Medication Guide App

Valganciclovir (Systemic)


VA CLASSIFICATION
Primary: AM890

Commonly used brand name(s): Valcyte.

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



Category:


Antiviral (systemic)—

Indications

General considerations
Viral resistance can occur after prolonged treatment with valganciclovir by selection of mutations in the viral protein kinase gene responsible for ganciclovir monophosphorylation and/or in the viral polymerase gene.{01} The mutations may cause resistance to ganciclovir or cross-resistance to other antivirals with similar mechanisms of action.{01} The possibility of viral resistance should be considered in patients who show poor clinical response or who experience persistent viral excretion during therapy.{01}

Accepted

Cytomegalovirus retinitis (treatment)—Valganciclovir is indicated for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS).{01} Although clinical data on the use of valganciclovir for maintenance of CMV retinitis are not available, this use is supported by the similarity of the plasma concentration–time profile of ganciclovir following administration of valganciclovir and the profiles following oral and parenteral administration of ganciclovir.{01} Both ganciclovir dosage forms are approved for maintenance therapy.{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Valganciclovir hydrochloride: 390.83{01}

pKa—
    Valganciclovir hydrochloride: 7.6{01}


pH
    7.{01}

Mechanism of action/Effect:

Valganciclovir is a prodrug of ganciclovir that exists as a mixture of two diastereomers. After administration, these diastereomers are rapidly converted to ganciclovir by hepatic and intestinal esterases.{01}

In cytomegalovirus (CMV)-infected cells, ganciclovir is initially phosphorylated to the monophosphate form by viral protein kinase, then it is further phosphorylated via cellular kinases to produce the triphosphate form. This triphosphate form is slowly metabolized intracellularly. The phosphorylation is dependent upon the viral kinase, and occurs preferentially in virus-infected cells. The virustatic activity of ganciclovir is due to the inhibition of viral DNA synthesis by ganciclovir triphosphate.{01}

Absorption:

Valganciclovir is well absorbed from the gastrointestinal tract and the absolute bioavailability from valganciclovir tablets (following administration with food) is approximately 60%.{01}

Distribution:

Vol D (steady state)— Approximately 0.7 L per kg following intravenous administration of ganciclovir.{01}

Protein binding:

Due to rapid conversion of valganciclovir to ganciclovir the plasma protein binding was not determined. Plasma protein binding of ganciclovir is 1% to 2% over concentrations of 0.5 and 51 mcg per mL (mcg/mL).{01}

Biotransformation:

Valganciclovir is rapidly hydrolyzed in the intestinal wall and liver to ganciclovir.{01} No other metabolites have been detected.{01}

Half-life:


Ganciclovir:

Terminal: Oral—Approximately 4.08 hours;{01} increased in patients with renal function impairment.{01}


Time to peak concentration:

Ganciclovir—1 to 3 hours.{01}

Peak plasma concentration:

Ganciclovir—Approximately 5.6 mcg/mL.{01}

Elimination:
    Renal; almost 100% excreted as unchanged ganciclovir in the urine by glomerular filtration and active tubular secretion.{01}
    In dialysis—The plasma concentrations of ganciclovir are decreased by approximately 50%.{01} Use of valganciclovir is not recommended in patients who have a creatinine clearance less than 10 mL per minute and who are undergoing hemodialysis because the required daily dose is less than 450 mg.{01}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to ganciclovir may also be hypersensitive to valganciclovir due to the chemical similarity of the two medications.{01}

Carcinogenicity

No long term carcinogenicity studies have been conducted with valganciclovir. However, ganciclovir is a potential carcinogen and due to the rapid conversion of valganciclovir to ganciclovir, it is also considered a potential carcinogen.{01}

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 plasma 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 a significantly increased incidence of tumors of the forestomach in males and females, preputial gland in males, and reproductive tissues and liver in females. No carcinogenic effect occurred at a dose of 1 mg/kg per day (approximately 0.01 time the human dose based on AUC comparison).{01}

Mutagenicity

Valganciclovir causes increased mutations in mouse lymphoma cells. In the mouse micronucleus assay, valganciclovir was clastogenic at a dose of 1500 mg/kg (60 times the mean human exposure of ganciclovir based on AUC). Valganciclovir was not mutagenic in the Ames Salmonella assay. Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human lymphocytes in vitro. In the mouse micronucleus assay, ganciclovir was clastogenic at intravenous doses of 150 and 500 mg/kg (2.8 to 10 times the human exposure based on AUC) but not 50 mg/kg (exposure approximately compared to the human based on AUC). Ganciclovir was not mutagenic in the Ames Salmonella assay.{01}

Pregnancy/Reproduction
Fertility—
Valganciclovir is converted to ganciclovir and is expected to have similar reproductive toxicity effects as ganciclovir. Ganciclovir caused decreased mating behavior, decreased fertility, and an increased incidence of embryolethality in female mice following intravenous doses of 90 mg/kg per day (approximately 1.7 times the mean drug exposure in humans following the dose of 5 mg/kg, based on AUC comparisons).{01}

Ganciclovir caused 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. Systemic drug exposure (AUC) at the lowest dose showing toxicity in each species ranged from 0.03 to 0.1 time the AUC of the recommended human intravenous dose. Valganciclovir caused similar effects on spermatogenesis in mice, rats, and dogs. It is considered likely that ganciclovir and valganciclovir could cause inhibition of human spermatogenesis.{01}

Pregnancy—
Valganciclovir is converted to ganciclovir and is expected to have reproductive toxicity effects similar to ganciclovir.{01}

Adequate and well-controlled studies in humans have not been done. However, ganciclovir has been found to cross the placenta. 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 has been shown to be embryotoxic in rabbits and mice following intravenous administration, and teratogenic in rabbits. Fetal resorptions were present in at least 85% of the rabbits and mice administered 60 and 108 mg/kg per day (2 times the human exposure based on AUC comparisons), respectively. Effects observed in rabbits included fetal growth retardation, embryolethality, teratogenicity and/or maternal toxicity. Teratogenic changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. In mice, effects observed were maternal/fetal toxicity and embryolethality.{01}

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}

Valganciclovir may be teratogenic or embryotoxic at dose levels recommended for human use.{01}

FDA Pregnancy Category C.{01}

Breast-feeding

It is not known whether valganciclovir or ganciclovir is distributed into breast milk. The potential of serious adverse events from ganciclovir in nursing infants exists and breast-feeding should be stopped during ganciclovir therapy.{01}

The Centers for Disease Control and Prevention (CDC) recommended that human immunodeficiency virus (HIV)-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.{01}

Pediatrics

No information is available on the relationship of age to the effects of valganciclovir in the pediatric population. Safety and efficacy have not been established.{01}


Geriatrics


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


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 the 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.
No in vivo drug-drug interaction studies were done with valganciclovir. Because valganciclovir is rapidly and extensively converted to ganciclovir, interactions associated with ganciclovir will be expected for valganciclovir. {01}

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


» Didanosine{01}    (concurrent and sequential [2 hours prior] administration of didanosine with valganciclovir results in a significant increase in the steady-state area under the plasma concentration–time curve [AUC] of didanosine [range, 50 to 111%]; patients should be closely monitored for signs of didanosine toxicity{01})


» Mycophenolate{01}    (patients with impaired renal function should be closely monitored as concentrations of metabolites of both drugs may increase{01})


» Probenecid{01}    (concurrent use with probenecid increases the AUC of ganciclovir by approximately 53% and decreases its renal clearance by approximately 22%; patients should be monitored for evidence of ganciclovir toxicity{01})


» Zidovudine    ( both valganciclovir and zidovudine have the potential to cause neutropenia and anemia;{01} some patients may not tolerate concomitant therapy at full dosage{01})



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
» Absolute neutrophil count{01} and
» Hemoglobin concentration{01} and
» Platelet count{01}    (values may be decreased{01})


» Creatinine clearance{01}    (value may be decreased{01})


» Creatinine, serum{01}    (value may be increased {01})


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).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Absolute neutrophil count (ANC) < 500 cells per microliter, hemoglobin concentration < 8 grams per deciliter, or platelet count < 25,000 cells per microliter{01}
Risk-benefit should be considered when the following medical problems exist
» Hypersensitivity to valganciclovir or ganciclovir{01}
» Renal function impairment    (because ganciclovir is excreted through the kidneys, the dose of valganciclovir should be reduced or the dosing interval increased in patients with renal function impairment;{01} use of valganciclovir is not recommended in patients who have a creatinine clearance less than 10 mL per minute and who are undergoing hemodialysis because the required daily dose is less than 450 mg{01})



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 count (CBC){01}    (because valganciclovir may cause granulocytopenia and thrombocytopenia, a complete blood count should be performed prior to treatment and frequently during treatment; increased frequency of monitoring may be required in patients with neutrophil counts less than 1000 cells/microliter and those in whom use of valganciclovir or ganciclovir or other nucleoside analogs previously resulted in leukopenia{01})


» Creatinine clearance{01} or
» Creatinine concentration, serum{01}    (values should be closely monitored in patients with renal function impairment to guide dosing{01})


» Ophthalmologic examinations{01}    (ophthalmologic examinations should be performed every 4 to 6 weeks during therapy since valganciclovir is not a cure for cytomegalovirus [CMV] retinitis, and progression of retinitis may occur during or following valganciclovir treatment;{01} some patients may require more frequent examinations{01})




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
    
Anemia {01}(pale skin; troubled breathing, exertional; unusual tiredness or weakness)
    
neutropenia {01}(chills; cough; fever; hoarseness; lower back or side pain; painful or difficult urination; sore throat; ulcers, sores, or white spots in mouth ; unusual tiredness or weakness)
    
pyrexia {01}(fever)
    
retinal detachment {01}(veil or curtain appearing across part of vision; seeing flashes or sparks of light; seeing floating spots before eyes ){01}
    
thrombocytopenia (black, tarry stools; blood in urine or stools; pinpoint red spots on skin; unusual bleeding or bruising)

Incidence less frequent
    
Bleeding {01}—associated with thrombocytopenia; may be life-threatening {01}
    
bone marrow depression {01}(fever; sore throat; unusual bleeding or bruising; unusual tiredness or weakness)
    
hallucinations {01}(feeling, hearing, or seeing things that are not there)
    
hypersensitivity reaction {01}( anaphylaxis; angioedema; asthma; dermatitis; rhinitis; urticaria )
    
infection, local or systemic, or sepsis {01}(chills; fever)
    
pancytopenia {01}(shortness of breath or troubled breathing; sores, ulcers, or white spots on lips or in mouth; tightness in chest and/or wheezing; unusual bleeding or bruising; unusual tiredness or weakness)
    
psychosis {01}(confusion; delusions; hallucinations ; illogical thinking)
    
seizures {01}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal pain {01}
    
diarrhea {01}
    
headache {01}
    
insomnia {01}(sleeplessness; trouble sleeping )
    
nausea and vomiting {01}
    
paresthesia {01}(tingling, burning, or prickly sensations )
    
peripheral neuropathy {01}(numbness, tingling, pain, or weakness of hands or feet)

Incidence less frequent
    
Agitation {01}
    
confusion {01}





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

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Abdominal pain {01}
    
acute renal failure (decreased frequency or amount of urine; fast or slow heartbeat; loss of appetite; nausea; shortness of breath; unusual tiredness or weakness){01}
    
bone marrow depression ( fever; sore throat; unusual bleeding or bruising; unusual tiredness or weakness)— progressed to medullary aplasia in one patient{01}
    
diarrhea {01}
    
elevated creatinine concentrations {01}
    
granulocytopenia or leukopenia (chills; cough; fever; hoarseness; lower back or side pain; painful or difficult urination ; shortness of breath; sore throat; ulcers, sores, or white spots in mouth; unusual tiredness or weakness){01}
    
hematuria {01}(blood in the urine)—in patients with existing renal function impairment{01}
    
hepatitis {01}(anorexia; diarrhea ; nausea; vomiting)
    
increased renal toxicity (agitation; coma; confusion; decreased urine output ; depression; dizziness; headache; hostility; irritability; lethargy; muscle twitching; nausea ; rapid weight gain; seizures; stupor; swelling of face, ankles, or hands; unusual tiredness or weakness){01}
    
liver function disorder {01}
    
pancytopenia (shortness of breath or troubled breathing; sores, ulcers, or white spots on lips or in mouth; tightness in chest and/or wheezing ; unusual bleeding or bruising; unusual tiredness or weakness){01}
    
seizures {01}
    
tremor, generalized (quivering; trembling){01}
    
vomiting {01}


Treatment of overdose


To enhance elimination :
Dialysis may be useful in reducing serum concentrations as ganciclovir is dialyzable.{01}



Specific treatment:
The use of hematopoietic growth factors should be considered.{01}



Supportive care:
Adequate hydration should be maintained. {01}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



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

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

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

Pregnancy—Use of valganciclovir 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 valganciclovir's potential for severe toxicity, breast-feeding should be stopped during therapy
Other medications, especially other bone marrow depressants, didanosine, mycophenolate, probenecid, or zidovudine
Other medical problems, especially an absolute neutrophil count (ANC) < 500 cells per microliter (cells/microliter), platelet count < 25,000 cells/microliter, hemoglobin concentration < 8 grams/deciliter, or renal function impairment

Proper use of this medication
» Taking valganciclovir capsules with food

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

» Proper dosing

Proper storage

Precautions while using this medication
» Regular visits to physician to check blood counts

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

Caution if bone marrow depression occurs:
» Avoiding exposure to persons with bacterial infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occur

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

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters
Not coming into contact with broken or crushed tablets; if contact is made with skin, washing with soap and water; if contact is made with eyes, rinsing with clear water


Side/adverse effects
Signs of potential side effects, especially anemia, neutropenia, pyrexia, retinal detachment, thrombocytopenia, bleeding, bone marrow depression, hallucinations, hypersensitivity reaction, infection or sepsis, pancytopenia, psychosis, and seizures


General Dosing Information
The bioavailability of ganciclovir from valganciclovir tablets is significantly higher than from ganciclovir capsules. Patients switching from ganciclovir capsules to valganciclovir tablets should be advised of the risk of overdosage if they take more than the prescribed number of valganciclovir tablets. Valganciclovir tablets cannot be substituted for ganciclovir capsules on a one-to-one basis.{01}

Diet/Nutrition
Valganciclovir should be taken with food for maximum absorption.{01}

Safety considerations for handling this medication
Caution should be exercised in the handling and preparation of valganciclovir. Because valganciclovir 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. Avoid inhalation, ingestion, or direct contact of broken or crushed valganciclovir tablets with the skin or mucous membranes. If contact does occur, wash area thoroughly with soap and water; rinse eyes thoroughly with plain water. {01}


Oral Dosage Forms

VALGANCICLOVIR HYDROCHLORIDE TABLETS

Note: Strict adherence to dosage recommendations is essential to avoid overdose.{01}
The dosing and strengths of the dosage form are expressed in terms of valganciclovir base (not the hydrochloride salt).{01}


Usual adult dose
Cytomegalovirus retinitis


Patients with normal renal function:
Induction—Oral, 900 mg (base) two times a day with food for twenty-one days.{01}

Maintenance—Oral, 900 mg once a day with food.{01}



Patients with renal function impairment:


Creatinine clearance ³ 60 mL per minute—
See Usual adult dose.




Creatinine clearance 40 to 59 mL per minute:
Induction: 450 mg two times a day with food for twenty-one days.{01}{02}

Maintenance: 450 mg once a day with food.{01}



Creatinine clearance 25 to 39 mL per minute:
Induction: 450 mg once a day with food for twenty-one days.{01}{02}

Maintenance: 450 mg every two days with food.{01}



Creatinine clearance 10 to 24 mL per minute:
Induction: 450 mg every two days with food for a total of twenty-one days.{01}{02}

Maintenance: 450 mg two times a week with food.{01}



Creatinine clearance < 10 mL per minute:
Use of valganciclovir is not recommended because the required daily dose is less than 450 mg.{01}



Usual pediatric dose
Safety and efficacy have not been established.{01}

Strength(s) usually available
U.S.—


450 mg (base) (Rx) [Valcyte (microcrystalline cellulose) (povidone K-30) ( crospovidone) (stearic acid)]{01}

Packaging and storage:
Store at 25 °C (77 °F), excursions permitted between 15 and 30 °C (59 and 86 °F).{01}
{01}
Note: Care should be taken in the handling of valganciclovir as it is a potential carcinogen and teratogen. Avoid direct contact of broken or crushed tablets with skin or mucous membranes. If contact occurs, wash with soap and water and rinse eyes thoroughly with plain water.{01}




Developed: 06/27/2001



References
  1. Product Information: Valcyte™, valganciclovir. Roche Pharmaceuticals, Nutley, New Jersey (PI issued 3/2001) reviewed 5/2001.
  1. Personal communication, 06/20/01.
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