valganciclovir hydrochloride
Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION
- Clinical toxicity of Valcyte, which is metabolized to ganciclovir, includes granulocytopenia, anemia, and thrombocytopenia [see Warnings and Precautions (5.1)].
- In animal studies, ganciclovir was carcinogenic, teratogenic, and caused aspermatogenesis [see Warnings and Precautions (5.2, 5.3, 5.4)].
Indications and Usage for Valcyte
Adult Patients
Treatment of Cytomegalovirus (CMV) Retinitis: Valcyte tablets are indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) [see Clinical Studies (14.1)].
Prevention of CMV Disease: Valcyte tablets are indicated for the prevention of CMV disease in kidney, heart, or kidney-pancreas transplant patients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]) [see Clinical Studies (14.1)].
Pediatric Patients
Prevention of CMV Disease: Valcyte for oral solution and tablets are indicated for the prevention of CMV disease in kidney or heart transplant patients (4 months to 16 years of age) at high risk [see Clinical Studies (14.2)].
Limitations of Use
Valcyte is not indicated for use in either adult or pediatric liver transplant patients [see Clinical Studies (14.1, 14.2)].
The safety and efficacy of Valcyte have not been established for:
- Prevention of CMV disease in solid organ transplants other than those indicated [see Clinical Studies (14.1, 14.2)].
- Prevention of CMV disease in pediatric solid organ transplant patients < 4 months of age [see Clinical Studies (14.2)].
- Treatment of congenital CMV disease [see Use in Specific Populations (8.4)]
Valcyte Dosage and Administration
General Dosing Information
- Valcyte for oral solution and tablets should be taken with food [see Clinical Pharmacology (12.3)].
- Valcyte for oral solution (50 mg/mL) must be prepared by the pharmacist prior to dispensing to the patient [see Dosage and Administration (2.4)].
- The bioavailability of ganciclovir from Valcyte is significantly higher than from ganciclovir capsules. Therefore, Valcyte tablets cannot be substituted for ganciclovir capsules on a one-to-one basis [see Clinical Pharmacology (12.3)].
- Adult patients should use Valcyte tablets, not Valcyte for oral solution.
Adult Patients With Normal Renal Function
For dosage recommendations in adult patients with renal impairment see Dosage and Administration (2.5).
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.
Pediatric Patients
Prevention of CMV Disease: For pediatric patients 4 months to 16 years of age who have received a kidney or heart transplant, the recommended once daily dose of Valcyte 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 × BSA × CrCl (calculated using a modified Schwartz formula). If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73m2, then a maximum value of 150 mL/min/1.73m2 should be used in the equation.
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.
All calculated doses should be rounded to the nearest 25 mg increment for the actual deliverable dose. If the calculated dose exceeds 900 mg, a maximum dose of 900 mg should be administered. Valcyte for oral solution is the preferred formulation since it provides the ability to administer a dose calculated according to the formula above; however, Valcyte tablets may be used if the calculated doses are within 10% of available tablet strength (450 mg). For example, if the calculated dose is between 405 mg and 495 mg, one 450 mg tablet may be taken.
Preparation of Valcyte for Oral Solution
Prior to dispensing to the patient, Valcyte for oral solution must be prepared by the pharmacist as follows [see How Supplied/Storage and Handling (16)]:
- Measure 91 mL of purified water in a graduated cylinder.
- Shake the Valcyte bottle to loosen the powder. Remove the child resistant bottle cap and add approximately half the total amount of water for constitution to the bottle and shake the closed bottle well for about 1 minute. Add the remainder of water and shake the closed bottle well for about 1 minute. This prepared solution contains 50 mg of valganciclovir free base per 1 mL.
- Remove the child resistant bottle cap and push the bottle adapter into the neck of the bottle.
- Close bottle with child resistant bottle cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child resistant status of the cap.
- Store constituted oral solution under refrigeration at 2°C to 8°C (36°F to 46°F) for no longer than 49 days. Do not freeze.
- Write the date of expiration of the constituted oral solution on the bottle label.
The patient package insert, which includes the dosing instructions for patients, and 2 oral dispensers should be dispensed to the patient [see Patient Counseling Information (17)].
Renal Impairment
Dosage recommendations for adult patients with reduced renal function are provided in Table 1. For adult patients on hemodialysis (CrCl <10 mL/min), a dose recommendation for Valcyte cannot be given [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)].
| Valcyte 450 mg Tablets | ||
|---|---|---|
| CrCl* (mL/min) | Induction Dose | Maintenance/ Prevention Dose |
| ||
| ≥ 60 | 900 mg twice daily | 900 mg once daily |
| 40 – 59 | 450 mg twice daily | 450 mg once daily |
| 25 – 39 | 450 mg once daily | 450 mg every 2 days |
| 10 – 24 | 450 mg every 2 days | 450 mg twice weekly |
| < 10 (on hemodialysis) | not recommended | not recommended |
Dosing in pediatric patients with renal impairment can be done using the recommended equations because CrCl is a component in the calculation [see Dosage and Administration (2.3)].
Handling and Disposal
Caution should be exercised in the handling of Valcyte tablets and Valcyte for oral solution. Tablets should not be broken or crushed. Because valganciclovir is considered a potential teratogen and carcinogen in humans, caution should be observed in handling broken tablets, the powder for oral solution, and the constituted oral solution [see Warnings and Precautions (5.3, 5.4)]. Avoid direct contact with broken or crushed tablets, the powder for oral solution, and the constituted oral solution with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with plain water.
Because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity), consideration should be given to handling and disposal according to guidelines issued for antineoplastic drugs. Several guidelines on this subject have been published. However, there is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate [see References (15)].
Dosage Forms and Strengths
Valcyte Tablets:
- 450 mg, pink, convex oval tablets with "VGC" on one side and "450" on the other side.
Valcyte for Oral Solution:
- 50 mg/mL, supplied as a white to slightly yellow powder for constitution, forming a colorless to brownish yellow tutti-frutti flavored solution. Available in glass bottles containing approximately 100 mL of solution after constitution. Valcyte for oral solution must be constituted by the pharmacist prior to dispensing to the patient [see Dosage and Administration (2.4)].
Contraindications
Valcyte is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valganciclovir, ganciclovir, or any component of the formulation [see Adverse Reactions (6.1)].
Warnings and Precautions
Hematologic Effects
Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia, and aplastic anemia have been reported in patients treated with Valcyte or ganciclovir. Valcyte should not be administered if the absolute neutrophil count is less than 500 cells/µL, the platelet count is less than 25,000/µL, or the hemoglobin is less than 8 g/dL. Valcyte should also be used with caution in patients with pre-existing cytopenias, or who have received or who are receiving myelosuppressive drugs or irradiation. Cytopenia may occur at any time during treatment and may worsen with continued dosing. Cell counts usually begin to recover within 3 to 7 days after discontinuing drug.
Due to the frequency of neutropenia, anemia, and thrombocytopenia in patients receiving Valcyte [see Adverse Reactions (6.1, 6.2)], complete blood counts with differential and platelet counts should be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in whom neutrophil counts are less than 1000 cells/µL at the beginning of treatment. Increased monitoring for cytopenias may be warranted if therapy with oral ganciclovir is changed to Valcyte, because of increased plasma concentrations of ganciclovir after Valcyte administration [see Clinical Pharmacology (12.3)].
Impairment of Fertility
Animal data indicate administration of ganciclovir causes inhibition of spermatogenesis and subsequent infertility. These effects were reversible at lower doses but irreversible at higher doses [see Nonclinical Toxicology (13.1)]. In men, Valcyte at the recommended doses may cause temporary or permanent inhibition of spermatogenesis. Animal data also indicate suppression of fertility in females may occur.
Teratogenesis and Mutagenesis
Animal data indicate ganciclovir is teratogenic and mutagenic. Therefore, Valcyte should be considered to have the potential to cause birth defects and cancers in humans. Women of childbearing potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with Valcyte. Similarly, men should be advised to practice barrier contraception during and for at least 90 days following treatment with Valcyte [see Dosage and Administration (2.6), Use in Specific Populations (8.1), Nonclinical Toxicology (13.1, 13.3)].
Carcinogenesis
Animal data indicate that administration of ganciclovir is carcinogenic. Valcyte should therefore be considered a potential carcinogen in humans [see Dosage and Administration (2.6), Nonclinical Toxicology (13.1)].
Acute Renal Failure
Acute renal failure may occur in:
- Elderly patients with or without reduced renal function. Caution should be exercised when administering Valcyte to geriatric patients, and dosage reduction is recommended for those with impaired renal function [see Dosage and Administration (2.5), Use in Specific Populations (8.5, 8.6)].
- Patients receiving potential nephrotoxic drugs. Caution should be exercised when administering Valcyte to patients receiving potential nephrotoxic drugs.
- Patients without adequate hydration. Adequate hydration should be maintained for all patients.
Adverse Reactions
The following serious adverse events are discussed in greater detail in other sections of the labeling:
- Hematologic adverse events [see Boxed Warning, Warnings and Precautions (5.1)].
- Acute renal failure [see Warnings and Precautions (5.5)].
The most common adverse events and laboratory abnormalities reported in at least one indication by ≥ 20% of adult patients treated with Valcyte tablets are diarrhea, pyrexia, nausea, tremor, neutropenia, anemia, graft rejection, thrombocytopenia, and vomiting. The most common reported adverse events and laboratory abnormalities reported in > 10% of pediatric solid organ transplant recipients treated with Valcyte for oral solution or tablets are diarrhea, pyrexia, hypertension, upper respiratory tract infection, vomiting, anemia, neutropenia, constipation, nausea, and cough.
Clinical Trial Experience in Adult Patients
Valganciclovir, a prodrug of ganciclovir, is rapidly converted to ganciclovir after oral administration. Adverse events known to be associated with ganciclovir usage can therefore be expected to occur with Valcyte.
Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.
Treatment of CMV Retinitis in AIDS Patients: In a clinical study for the treatment of CMV retinitis in HIV-infected patients, the adverse events reported by patients receiving Valcyte tablets (n=79) or intravenous ganciclovir (n=79) for 28 days of randomized therapy (21 days induction dose and 7 days maintenance dose), respectively, included diarrhea (16%, 10%), nausea (8%, 14%), headache (9%, 5%), and catheter-related infections (3%, 11%). The incidence of adverse events was similar between the group who received Valcyte tablets and the group who received intravenous ganciclovir, with the exception of catheter-related infections, which occurred with greater frequency in patients randomized to receive intravenous ganciclovir. The frequencies of neutropenia (ANC < 500/µL) were 11% for patients receiving Valcyte tablets compared with 13% for patients receiving intravenous ganciclovir. Anemia (Hgb < 8 g/dL) occurred in 8% of patients in each group. Other laboratory abnormalities occurred with similar frequencies in the two groups.
Adverse events and abnormal laboratory values data are available for 370 patients who received maintenance therapy with Valcyte tablets 900 mg once daily in two open-label clinical trials. Approximately 252 (68%) of these patients received Valcyte tablets for more than nine months (maximum duration was 36 months). Table 2 and Table 3 show the pooled adverse event data and abnormal laboratory values from these patients.
| Patients with CMV Retinitis | |
|---|---|
| Adverse Events According to Body System | Valcyte Tablets (N=370) % |
| Gastrointestinal system | |
| Diarrhea | 41 |
| Nausea | 30 |
| Vomiting | 21 |
| Abdominal pain | 15 |
| Body as a whole | |
| Pyrexia | 31 |
| Headache | 22 |
| Central and peripheral nervous system | |
| Insomnia | 16 |
| Peripheral neuropathy | 9 |
| Paresthesia | 8 |
| Special senses | |
| Retinal detachment | 15 |
| Patients with CMV Retinitis | |
|---|---|
| Laboratory Abnormalities | Valcyte Tablets (N=370) % |
| Neutropenia: ANC/µL | |
| < 500 | 19 |
| 500 – < 750 | 17 |
| 750 – < 1000 | 17 |
| Anemia: Hemoglobin g/dL | |
| < 6.5 | 7 |
| 6.5 – < 8.0 | 13 |
| 8.0 – < 9.5 | 16 |
| Thrombocytopenia: Platelets/µL | |
| < 25000 | 4 |
| 25000 – < 50000 | 6 |
| 50000 – < 100000 | 22 |
| Serum Creatinine: mg/dL | |
| > 2.5 | 3 |
| > 1.5 – 2.5 | 12 |
Prevention of CMV Disease in Selected Solid Organ Transplantation: Table 4 shows selected adverse events regardless of severity and drug relationship with an incidence of ≥ 5% from a clinical trial (up to 28 days after study treatment) where heart, kidney, kidney-pancreas and liver transplant patients received Valcyte tablets (N=244) or oral ganciclovir (N=126) until Day 100 post-transplant. The majority of the adverse events were of mild or moderate intensity.
| Adverse Event | Valcyte Tablets (N=244) % | Oral Ganciclovir (N=126) % |
|---|---|---|
| Diarrhea | 30 | 29 |
| Tremors | 28 | 25 |
| Graft rejection | 24 | 30 |
| Nausea | 23 | 23 |
| Headache | 22 | 27 |
| Insomnia | 20 | 16 |
| Hypertension | 18 | 15 |
| Vomiting | 16 | 14 |
| Pyrexia | 13 | 14 |
The overall safety profile of Valcyte did not change with the extension of prophylaxis until Day 200 post-transplant in high risk kidney transplant patients (see Table 5).
| Adverse Event | Valcyte Tablets Day 100 Post-transplant (N=164) % | Valcyte Tablets Day 200 Post-transplant (N=156) % |
|---|---|---|
| Diarrhea | 26 | 31 |
| Tremors | 12 | 17 |
| Hypertension | 13 | 12 |
| Nausea | 11 | 11 |
| Pyrexia | 12 | 9 |
| Transplant rejection | 9 | 6 |
| Headache | 10 | 6 |
| Insomnia | 7 | 6 |
| Vomiting | 3 | 6 |
Adverse events not included in Table 4 and Table 5, which either occurred at a frequency of ≥ 5% in clinical studies with solid organ transplant patients, or were selected serious adverse events reported in studies with patients with CMV retinitis or in studies with solid organ transplant patients with a frequency of < 5% are listed below.
Allergic reactions: valganciclovir hypersensitivity
Bleeding complications: potentially life-threatening bleeding associated with thrombocytopenia
Central and peripheral nervous system: paresthesia, dizziness (excluding vertigo), convulsion
Gastrointestinal disorders: abdominal pain, constipation, dyspepsia, abdominal distention, ascites
General disorders and administration site disorders: fatigue, pain, edema, peripheral edema, weakness
Hemic system: anemia, neutropenia, thrombocytopenia, pancytopenia, bone marrow depression, aplastic anemia
Hepatobiliary disorders: abnormal hepatic function
Infections and infestations: pharyngitis/nasopharyngitis, upper respiratory tract infection, urinary tract infection, local and systemic infections and sepsis, postoperative wound infection
Injury, poisoning, and procedural complications: postoperative complications, postoperative pain, increased wound drainage, wound dehiscence
Metabolism and nutrition disorders: hyperkalemia, hypokalemia, hypomagnesemia, hyperglycemia, appetite decreased, dehydration, hypophosphatemia, hypocalcemia
Musculoskeletal and connective tissue disorders: back pain, arthralgia, muscle cramps, limb pain
Psychiatric disorders: depression, psychosis, hallucinations, confusion, agitation
Renal and urinary disorders: renal impairment, dysuria, decreased creatinine clearance
Respiratory, thoracic and mediastinal disorders: cough, dyspnea, rhinorrhea, pleural effusion
Skin and subcutaneous tissue disorders: dermatitis, pruritus, acne
Vascular disorders: hypotension
Laboratory abnormalities reported with Valcyte tablets in two studies in solid organ transplant patients are listed in Table 6 and Table 7.
| Laboratory Abnormalities | Valcyte Tablets (N=244) % | Ganciclovir Capsules (N=126) % |
|---|---|---|
| ||
| Neutropenia: ANC/µL | ||
| < 500 | 5 | 3 |
| 500 – < 750 | 3 | 2 |
| 750 – < 1000 | 5 | 2 |
| Anemia: Hemoglobin g/dL | ||
| < 6.5 | 1 | 2 |
| 6.5 – < 8.0 | 5 | 7 |
| 8.0 – < 9.5 | 31 | 25 |
| Thrombocytopenia: Platelets/µL | ||
| < 25000 | 0 | 2 |
| 25000 – < 50000 | 1 | 3 |
| 50000 – < 100000 | 18 | 21 |
| Serum Creatinine: mg/dL | ||
| > 2.5 | 14 | 21 |
| > 1.5 – 2.5 | 45 | 47 |
| Laboratory Abnormalities | Valcyte Tablets Day 100 Post-transplant (N=164) % | Valcyte Tablets Day 200 Post-transplant (N=156) % |
|---|---|---|
| ||
| Neutropenia: ANC/µL | ||
| < 500 | 9 | 10 |
| 500 – < 750 | 6 | 6 |
| 750 – < 1000 | 7 | 5 |
| Anemia: Hemoglobin g/dL | ||
| < 6.5 | 0 | 1 |
| 6.5 – < 8.0 | 5 | 1 |
| 8.0 – < 9.5 | 17 | 15 |
| Thrombocytopenia: Platelets/µL | ||
| < 25000 | 0 | 0 |
| 25000 – < 50000 | 1 | 0 |
| 50000 – < 100000 | 7 | 3 |
| Serum Creatinine: mg/dL | ||
| > 2.5 | 17 | 14 |
| > 1.5 – 2.5 | 50 | 48 |
Clinical Trial Experience in Pediatric Patients
Valcyte for oral solution and tablets have been studied in 109 pediatric solid organ transplant patients who were at risk for developing CMV disease (aged 4 months to 16 years) and in 24 neonates with symptomatic congenital CMV disease (aged 8 to 34 days), with duration of ganciclovir exposure ranging from 2 to 100 days. The overall safety profile was similar in pediatric patients as compared to adult patients. However, the rates of certain adverse events and laboratory abnormalities, such as upper respiratory tract infection, pyrexia, nasopharyngitis, anemia, and neutropenia, were reported more frequently in pediatric patients than in adults [see Use in Specific Populations (8.4), Clinical Studies (14.2)].
Postmarketing Experience
In general, the adverse events reported during the postmarketing use of Valcyte were similar to those identified during the clinical trials and to those reported during the postmarketing use of ganciclovir. Please also refer to the intravenous ganciclovir product information and ganciclovir capsule product information for more information on postmarketing adverse events associated with ganciclovir.
Drug Interactions
In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, drug-drug interactions associated with ganciclovir will be expected for Valcyte. Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 8.
| Name of the Concomitant Drug | Change in the Concentration of Ganciclovir or Concomitant Drug | Clinical Comment |
|---|---|---|
| Zidovudine | ↓ Ganciclovir ↑ Zidovudine | Zidovudine and Valcyte each have the potential to cause neutropenia and anemia |
| Probenecid | ↑ Ganciclovir | Patients taking probenecid and Valcyte should be monitored for evidence of ganciclovir toxicity |
| Mycophenolate Mofetil (MMF) | ↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function) | Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase |
| Didanosine | ↓ Ganciclovir | Patients should be closely monitored for didanosine toxicity |
| ↑ Didanosine |
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C After oral administration, valganciclovir (prodrug) is converted to ganciclovir (active drug) and, therefore, is expected to have reproductive toxicity effects similar to ganciclovir. There are no adequate and well-controlled studies of valganciclovir or ganciclovir use in pregnant women. In animal studies of ganciclovir, embryo-fetal toxicity and structural malformations occurred. Valganciclovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In animal studies, pregnant mice and rabbits received ganciclovir at doses that produced 2x the human exposure (based on AUC comparison). Treated rabbits had increased rates of fetal resorption, fetal growth retardation, embryolethality, maternal toxicity, cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and pancreas), hydrocephaly and brachygnathia. In mice, increased fetal resorptions and embryolethality occurred in the presence of maternal/fetal toxicity.
Daily intravenous doses of approximately 1.7x the human exposure (based on AUC) administered to female mice prior to mating, during gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in month-old male offspring, as well as pathologic changes in the nonglandular region of the stomach.
Data from an ex-vivo human placental model showed that ganciclovir crosses the human placenta. The transfer occurred by passive diffusion and was not saturable over a concentration range of 1 to 10 mg/mL [see Nonclinical Toxicology (13.3)].
Nursing Mothers
It is not known whether valganciclovir (prodrug) or ganciclovir (active drug) are excreted in human milk. Because valganciclovir caused granulocytopenia, anemia and thrombocytopenia in clinical trials and ganciclovir was mutagenic and carcinogenic in animal studies, serious adverse events may occur from ganciclovir exposure in nursing infants [see Boxed Warning, Warnings and Precautions (5.1, 5.3, 5.4)]. Because of the potential for serious adverse events in nursing infants, a decision should be made whether to discontinue nursing or discontinue drug, taking into consideration the importance of the drug to the mother. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.
Pediatric Use
Valcyte for oral solution and tablets are indicated for the prevention of CMV disease in kidney or heart transplant pediatric patients 4 months to 16 years of age at risk for developing CMV disease [see Indications and Usage (1.2), Dosage and Administration (2.3)].
The use of Valcyte for oral solution and tablets for the prevention of CMV disease in pediatric patients 4 months to 16 years of age with kidney or heart transplant is based on pharmacokinetic, safety, and efficacy data from an open-label trial with oral Valcyte (Valcyte for oral solution or tablets) in pediatric solid organ transplant recipients at risk for developing CMV disease. The results of this study were supported by previous demonstration of efficacy in adult patients [see Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.2)].
The safety and efficacy of Valcyte for oral solution and tablets have not been established in children for:
- Prevention of CMV disease in liver transplant patients
- Prevention of CMV disease in solid organ transplants other than those indicated
- Prevention of CMV disease in pediatric solid organ transplant patients < 4 months of age
- Treatment of congenital CMV disease
The pharmacokinetic profile and safety of Valcyte for oral solution in children were studied in two open-label studies.
Study 1 was an open-label trial with oral Valcyte (Valcyte for oral solution or tablets) in pediatric solid organ transplant recipients at risk for developing CMV disease [see Clinical Pharmacology (12.3), Clinical Studies (14.2)].
Study 2 was a pharmacokinetic and pharmacodynamic evaluation of Valcyte for oral solution in neonates with congenital CMV infection involving the central nervous system. Twenty-four neonates were enrolled in this study. All patients were treated for 6 weeks with a combination of intravenous ganciclovir 6 mg/kg twice daily and Valcyte for oral solution at doses ranging from 14 mg/kg to 20 mg/kg twice daily. The pharmacokinetic results showed that in infants > 7 days to 3 months of age, a dose of 16 mg/kg twice daily of Valcyte for oral solution provided ganciclovir systemic exposures (median AUC0-12h = 23.6 [range 16.8 – 35.5] µg∙h/mL; n = 6) comparable to those obtained in infants up to 3 months from a 6 mg/kg dose of intravenous ganciclovir twice daily (AUC0-12h = 25.3 [range 2.4 – 89.7] µg∙h/mL; n = 18) or to the ganciclovir systemic exposures obtained in adults from a 900 mg dose of Valcyte tablets twice daily.
The safety and efficacy of intravenous ganciclovir have not been established for the treatment of congenital CMV infection in infants and no similar disease occurs in adults; therefore, efficacy cannot be extrapolated from intravenous ganciclovir use in adults.
Geriatric Use
Studies of Valcyte for oral solution or tablets have not been conducted in adults older than 65 years of age. Clinical studies of Valcyte did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Valcyte is known to be substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration (2.5), Warnings and Precautions (5.5), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
Renal Impairment
Dose reduction is recommended when administering Valcyte to patients with renal impairment [see Dosage and Administration (2.5), Warnings and Precautions (5.5), Clinical Pharmacology (12.3)].
For adult patients on hemodialysis (CrCl <10 mL/min) Valcyte tablets should not be used. Adult hemodialysis patients should use ganciclovir in accordance with the dose-reduction algorithm cited in the Cytovene®-IV and ganciclovir capsules complete product information section on DOSAGE AND ADMINISTRATION: Renal Impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].
Hepatic Impairment
The safety and efficacy of Valcyte have not been studied in patients with hepatic impairment.
Overdosage
Experience With Valcyte Tablets: One adult developed fatal bone marrow depression (medullary aplasia) after several days of dosing that was at least 10-fold greater than recommended for the patient's estimated degree of renal impairment.
An overdose of Valcyte could also possibly result in increased renal toxicity [see Dosage and Administration (2.5), Use in Specific Populations (8.6)].
Because ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of Valcyte [see Clinical Pharmacology (12.3)]. Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered [see Clinical Pharmacology (12.3)].
Experience With Intravenous Ganciclovir: Reports of overdoses with intravenous ganciclovir have been received from clinical trials and during postmarketing experience. The majority of patients experienced one or more of the following adverse events:
Hematological toxicity: pancytopenia, bone marrow depression, medullary aplasia, leukopenia, neutropenia, granulocytopenia
Hepatotoxicity: hepatitis, liver function disorder
Renal toxicity: worsening of hematuria in a patient with pre-existing renal impairment, acute renal failure, elevated creatinine
Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting
Neurotoxicity: generalized tremor, convulsion
Valcyte Description
Valcyte contains valganciclovir hydrochloride (valganciclovir HCl), a hydrochloride salt of the L-valyl ester of ganciclovir that exists as a mixture of two diastereomers. Ganciclovir is a synthetic guanine derivative active against CMV.
Valcyte is available as a 450
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