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Valcyte Side Effects, and Drug Interactions - valganciclovir

Valcyte Side Effects, and Drug Interactions - valganciclovir

SIDE EFFECTS

Experience With Valcyte Tablets

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 tablets.

As shown in Table 6, the safety profiles of Valcyte tablets and intravenous ganciclovir during 28 days of randomized therapy (21 days induction dose and 7 days maintenance dose) in 158 patients were comparable, with the exception of catheter-related infection, which occurred with greater frequency in patients randomized to receive IV ganciclovir (see Table 6).

 

Table 6. Percentage of Selected Adverse Events Occurring During the
Randomized Phase of Study WV15376

Adverse Event	Valganciclovir Arm N=79	Intravenous Ganciclovir Arm N=79
Diarrhea	16%	10%
Neutropenia	11%	13%
Nausea	8%	14%
Headache	9%	5%
Anemia	8%	8%
Catheter-related infection	3%	11%

Tables 7 and 8 show the pooled adverse event data and abnormal laboratory values from two single arm, open-label clinical trials, WV15376 (after the initial four weeks of randomized therapy) and WV15705. A total of 370 patients received maintenance therapy with valganciclovir tablets 900 mg q day. Approximately 252 (68%) of these patients received Valcyte tablets for more than nine months (maximum duration was 36 months).

 

Table 7. Pooled Selected Adverse Events Reported in · 5% of Patients
in Two Clinical Studies

Adverse Events According to Body System	% Patients N=370
Gastrointestinal system
Diarrhea	41%
Nausea	30%
Vomiting	21%
Abdominal pain	15%
Body as a whole
Pyrexia	31%
Headache	22%
Hemic and lymphatic system
Neutropenia	27%
Anemia	26%
Thrombocytopenia	6%
Central and peripheral nervous system
Insomnia	16%
Peripheral neuropathy	9%
Parethesia	8%
Special senses
Retinal detachment	15%

Serious adverse events reported from these two clinical trials (N=370) with a frequency of less than 5% and which are not mentioned in the two tables above, are listed below:

Hemic and lymphatic system:   pancytopenia, bone marrow depression, aplastic anemia

Urogenital system:   decreased creatinine clearance

Infections:   local and systemic infections and sepsis

Bleeding complications:   potentially life-threatening bleeding associated with thrombocytopenia

Central and peripheral nervous system:   convulsion, psychosis, hallucinations, confusion, agitation

Body as a whole:   valganciclovir hypersensitivity

Laboratory abnormalities reported with Valcyte tablets are listed below:

 

Table 8. Pooled Laboratory Abnormalities Reported in
Two Clinical Studies

Laboratory Abnormalities	N=370
Neutropenia: AUC /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%

Experience with Ganciclovir

Valganciclovir is rapidly converted to ganciclovir upon oral administration. Adverse events reported with Valcyte in general were similar to those reported with ganciclovir (Cytovene). Please refer to the Cytovene label for more information on post-marketing adverse events associated with ganciclovir.

 

DRUG INTERACTIONS

Drug Interaction Studies Conducted With Valganciclovir:

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 4. Results of Drug Interaction Studies with Ganciclovir: Effects of Co-administered
Drug on Ganciclovir Plasma AUC and C _max Values

Co-administered Drug	Ganciclovir Dosage	n	Ganciclovir Pharmacokinetic (PK) Parameter	Clinical Comment
Zidovudine 100 mg every 4 hours	1000 mg every 8 hours	12	AUC down 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 down 21 ± 17% (range: -44% to 5%)	Effect not likely to be clinically significant.
Didanosine 200 mg every 12 hours stimultaneously 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 up 53 ± 91% (range: -14% to 299%) Ganciclovir renal clearance down 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 up 13%	Effect not likely to be clinically significant.
Trimethoprim 200 mg once daily	1000 mg every 8 hours	12	Ganciclovir renal clearance down16.3% Half-life up15%	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 5. Results of Drug Interaction Studies with ganciclovir: Effects of ganciclovir on
Plasma AUC and C _max Values of Co-administered Drug

Co-administered Drug	Ganciclovir Dosage	n	Co-administered Drug Pharmacokinetic (PK) Parameter	Clinical Comment
Zidovudine 100 mg every 4 hours	1000 mg every 8 hours	12	AUC 0-4 up 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	AUC 0-12 up111 ± 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	AUC 0-12 up70 ± 40% (range: 3% to 121%)    C max up49 ± 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	AUC 0-12 up50 ± 26% (range: 22% to 110%)    C max up36 ± 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 in C min	Effect not likely to be clinically significant.
Mycophenolate Mofetil 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.

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