VALGANCICLOVIR Drug Interactions: What You Need to Know

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. Drug-drug interaction studies with ganciclovir were conducted in patients with normal renal function. Following concomitant administration of VALCYTE and other renally excreted drugs, patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug. Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 9 .

Table

9 Established and Other Potentially Significant Drug Interactions with Ganciclovir Name of the Concomitant Drug Change in the Concentration of Ganciclovir or Concomitant Drug Clinical Comment Imipenem-cilastatin Unknown Coadministration with imipenem-cilastatin is not recommended because generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin. Cyclosporine or amphotericin B Unknown Monitor renal function when VALCYTE is coadministered with cyclosporine or amphotericin B because of potential increase in serum creatinine [see Warnings and Precautions (5.2) ]. Mycophenolate mofetil (MMF) ↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function) Based on increased risk, patients should be monitored for hematological and renal toxicity. Other drugs associated with myelosuppression or nephrotoxicity (e.g., adriamycin, dapsone, doxorubicin, flucytosine, hydroxyurea, pentamidine, tacrolimus, trimethoprim/ sulfamethoxazole, vinblastine, vincristine, and zidovudine)

Unknown

Because of potential for higher toxicity, coadministration with VALCYTE should be considered only if the potential benefits are judged to outweigh the risks. Didanosine ↔ Ganciclovir ↑ Didanosine Patients should be closely monitored for didanosine toxicity (e.g., pancreatitis) Probenecid ↑ Ganciclovir VALCYTE dose may need to be reduced. Monitor for evidence of ganciclovir toxicity. Imipenem-cilastatin: Seizures were reported in patients receiving ganciclovir and imipenem-cilastatin. Concomitant use is not recommended unless the potential benefits outweigh the risks. ( 7 ) Cyclosporine or amphotericin B: When coadministered with valganciclovir, the risk of nephrotoxicity may be increased. Monitor renal function. ( 5.2 , 7 ) Mycophenolate mofetil (MMF): When coadministered with valganciclovir, the risk of hematological and renal toxicity may be increased. Monitor for ganciclovir and MMF toxicity. ( 7 ) Other drugs associated with myelosuppression or nephrotoxicity: Due to potential for increased toxicity, consider for concomitant use with valganciclovir only if the potential benefits are judged to outweigh the risks. ( 7 ) Didanosine: Ganciclovir coadministered with didanosine may increase didanosine levels. Monitor for didanosine toxicity (e.g., pancreatitis). ( 7 ) Probenecid: May increase ganciclovir levels. Monitor for evidence of ganciclovir toxicity. ( 7 )

Drug

Interactions: In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, interactions associated with ganciclovir will be expected for VALCYTE [see Drug Interactions (7) ].

Table

15 and Table 16 provide a listing of established drug interaction studies with ganciclovir.

Table

15 provides the effects of coadministered drug on ganciclovir plasma pharmacokinetic parameters, whereas Table 16 provides the effects of ganciclovir on plasma pharmacokinetic parameters of coadministered drug.

Table

15 Results of Drug Interaction Studies with Ganciclovir: Effects of Coadministered Drug on Ganciclovir Pharmacokinetic Parameters Coadministered Drug Ganciclovir Dosage N Ganciclovir Pharmacokinetic (PK)

Parameter

Mycophenolate mofetil (MMF) 1.5 g single dose 5 mg/kg IV single dose 12 No effect on ganciclovir PK parameters observed (patients with normal renal function)

Trimethoprim

200 mg once daily 1000 mg every 8 hours 12 No effect on ganciclovir PK parameters observed Didanosine 200 mg every 12 hours simultaneously administered with ganciclovir 5 mg/kg IV twice daily 11 No effect on ganciclovir PK parameters observed 5 mg/kg IV once daily 11 No effect on ganciclovir PK parameters observed Probenecid 500 mg every 6 hours 1000 mg every 8 hours 10 AUC ↑ 53 ± 91% (range: -14% to 299%) Ganciclovir renal clearance ↓ 22 ± 20% (range: -54% to -4%)

Table

16 Results of Drug Interaction Studies with Ganciclovir: Effects of Ganciclovir on Pharmacokinetic Parameters of Coadministered Drug Coadministered Drug Ganciclovir Dosage N Coadministered Drug Pharmacokinetic (PK)

Parameter

Oral cyclosporine at therapeutic doses 5 mg/kg infused over 1 hour every 12 hours 93 In a retrospective analysis of liver allograft recipients, there was no evidence of an effect on cyclosporine whole blood concentrations. Mycophenolate mofetil (MMF) 1.5 g single dose 5 mg/kg IV single dose 12 No PK interaction observed (patients with normal renal function)

Trimethoprim

200 mg once daily 1000 mg every 8 hours 12 No effect on trimethoprim PK parameters observed Didanosine 200 mg every 12 hours 5 mg/kg IV twice daily 11 AUC 0-12 ↑70 ± 40% (range: 3% to 121%) C max ↑49 ± 48% (range: -28% to 125%)

Didanosine

200 mg every 12 hours 5 mg/kg IV once daily 11 AUC 0-12 ↑50 ± 26% (range: 22% to 110%) C max ↑36 ± 36% (range: -27% to 94%)

Valganciclovir for oral solution 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 )]. Hypersensitivity to valganciclovir or ganciclovir. ( 4 )

AND PRECAUTIONS

• Hematologic toxicity: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression, and aplastic anemia have occurred with the use of valganciclovir tablets or ganciclovir. Avoid valganciclovir tablets use if absolute neutrophil count is less than 500 cells/µL, platelet count is less than 25,000/µL, or hemoglobin is less than 8 g/dL. Use with caution in pre-existing cytopenias and when receiving myelosuppressive drugs or irradiation. Monitor with frequent testing of platelet and complete blood counts ( 5.1 ).
• Impairment of fertility: Based on animal studies, valganciclovir tablets may cause temporary or permanent inhibition of spermatogenesis ( 5.2 ).
• Fetal toxicity: Based on animal studies, valganciclovir tablets may cause fetal harm. Females of reproductive potential should use effective contraception during and following treatment and males should practice barrier contraception during and following treatment (5.3 ).
• Mutagenicity and carcinogenicity: Based on animal studies, valganciclovir tablets are potentially mutagenic and carcinogenic ( 5.4 ).
• Acute renal failure: Acute renal failure may occur in elderly patients (with or without reduced renal function), patients who receive concomitant nephrotoxic drugs, or inadequately hydrated patients. Use with caution in elderly patients or those taking nephrotoxic drugs, reduce dosage in patients with renal impairment, and monitor renal function ( 2.5 , 5.5 , 8.5 , 8.6 , 12.3 ). 5.1Hematologic Toxicity Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia, and aplastic anemia have been reported in patients treated with valganciclovir tablets or ganciclovir. Valganciclovir tablets should be avoided 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. Valganciclovir tablets 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 valganciclovir tablets [see Adverse Reactions ( 6.1 )], 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 valganciclovir tablets, because of increased plasma concentrations of ganciclovir after valganciclovir tablets administration [see Clinical Pharmacology ( 12.3 )].

5.2 Impairment of Fertility Based on animal data with ganciclovir, valganciclovir tablets at the recommended human doses may cause temporary or permanent inhibition of spermatogenesis in males, and may cause suppression of fertility in females. Advise patients that fertility may be impaired with use of valganciclovir tablets <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1, 8.3 ), Nonclinical Toxicology ( 13.1 )]</span>.

5.3 Fetal Toxicity Ganciclovir may cause fetal toxicity when administered to pregnant women based on findings in animal studies. When given to pregnant rabbits at dosages resulting in 2-times the human exposure (based on AUC), ganciclovir caused malformations in multiple organs of the fetuses. Maternal and fetal toxicity were also observed in pregnant mice and rabbits. Therefore, valganciclovir has the potential to cause birth defects. Pregnancy should be avoided in female patients taking valganciclovir tablets and in females with male partners taking valganciclovir tablets. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with valganciclovir tablets. Similarly, males should be advised to practice barrier contraception during and for at least 90 days following treatment with valganciclovir tablets <span class="opacity-50 text-xs">[see Dosage and Administration (2.6), Use in Specific Populations ( 8.1, 8.3 ), Nonclinical Toxicology ( 13.1 )]</span>.

5.4 Mutagenesis and Carcinogenesis Animal data indicate that ganciclovir is mutagenic and carcinogenic. Valganciclovir tablets should therefore be considered a potential carcinogen in humans <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 ), Nonclinical Toxicology ( 13.1 )]</span>.

5.5 Acute Renal Failure Acute renal failure may occur in:

• Elderly patients with or without reduced renal function. Caution should be exercised when administering valganciclovir tablets 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 valganciclovir tablets to patients receiving potential nephrotoxic drugs.
• Patients without adequate hydration. Adequate hydration should be maintained for all patients.