Valganciclovir

J05A - Direct acting antivirals ATC J05AB14 Small molecule approved 2001 Oral Prodrug Natural product Black-box warning

Active form: Ganciclovir Triphosphate.

JFDA label: Valcyte F.C.Tablet

⚠ Black-Box Warning

Hematologic toxicity:
Impairment of fertility:
Fetal toxicity:
Mutagenesis and carcinogenesis:

Mechanism of Action

Valganciclovir is rapidly converted to ganciclovir in the body. Ganciclovir is phosphorylated to a substrate which competitively inhibits the binding of deoxyguanosine triphosphate to DNA polymerase resulting in inhibition of viral DNA synthesis.

Indications

Approved

CMV retinitis, treatment (AIDS-related)
Cytomegalovirus, prophylaxis (solid organ transplant recipients)

Off-label

CMV esophagitis or colitis treatment in HIV-infected patients (adolescents and adults)
CMV, preemptive therapy (hematopoietic cell transplant recipients)
CMV, secondary prophylaxis (solid organ transplant recipients)
Cytomegalovirus disease, treatment (solid organ transplant recipients)

Antimicrobial Spectrum

Expected / intrinsic spectrum (EUCAST breakpoints & labels) — not local resistance. Source: openfda-label.

Viruses

Organism	Activity	MIC
Cmv	Active	—
Cytomegalovirus	Active	—

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Hypersensitivity to acyclovir or valacyclovir Absolute
Hypersensitivity (eg, anaphylaxis) to valganciclovir, ganciclovir, or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (4)

Very Common Hypertension

Common cardiac arrhythmia, paresthesia, anxiety, chills, depression, dizziness, fatigue, malaise, pain, agitation, increased wound secretion, night sweats, pruritus, cellulitis, hypophosphatemia, weight loss · Hypotension · peripheral edema

Nervous system disorders (2)

Very Common Headache · insomnia

Renal and urinary disorders (1)

Very Common Increased serum creatinine

Blood and lymphatic system disorders (4)

Very Common Anemia · neutropenia · thrombocytopenia

Common Bone marrow depression, increased serum ALT

Immune system disorders (1)

Very Common Graft rejection

Gastrointestinal disorders (10)

Very Common abdominal pain · Diarrhea · nausea · vomiting

Common Abdominal distention · constipation · decreased appetite · dysgeusia, urinary tract infection · dyspepsia · oral mucosa ulcer

Musculoskeletal and connective tissue disorders (1)

Very Common Tremor

Eye disorders (1)

Very Common Retinal detachment

Infections and infestations (4)

Common Candidiasis · influenza · sepsis, back pain, muscle spasm, myalgia, weakness, limb pain, macular edema, renal impairment, renal failure, dyspnea, pharyngitis, upper respiratory tract infection · wound infection

General disorders and administration site conditions (3)

Very Common Fever

Common Postoperative complication · postoperative pain (Frequency not defined: Genitourinary: Reduced fertility

Dosing

Source: Lexicomp

Cytomegalovirus (CMV) retinitis, treatment (AIDS-related): Oral: Manufacturer's labeling: Induction: 900 mg twice daily for 21 days Maintenance: Following induction treatment, or for patients with inactive CMV retinitis who require maintenance therapy: 900 mg once daily Alternate dosing (HHS [OI adult 2016]): Induction: 900 mg twice daily for 14 to 21 days Maintenance: 900 mg once daily; may consider discontinuation of chronic maintenance therapy in patients that have received 3 to 6 months of treatment, have inactive lesions, and CD4 count >100 cells/mm3 for 3 to 6 months in response to antiretroviral therapy CMV, prophylaxis (solid organ transplant recipients): Oral: Manufacturer's labeling: 900 mg once daily beginning within 10 days of transplantation; continue therapy until 100 days (heart or kidney-pancreas transplant) or 200 days (kidney transplant) post-transplantation Alternate dosing: 900 mg once daily; duration of prophylaxis is dependent on type of transplant, as well as donor and recipient CMV serostatus (Kotton 2013) CMV disease (nonsevere), treatment (solid organ transplant recipients) (off-label use): Oral: 900 mg twice daily until 1 or 2 consecutive undetectable CMV viral load samples are obtained (minimum treatment course: 2 weeks) (Kotton 2013) CMV esophagitis or colitis in HIV-infected patients (off-label use): Oral: Treat initially with ganciclovir IV; once patient is able to absorb and tolerate oral therapy, may switch to oral valganciclovir 900 mg twice daily for a total duration of 21 to 42 days, or until signs and symptoms have resolved (HHS [OI adult 2016]) CMV, preemptive therapy (hematopoietic cell transplant recipients) (off-label use) (Tomblyn 2009): Oral: 900 mg twice daily for 7 days (autologous transplant) or 7 to 14 days (allogenic transplant), then 900 mg once daily for 1 to 2 weeks or until the indicator test is negative (minimum total induction and maintenance treatment is 2 weeks when 14 days of twice daily is used and 3 weeks when a 7-day induction course is used) >100 days post-transplant: 900 mg twice daily for 7 to 14 days, then 900 mg once daily for 1 to 2 weeks or until the indicator test is negative CMV, secondary prophylaxis (solid organ transplant recipients) (off-label use): Oral: 900 mg once daily for 1 to 3 months after completion of treatment for CMV disease (Kotton 2013)

(For additional information see "Valganciclovir: Pediatric drug information") Infants, Children, and Adolescents 1 month to 16 years: CMV disease (prophylaxis) following heart transplantation: Oral: Dose (mg) = 7 x body surface area x creatinine clearance (see Calculation below) once daily beginning within 10 days of transplantation; continue therapy until 100 days post-transplantation. Doses should be rounded to the nearest 10 mg increment; maximum dose: 900 mg daily. Infants, Children, and Adolescents 4 months to 16 years: CMV disease (prophylaxis) following kidney transplantation: Oral: Dose (mg) = 7 x body surface area x creatinine clearance (see Calculation below) once daily beginning within 10 days of transplantation; continue therapy until 200 days post-transplantation. Doses should be rounded to the nearest 10 mg increment; maximum dose: 900 mg daily. Calculation of creatinine clearance: CrCl (mL/minute/1.73 m2) = [k x Height (cm)] divided by serum creatinine (mg/dL) Note: If the calculated CrCl is >150 mL/minute/1.73 m2, then a maximum value of 150 mL/minute/1.73 m2 should be used to calculate the dose. Note: Calculated using modified Schwartz formula where k is as follows: Infants with low birth weight for gestational age: k = 0.33 Infants with birth weight appropriate for gestational age: k = 0.45 Children 1 to Girls 2 to 16 years: k = 0.55 Boys 2 to Boys 13 to 16 years: k = 0.7 Adolescents >16 years: Oral: Refer to adult dosing

Refer to adult dosing.

Infants, Children, and Adolescents 1 month to 16 years: No dosage adjustment necessary; calculation for pediatric dosing adjusts for renal function. Adolescents >16 years and Adults: Induction dose: CrCl ≥60 mL/minute: No dosage adjustment necessary CrCl 40 to 59 mL/minute: 450 mg twice daily CrCl 25 to 39 mL/minute: 450 mg once daily CrCl 10 to 24 mL/minute: 450 mg every 2 days CrCl Manufacturer labeling: Use not recommended; ganciclovir (with appropriately specified renal dosage adjustment) should be used instead of valganciclovir Alternate dosing: HIV-1 infected persons: Consider valganciclovir solution 200 mg 3 times weekly (Lucas, 2014) End stage renal disease (ESRD) on intermittent hemodialysis (IHD): Manufacturer labeling: Use not recommended; ganciclovir (with appropriately specified renal dosage adjustment) should be used instead of valganciclovir. Alternate dosing: HIV-1 infected persons: Consider valganciclovir solution 200 mg 3 times weekly (Lucas, 2014); valganciclovir is dialyzable and should be administered following dialysis. Maintenance/prevention dose: CrCl ≥60 mL/minute: No dosage adjustment necessary CrCl 40 to 59 mL/minute: 450 mg once daily CrCl 25 to 39 mL/minute: 450 mg every 2 days CrCl 10 to 24 mL/minute: 450 mg twice weekly CrCl Manufacturer labeling: Use not recommended; ganciclovir (with appropriately specified renal dosage adjustment) should be used instead of valganciclovir Alternate dosing: HIV infected persons: Consider valganciclovir solution 100 mg 3 times weekly (Lucas, 2014) End stage renal disease (ESRD) on intermittent hemodialysis (IHD): Manufacturer labeling: Use not recommended; ganciclovir (with appropriately specified renal dosage adjustment) should be used instead of valganciclovir. Alternate dosing: HIV-1 infected persons: Consider valganciclovir solution: 100 mg 3 times weekly (Lucas, 2014); valganciclovir is dialyzable and should be administered following dialysis.

There are no dosage adjustments provided in the manufacturer labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

Acute renal failure

Acute renal failure may occur; ensure adequate hydration and use with caution in patients receiving concomitant nephrotoxic agents.

Blood dyscrasias

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure, including aplastic anemia have been reported. May occur at any time during treatment and worsen with continued use; cell counts usually begin to recover within 3 to 7 days of treatment discontinuation. Do not use in patients with an absolute neutrophil count 3, platelet count 3, or hemoglobin 3 at treatment initiation.

Carcinogenic/teratogenic

May cause temporary or permanent inhibition of spermatogenesis and suppression of fertility; has the potential to cause birth defects and cancers in humans. Due to its teratogenic potential, females should undergo pregnancy testing prior to initiation and use effective contraception during treatment and for 30 days after; males should use barrier contraception during treatment and for 90 days after. Disease-related concerns:

Renal impairment

Use with caution in patients with impaired renal function; dosage adjustment required. Special populations:

Elderly

Acute renal failure may occur in elderly patients with or without preexisting renal impairment; use with caution and adjust dose as needed based on renal function.

Liver transplant recipients

Not indicated for use in liver transplant patients (higher incidence of tissue-invasive cytomegalovirus [CMV] relative to oral ganciclovir was observed in trials).

Pediatric

The preferred dosage form for pediatric patients is the oral solution; however, valganciclovir tablets may be used so long as the calculated dose is within 10% of the available tablet strength (450 mg). Use of valganciclovir for the treatment of congenital CMV disease has not been evaluated. Dosage form specific issues:

Benzyl alcohol and derivatives

Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

Pregnancy & Lactation

Pregnancy

Teratogenic

[US Boxed Warning]: May cause temporary or permanent inhibition of spermatogenesis and suppression of fertility; has the potential to cause birth defects in humans. Valganciclovir is converted to ganciclovir and shares its reproductive toxicity. Ganciclovir crosses the placenta. Based on animal data, temporary or permanent impairment of fertility may occur in males and females. Ganciclovir is also teratogenic in animals. The manufacturer recommends females of reproductive potential undergo pregnancy testing prior to therapy. Females should use effective contraception during treatment and for 30 days after; males should use barrier contraception during treatment and for 90 days after. Adverse events following congenital cytomegalovirus (CMV) infection may also occur. Hearing loss, mental retardation, microcephaly, seizures, and other medical problems have been observed. The indications for treating CMV retinitis during pregnancy are the same as in non-pregnant HIV infected woman; howe

Lactation

Avoid

It is not known if ganciclovir or valganciclovir are present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer. Females with HIV infection should completely avoid breastfeeding to decrease the potential transmission of HIV (HHS [perinatal] 2017).

Monitoring

Clinical pearl	CBC, platelet count, serum creatinine at baseline and periodically during therapy; monitor CBC and platelet count more frequently during therapy in patients with renal impairment, those with previous drug-induced leukopenia, and those with neutrophil counts 3 at treatment initiation; pregnancy test prior to initiation in females of reproductive potential.

Chemistry & Properties

Formula	C14H22N6O5
Molecular weight	354.37 g/mol
IUPAC name	[2-[(2-amino-6-oxo-1H-purin-9-yl)methoxy]-3-hydroxypropyl] (2S)-2-amino-3-methylbutanoate
CAS	175865-60-8
PubChem CID	135413535
InChIKey	`WPVFJKSGQUFQAP-GKAPJAKFSA-N`
logP	-1.44 (XLogP -1.5)
Polar surface area	171.37 Å²
H-bond acceptors / donors	10 / 4
Drug-likeness (QED)	0.41
Lipinski violations	0

SMILES

CC(C)[C@H](N)C(=O)OCC(CO)OCn1cnc2c(=O)[nH]c(N)nc21

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)PEPT1 (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Adalimumab	major
Certolizumab pegol	major
Cladribine	major
Deferiprone	major
Etanercept	major
Golimumab	major
Infliximab	major
Abemaciclib	moderate
Acalabrutinib	moderate
Aflibercept	moderate
Albendazole	moderate
Aldesleukin	moderate
Alemtuzumab	moderate
Altretamine	moderate
Amphotericin B	moderate
Amphotericin B (cholesteryl sulfate)	moderate
Amphotericin B (lipid complex)	moderate
Amphotericin B (liposomal)	moderate
Asparaginase Escherichia coli	moderate
Azacitidine	moderate
Azathioprine	moderate
Baricitinib	moderate
Belinostat	moderate
Bendamustine	moderate
Bexarotene	moderate
Bleomycin	moderate
Blinatumomab	moderate
Bortezomib	moderate
Bosutinib	moderate
Brentuximab vedotin	moderate
Busulfan	moderate
Cabazitaxel	moderate
Capecitabine	moderate
Carboplatin	moderate
Carfilzomib	moderate
Carmustine	moderate
Chlorambucil	moderate
Chloramphenicol	moderate
Cisplatin	moderate
Clofarabine	moderate

Showing 40 of 100+.

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Vagacyte	Tablet 450 mg	10 tab	JAWEDA INT. DRUD STORE	—
Valcyte F.C.Tablet	Film-Coated Tablet 450 mg	60 tab	Shawi & Rushedat Drug Store	—