27/89.
    

32. Gudnason T, Belani KK, Balfour HH. Ganciclovir treatment of cytomegalovirus disease in immunocompromised children. Pediatr Infect Dis J 1989; 8(7): 436-40.
    

33. Panel comments, 2/6/90.
    

34. Henry K, Cantrill H, Fletcher C, Chinnock BJ, Balfour HH. Use of intravitreal ganciclovir (dihydroxy propoxymethyl guanine) for cytomegalovirus retinitis in a patient with AIDS. Am J Ophthalmol 1987; 103(1): 17-23.
    

35. Faulds D, Heel RC. Ganciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections. Drugs 1990; 39(4): 597-638.
    

36. Heinemann M-H. Long-term intravitreal ganciclovir therapy for cytomegalovirus retinopathy. Arch Ophthalmol 1989; 107: 1767-72.
    

37. Hochster H, Dieterich D, Bozzette S, et al. Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS. Ann Intern Med 1990; 113(2): 111-7.
    

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

39. Fuller GN, Gill SK, Guiloff RJ, et al. Ganciclovir for lumbosacral polyradiculopathy in AIDS. Lancet 1990; 335: 48-9.
    

40. Miller RG, Storey JR, Greco CM. Ganciclovir in the treatment of progressive AIDS-related polyradiculopathy. Neurology 1990; 40: 569-74.
    

41. Davis CL, Springmeyer S, Gmerek BJ. Central nervous system side effects of ganciclovir. N Engl J Med 1990; 322(13): 933-4.
    

42. Cytovene package insert (Syntex—US), Rev 8/90, Rec 3/91.
    

43. Drew WL, Miner RC, Busch DF, et al. Prevalence of resistance in patients receiving ganciclovir for serious cytomegalovirus infection. J Infect Dis 1991; 163: 716-9.
    

44. Panel comment, 3/91.
    

45. Grossberg HS, Bonnem EM, Buhles WC. GM-CSF with ganciclovir for the treatment of CMV retinitis in AIDS. N Engl J Med 1989; 320(23): 1560.
    

46. Fouillard L, Gorin NC, Laporte JP, Eugene-Jolchine I, Isnard F, Najman A. GM-CSF and ganciclovir for cytomegalovirus infection after autologous bone-marrow transplantation. Lancet 1989; 2: 1273.
    

47. Sulecki M, Rosenfeld CS, Przepiorka D, Bloom EJ, Buhles W, Shadduck RK. Treatment of ganciclovir-induced neutropenia with recombinant human GM-CSF. Am J Med 1991; 90: 401-2.
    

48. Prichard MN, Prichard LE, Baguley WA, Nassiri MR, Shipman C. Three-dimensional analysis of the synergistic cytotoxicity of ganciclovir and zidovudine. Antimicrob Agents Chemother 1991; 35(6): 1060-5.
    

49. PDR Physicians" desk reference. 47th ed. 1993. Montvale NJ: Medical Economics Data, 1993: 2397-401.
    

50. 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.
    

51. 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.
    

52. 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.
    

53. 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.
    

54. Goodrich JM, Bowden RA, Fisher L, Keller C, Schoch G, Meyers JD. Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogenic marrow transplant. Ann Intern Med 1993; 118: 173-8.
    

55. Silvestri AP, Mitrano FP, Baptista RJ, Williams DA. Stability and compatibility of ganciclovir sodium in 5% dextrose injection over 365 days. Am J Hosp Pharm 1991; 48: 2641-3.
    

56. Mole L, Oliva C, O"Hanely P. Extended stability of ganciclovir for outpatient parenteral therapy for cytomegalovirus retinitis. J Acquir Immune Defic Syndr 1992; 5(4): 354-8.
    

57. Trang JM, Kidd L, Gruber W, et al. Linear single-dose pharmacokietics of ganciclovir in newborns with congenital cytomegalovirus infections. Clin Pharmacol Ther 1993; 53: 15-21.
    

58. Gilstrap LC, Bawdon RE, Roberts SW, Sobhi S. The transfer of the nucleoside analog ganciclovir across the perfused human placenta. Am J Obstet Gynecol 1994; 170: 967-73.
    

59. Spector SA, Busch DF, Follansbee S, et al. Pharmacokinetic, safety, and antiviral profiles of oral ganciclovir in persons infected with human immunodeficiency virus: a phase I/II study. J Infect Dis 1995; 171: 1431-7.
    

60. The Oral Ganciclovir European and Australian Cooperative Study Group. Intravenous versus oral ganciclovir: European/Australian comparative study of efficacy and safety in the prevention of cytomegalovirus retinitis recurrence in patients with AIDS. AIDS 1995; 9(5): 471-7.
    

61. Panel comment, 5/95.
    

62. Panel comment, 5/95.
    

63. Panel comment, 5/95.
    

64. Panel comment, 5/95.
    

65. Cytovene (Roche). In: PDR Physicians" desk reference. 52nd ed. 1998. Montvale, NJ: Medical Economics Company; 1998. p. 2452-8.
    

66. Cytovene (Roche). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 418-21.
    

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69. Zhou XJ, Gruber W, Demmler G, et al. Population pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. NIAID Collaborative Antiviral Study Group. Antimicrob Agents Chemother 1996 Sep; 40(9): 2202-5.
    

70. Stronati M, Revello MG, Cerbo RM, et al. Ganciclovir therapy of congenital human cytomegalovirus hepatitis. Acta Paediatr 1995 Mar; 84(3): 340-1.
    

71. Vallejo JG, Englund JA, Garcia-Prats JA, et al. Ganciclovir treatment of steroid-associated cytomegalovirus disease in a congenitally infected neonate. Pediatr Infect Dis J 1994 Mar; 13(3): 239-41.
    

72. Nigro G, Scholz H, Bartmann U. Ganciclovir therapy for symptomatic congenital cytomegalovirus infection in infants: a two-regimen experience. J Pediatr 1994 Feb; 124(2): 318-22.
    

73. Attard-Montalto SP, English MC, Stimmler L, et al. Ganciclovir treatment of congenital cytomegalovirus infection: a report of two cases. Scand J Infect Dis 1993; 25(3): 385-8.
    

74. Trang JM, Kidd L, Gruber W, et al. Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. NIAID Collaborative Antiviral Study Group. Clin Pharmacol Ther 1993 Jan; 53(1): 15-21
    

75. Reigstad H, Bjerknes R, Markestad T, et al. Ganciclovir therapy of congenital cytomegalovirus disease. Acta Paediatr 1992 Sep; 81(9): 707-8.
    

76. Hocker JR, Cook LN, Adams G, et al. Ganciclovir therapy of congenital cytomegalovirus pneumonia. Pediatr Infect Dis J 1990 Oct; 9(10): 743-5.
    

77. Fan-Havard P, Nahata MC, Brady MT. Ganciclovir-a review of pharmacology, therapeutic efficacy and potential use for treatment of congenital cytomegalovirus infections. J Clin Pharm Ther 1989 Oct; 14(5): 329-40.
    

78. Panel consensus, 3/2000.
    

79. Product Information: Cytovene®, ganciclovir. Hoffman-LaRoche, Mississauga, Ontario (PI revised 8/1999) PI reviewed 3/2001.
    

80. Product Information: Cytovene®, ganciclovir. Roche Pharmaceuticals, Nutley, NJ (PI revised 9/2000) PI reviewed 3/2001.
    

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