Valganciclovir, also known as Valcyte, belongs to the class of medicines known as antivirals. These medicines kill viruses or stop viruses from multiplying.
HIV/AIDS-Related Uses
Valganciclovir was approved by the FDA on March 29, 2001, for treatment of the symptoms of cytomegalovirus (CMV) retinitis (an eye infection) in patients with weakened immune systems, including people with HIV and AIDS. This medicine does not cure CMV retinitis, but it can help to keep the symptoms from becoming worse. Studies are now being done to see if valganciclovir is safe and effective in preventing advanced CMV disease in HIV infected patients and in treating CMV in babies born to HIV infected mothers. Valganciclovir was approved by the FDA on September 12, 2003, for preventing CMV disease in certain organ transplant patients.
Dosage Form/Administration
Valganciclovir comes in tablet and solution forms and is taken by mouth. Valganciclovir must be taken with food.
Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take valganciclovir exactly as directed.
Contraindications
Individuals should tell a doctor about any medical problems before taking this medicine.
Possible Side Effects
Along with its desired effects, valganciclovir may cause some unwanted effects. Serious side effects of this medicine include black or tarry stools; blood in urine or stools; chills; cough; fever; hoarseness; lower back or side pain; pain or trouble urinating; pale skin; seeing flashes or sparks of light, floating spots, or a partial veil across vision; sore throat; sores or white spots in the mouth; tiny red spots on skin; trouble breathing; unusual bleeding or bruising; and unusual tiredness or weakness. Individuals should tell a doctor if they have any of these symptoms.Other side effects may not be serious and may lessen or disappear with continued use of valganciclovir. Less serious side effects of this medicine include abdominal pain; diarrhea, nausea, and vomiting; headache; numbness or tingling in the hands or feet; and trouble sleeping. Individuals should tell a doctor if these effects continue or are bothersome.
Drug and Food Interactions
A doctor should be notified of any other medications being taken, including prescription, nonprescription (over-the-counter), or herbal medications.
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use Valganciclovir.
Manufacturer Information
Valcyte
Roche Laboratories
340 Kingsland Street
Nutley, NJ 07110
Phone: 973-235-5000
Valganciclovir
Roche Laboratories
340 Kingsland Street
Nutley, NJ 07110
Phone: 973-235-5000
All Content Last Reviewed: March 16, 2007
Last Updated: September 16, 2010
Drug Description
Valganciclovir hydrochloride is a hydrochloride salt of the L-valyl ester of ganciclovir that exists as a mixture of two diastereomers. Ganciclovir is a synthetic analogue of 2-deoxyguanosine. [1]
References
[1] Roche Laboratories Valcyte Product Information, January 2006, p. 1. Available at: http://www.rocheusa.com/products/valcyte/pi.html. Accessed 03/16/07.
HIV/AIDS-Related Uses
Valganciclovir hydrochloride was approved by the FDA on March 29, 2001, for the treatment of cytomegalovirus (CMV) retinitis in patients with weakened immune systems, including individuals with HIV and AIDS. [1] Valganciclovir is also used to prevent CMV disease in heart, kidney, or kidney-pancreas transplant adult patients at high risk, and in heart or kidney transplant patients 4 months to 16 years of age at high risk. [2] [3] It is currently being investigated to determine its efficacy in preventing CMV end-organ disease in HIV infected patients. [4] It is also being investigated for safety and efficacy in treating congenital CMV disease in neonates. [5]
References
[1] USP DI 2005; p. 2886
[2] FDA – Press Release. “FDA Drug Safety Communication: New dosing recommendations to prevent potential Valcyte (valganciclovir) overdose in pediatric transplant patients.” Available at: http://www.fda.gov/Drugs/DrugSafety/ucm225727.htm. Accessed on: 9/16/2010.
[3] FDA Valcyte Prescribing Information, August 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021304s008,022257s003lbl.pdf. Accessed on: 9/16/10.
[4] ClinicalTrials.gov Valganciclovir Prevention of Cytomegalovirus (CMV) organ damage. Available at: http://www.clinicaltrials.gov/ct/show/NCT00006145. Accessed 03/16/07.
[5] ClinicalTrials.gov Assessment of Valganciclovir in Neonates With CMV. Available at: http://www.clinicaltrials.gov/ct/show/NCT00031434. Accessed 03/16/07.
Dosing Information
Mode of Delivery
Oral. [1]
Dosage Form
Tablets 450 mg. Oral solution 50 mg/mL. [2]
Adult Patients with Normal Renal Function
Treatment of CMV retinitis:
• Induction: The recommended dose is 900 mg (two 450 mg tablets) twice a day for 21 days.
• Maintenance: Following induction treatment, or in adult patients with inactive CMV retinitis, the recommended dose is 900 mg (two 450 mg tablets) once a day.
Prevention of CMV disease:
• For adult patients who have received a heart or kidney-pancreas transplant, the recommended dose is 900 mg (two 450 mg tablets) once a day starting within 10 days of transplantation until 100 days post-transplantation.
• For adult patients who have received a kidney transplant, the recommended dose is 900 mg (two 450 mg tablets) once a day starting within 10 days of transplantation until 200 days post-transplantation.[3]
Prevention of CMV Disease in Pediatric Patients
• Health professionals should be aware of possible overdose in pediatric patients with low body weight, low body surface area, or below normal serum creatine. In September, 2010, the FDA updated the dosing algorithm to prevent overdosing among pediatric patients.
• When calculating the pediatric dose, a maximum value of 150 mL/min/1.73 m2 should be used in the formula, even if the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73 m2. Furthermore, if the calculated valganciclovir dose exceeds 900 mg, a dose of 900 mg should be given to the child.
• For pediatric patients 4 months to 16 years of age who have received a kidney or heart transplant, the recommended once daily dose of valganciclovir starting within 10 days of transplantation until 100 days post-transplantation is based on body surface area (BSA) and creatinine clearance (CrCl) derived from a modified Schwartz formula, and is calculated using the equation below:
Pediatric Dose (mg) = 7 x BSA x CrCl (calculated using a modified Schwartz formula). If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73 m2, then a maximum value of 150 mL/min/1.73m2 should be used in the equation.
Mosteller BSA (m2) = Square root of [Height (cm) x Weight (kg)/3600]
Schwartz Creatinine Clearance (mL/min/1.73 m2) = k x Height (cm)/Serum Creatinine (mg/dL)
Where k =
0.45 for patients aged 4 months to < 1 year,
0.45 for patients aged 1 to < 2 years (note k value is 0.45 instead of the typical value of 0.55),
0.55 for boys aged 2 to < 13 years and girls aged 2 to 16 years, and
0.7 for boys aged 13 to 16 years.[4] [5]
Storage
Store tablets at 25 C (77 F); excursions permitted between 15 C to 30 C (59 F to 86 F). [6]
Store dry powder at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store constituted solution under refrigeration at 2°C to 8°C (36°F to 46°F) for no longer than 49 days. Do not freeze. [7]
References
[1] USP DI 2004; p. 2780
[2] FDA Valcyte Prescribing Information, August 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021304s008,022257s003lbl.pdf. Accessed on: 9/16/10.
[3] FDA Valcyte Prescribing Information, August 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021304s008,022257s003lbl.pdf. Accessed on: 9/16/10.
[4] FDA Valcyte Prescribing Information, August 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021304s008,022257s003lbl.pdf. Accessed on: 9/16/10.
[5] FDA – Press Release. “FDA Drug Safety Communication: New dosing recommendations to prevent potential Valcyte (valganciclovir) overdose in pediatric transplant patients.” Available at: http://www.fda.gov/Drugs/DrugSafety/ucm225727.htm. Accessed on: 9/16/2010.
[6] FDA Valcyte Prescribing Information, August 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021304s008,022257s003lbl.pdf. Accessed on: 9/16/10.
[7] FDA Valcyte Prescribing Information, August 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021304s008,022257s003lbl.pdf. Accessed on: 9/16/10.
Pharmacology
Valganciclovir is a prodrug of ganciclovir; it is converted rapidly to ganciclovir by intestinal and hepatic esterases. Subsequent intracellular phosphorylation converts ganciclovir to ganciclovir triphosphate, which inhibits viral DNA synthesis by competing with deoxyguanosine for incorporation into viral DNA, thus terminating DNA synthesis at the point of incorporation. Because initial phosphorylation depends largely on the presence of the viral protein kinase pUL97, phosphorylation of ganciclovir occurs preferentially in virus-infected cells. [1]
The absolute bioavailability of ganciclovir following oral administration of valganciclovir is approximately 60%, about 10-fold higher than that following oral administration of ganciclovir. The mean 24-hour area under the plasma concentration-time curve (AUC24) for ganciclovir following once-daily administration of 900 mg of oral valganciclovir is comparable to that for once-daily administration of 5 mg/kg intravenous (IV) ganciclovir and exceeds the AUC24 for 1 g of oral ganciclovir administered three times daily. [2] Peak plasma concentration of ganciclovir is approximately 5.6 mcg/ml, and time to peak concentration following administration of 450 mg to 2,625 mg valganciclovir tablets is from 1 to 3 hours. [3] [4]
Valganciclovir is in FDA Pregnancy Category C. There have been no adequate or well-controlled studies in pregnant women; however, data obtained using an ex vivo human placental model show that ganciclovir crosses the placenta, likely through simple diffusion. Because valganciclovir is rapidly converted to ganciclovir in vivo, it is expected to have reproductive toxicity similar to ganciclovir. It is not known whether valganciclovir is excreted in human milk; however, valganciclovir caused granulocytopenia, anemia, and thrombocytopenia in clinical trials, and ganciclovir was mutagenic and carcinogenic in animal studies. Because of the potential for HIV transmission and for serious adverse events from valganciclovir to breastfed infants, women should be instructed not to breastfeed while taking valganciclovir. [5] [6]
Due to valganciclovir's rapid conversion to ganciclovir following oral administration, protein binding of valganciclovir has not been established. Plasma protein binding of ganciclovir is 1% to 2% over concentrations of 0.5 and 51 mcg/ml. In one study, the steady state volume of IV ganciclovir was reported to be 0.703 +/- 0.134 l/kg. [7]
Valganciclovir is rapidly hydrolyzed to ganciclovir; no other metabolites have been detected. For a single 1,000 mg dose of radiolabeled oral ganciclovir, no metabolite accounts for more than 1% to 2% of the radioactivity recovered in the feces or urine. The terminal half-life of ganciclovir following oral administration of valganciclovir is approximately 4.08 hours. [8]
Valganciclovir is eliminated as ganciclovir via renal excretion through both glomerular filtration and active tubular secretion. Renal impairment decreases the clearance of ganciclovir and increases terminal half-life. [9]
Viral resistance can arise after prolonged treatment with valganciclovir. Selection of mutations in the viral protein kinase gene UL97 results in resistance to ganciclovir only, whereas mutations in the viral polymerase gene UL54 may show cross resistance to other antivirals with a similar mechanism of action. Viral resistance has been observed in patients receiving prolonged treatment for CMV retinitis with ganciclovir. CMV resistance to ganciclovir has also been observed in individuals with both AIDS and CMV retinitis who have never received ganciclovir therapy. [10]
References
[1] AHFS Drug Information 2005; p. 817
[2] AHFS Drug Information 2005; p. 817
[3] USP DI 2005; p. 2886
[4] Roche Laboratories Valcyte Product Information, January 2006, p. 5. Available at: http://www.rocheusa.com/products/valcyte/pi.html. Accessed 03/16/07.
[5] Roche Laboratories Valcyte Product Information, January 2006, pp. 16-7. Available at: http://www.rocheusa.com/products/valcyte/pi.html. Accessed 03/16/07.
[6] AHFS Drug Information 2005; p. 817
[7] Roche Laboratories Valcyte Product Information, January 2006, p. 6. Available at: http://www.rocheusa.com/products/valcyte/pi.html. Accessed 03/16/07.
[8] Roche Laboratories Valcyte Product Information, January 2006, p. 6. Available at: http://www.rocheusa.com/products/valcyte/pi.html. Accessed 03/16/07.
[9] Roche Laboratories Valcyte Product Information, January 2006, pp. 6-7. Available at: http://www.rocheusa.com/products/valcyte/pi.html. Accessed 03/16/07.
[10] Roche Laboratories Valcyte Product Information, January 2006, p. 2. Available at: http://www.rocheusa.com/products/valcyte/pi.html. Accessed 03/16/07.
Adverse Events/Toxicity
In animal studies, ganciclovir caused aspermatogenesis and was found to be carcinogenic, mutagenic, and teratogenic. Valganciclovir should therefore be considered a potential teratogen and carcinogen in humans. Women of childbearing age should use effective contraception during treatment, and men should practice barrier contraception during treatment and for at least 90 days following treatment. [1]
The most frequent and clinically significant adverse effects of valganciclovir are fever; retinal detachment; and hematologic reactions, including anemia, neutropenia, and thrombocytopenia. Other frequently reported but less serious adverse effects include abdominal pain, diarrhea, headache, insomnia, nausea and vomiting, paresthesia, and peripheral neuropathy. [2]
References
[1] Roche Laboratories Valcyte Product Information, January 2006, pp. 10-1. Available at: http://www.rocheusa.com/products/valcyte/pi.html. Accessed 03/16/07.
[2] Roche Laboratories Valcyte Product Information, January 2006, p. 19. Available at: http://www.rocheusa.com/products/valcyte/pi.html. Accessed 03/16/07.
Drug and Food Interactions
Because valganciclovir is rapidly and extensively converted to ganciclovir, drug interactions associated with ganciclovir would be expected for valganciclovir. Concurrent administration of valganciclovir with nephrotoxic medications (or if valganciclovir is administered to individuals with renal impairment) increases the chance of renal function impairment and may cause toxic accumulation of ganciclovir in the body. Patients should be closely monitored for toxicity of ganciclovir and the coadministered drug. [1] Drugs with potential for clinically significant interactions with ganciclovir include didanosine, myelosuppressive agents or irradiation, mycophenolate, probenecid, and zidovudine. [2]
References
[1] Roche Laboratories Valcyte Product Information, January 2006, pp. 13-5. Available at: http://www.rocheusa.com/products/valcyte/pi.html. Accessed 03/16/07.
[2] AHFS Drug Information 2005; pp. 816-7
Contraindications
Valganciclovir is contraindicated in patients with hypersensitivity to valganciclovir or ganciclovir. Valganciclovir should not be administered to patients undergoing hemodialysis because the appropriate daily dose for these patients is lower than 450 mg, which would require breaking a tablet. Broken valganciclovir tablets pose a hazard to skin and mucous membranes. [1]
References
[1] AHFS Drug Information 2004; p. 812
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use Valganciclovir.
Chemistry
CAS Name
L-Valine, 2-((2-amino-1,6- dihydro-6-oxo-9H-purin-9-yl)methoxy)- 3-hydroxypropyl ester, monohydrochloride [1]
CAS Number
175865-60-8 [2]
Molecular Formula
C14-H22-N6-O5.Cl-H
Elemental Composition
C43.02%, H5.93%, N21.51%, O20.47%, Cl9.07%
Molecular Weight
390.83
Physical Description
White to off-white crystalline powder. [3]
Solubility
70 mg/ml in water at 25 C and pH of 7.0. [4]
References
[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 03/16/07
[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 03/16/07.
[3] Roche Laboratories Valcyte Product Information, January 2006, p. 1. Available at: http://www.rocheusa.com/products/valcyte/pi.html. Accessed 03/16/07.
[4] Roche Laboratories Valcyte Product Information, January 2006, p. 1. Available at: http://www.rocheusa.com/products/valcyte/pi.html. Accessed 03/16/07.
Further Reading
Valcyte Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Biron KK. Antiviral drugs for cytomegalovirus diseases. Antiviral Res. 2006 Sep;71(2-3):154-63. Epub2006 May 23. Review.
Burri M, Wiltshire H, Kahlert C, Wouters G, Rudin C. Oral valganciclovir in children: single dose pharmacokinetics in a six-year-old girl. Pediatr Infect Dis J. 2004 Mar;23(3):263-6.
Erice A, Tierney C, Hirsch M, Caliendo AM, Weinberg A, Kendall MA, Polsky B; AIDS Clinical Trials Group Protocol 360 Study Team. Cytomegalovirus (CMV) and human immunodeficiency virus (HIV) burden, CMV end-organ disease, and survival in subjects with advanced HIV infection. Clin Infect Dis. 2003 Aug 15;37(4):567-78. Epub 2003 Jul 29.
Somerville KT. Cost advantages of oral drug therapy for managing cytomegalovirus disease. Am J Health Syst Pharm. 2003 Dec 1;60(23 Suppl 8):S9-12. Review.
Manufacturer Information
Valcyte
Roche Laboratories
340 Kingsland Street
Nutley, NJ 07110
Phone: 973-235-5000
Valganciclovir
Roche Laboratories
340 Kingsland Street
Nutley, NJ 07110
Phone: 973-235-5000
All Content Last Reviewed: March 16, 2007
Last Updated: September 17, 2010