Valcyte (Valganciclovir Hydrochloride) - Drug Interactions, Contraindications, Overdosage

DRUG INTERACTIONS

Drug Interaction Studies Conducted With Valcyte

No in vivo drug-drug interaction studies were conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, interactions associated with ganciclovir will be expected for Valcyte tablets.

Drug Interaction Studies Conducted With Ganciclovir

Binding of ganciclovir to plasma proteins is only about 1% to 2%, and drug interactions involving binding site displacement are not anticipated.

Drug-drug interaction studies were conducted in patients with normal renal function. Patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug following concomitant administration of Valcyte tablets and drugs excreted by the same pathway as ganciclovir. Therefore, these patients should be closely monitored for toxicity of ganciclovir and the coadministered drug.

Table 6 Results of Drug Interaction Studies With Ganciclovir: Effects of Coadministered Drug on Ganciclovir Plasma AUC and C_max Values

Coadministered Drug	Ganciclovir Dosage	n	Ganciclovir Pharmacokinetic (PK) Parameter	Clinical Comment
Zidovudine 100 mg every 4 hours	1000 mg every 8 hours	12	AUC ↓ 17 ± 25% (range: -52% to 23%)	Zidovudine and Valcyte each have the potential to cause neutropenia and anemia. Some patients may not tolerate concomitant therapy at full dosage.
Didanosine 200 mg every 12 hours administered 2 hours before ganciclovir	1000 mg every 8 hours	12	AUC ↓ 21 ± 17% (range: -44% to 5%)	Effect not likely to be clinically significant.
Didanosine 200 mg every 12 hours simultaneously administered with ganciclovir	1000 mg every 8 hours	12	No effect on ganciclovir PK parameters observed	No effect expected.
	IV ganciclovir 5 mg/kg twice daily	11	No effect on ganciclovir PK parameters observed	No effect expected.
	IV ganciclovir 5 mg/kg once daily	11	No effect on ganciclovir PK parameters observed	No effect expected.
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%)	Patients taking probenecid and Valcyte should be monitored for evidence of ganciclovir toxicity.
Zalcitabine 0.75 mg every 8 hours administered 2 hours before ganciclovir	1000 mg every 8 hours	10	AUC ↑13%	Effect not likely to be clinically significant.
Trimethoprim 200 mg once daily	1000 mg every 8 hours	12	Ganciclovir renal clearance ↓ 16.3% Half-life ↑15%	Effect not likely to be clinically significant.
Mycophenolate Mofetil 1.5 g single dose	IV ganciclovir 5 mg/kg single dose	12	No effect on ganciclovir PK parameters observed (patients with normal renal function)	Patients with renal impairment should be monitored carefully as levels of metabolites of both drugs may increase.

Table 7 Results of Drug Interaction Studies With Ganciclovir: Effects of Ganciclovir on Plasma AUC and C_max Values of Coadministered Drug

Coadministered Drug	Ganciclovir Dosage	N	Coadministered Drug Pharmacokinetic (PK) Parameter	Clinical Comment
Zidovudine 100 mg every 4 hours	1000 mg every 8 hours	12	AUC0-4↑ 19 ± 27% (range: -11% to 74%)	Zidovudine and Valcyte each have the potential to cause neutropenia and anemia. Some patients may not tolerate concomitant therapy at full dosage.
Didanosine 200 mg every 12 hours when administered 2 hours prior to or concurrent with ganciclovir	1000 mg every 8 hours	12	AUC0-12↑111 ± 114% (range: 10% to 493%)	Patients should be closely monitored for didanosine toxicity.
Didanosine 200 mg every 12 hours	IV ganciclovir 5 mg/kg twice daily	11	AUC0-12↑70 ± 40% (range: 3% to 121%) Cmax↑49 ± 48% (range: -28% to 125%)	Patients should be closely monitored for didanosine toxicity.
Didanosine 200 mg every 12 hours	IV ganciclovir 5 mg/kg once daily	11	AUC0-12↑50 ± 26% (range: 22% to 110%) Cmax↑36 ± 36% (range: -27% to 94%)	Patients should be closely monitored for didanosine toxicity.
Zalcitabine 0.75 mg every 8 hours administered 2 hours before ganciclovir	1000 mg every 8 hours	10	No clinically relevant PK parameter changes	No effect expected.
Trimethoprim 200 mg once daily	1000 mg every 8 hours	12	Increase (12%) in Cmin	Effect not likely to be clinically significant.
Mycophenolate Mofetil (MMF) 1.5 g single dose	IV ganciclovir 5 mg/kg single dose	12	No PK interaction observed (patients with normal renal function)	Patients with renal impairment should be monitored carefully as levels of metabolites of both drugs may increase.

OVERDOSAGE

Overdose 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.

It is expected that an overdose of Valcyte tablets could also possibly result in increased renal toxicity (see PRECAUTIONS: General and DOSAGE AND ADMINISTRATION: Renal Impairment).

Since ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations in patients who have received an overdose of Valcyte tablets (see CLINICAL PHARMACOLOGY: Special Populations: Hemodialysis). Adequate hydration should be maintained. The use of hematopoietic growth factors should be considered (see CLINICAL PHARMACOLOGY: Special Populations: Hemodialysis).

Overdose 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

CONTRAINDICATIONS

Valcyte tablets are contraindicated in patients with hypersensitivity to valganciclovir or ganciclovir.