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Letter From Bristol Myers Squibb About DDI and Tenofovir Interaction
 
 
  May 7, 2002
 
Dear HIV Treating Professional:
 
Bristol-Myers Squibb Virology would like to make HIV clinicians aware of new pharmacoki-netic (PK) data concerning the co-administration of VIDEX EC (didanosine) Delayed-Release Capsules Enteric Coated Beadlets and Viread (tenofovir disoproxil fumarate, Gilead Sciences, Inc.). A previous Gilead Study demonstrated an increase in didanosine exposure when VIDEX Chewable Buffered Tablets (TABS) were administered with tenofovir disoproxil fumarate (DF).
 
In a recent study, conducted in partnership between BMS and Gilead Sciences, the phar-macokinetics of VIDEX EC were investigated when co-administered with tenofovir DF in two dosing approaches: 1) VIDEX EC administered without food two hours prior to administration of tenofovir DF with food and, 2) both drugs administered together with food.
 
The results of this recent study showed that administration of once daily (QD) VIDEX EC 400 mg (all subjects ⋅60 kg) two hours before tenofovir DF 300 mg with a light meal, resulted in an approximate 46% increase in didanosine exposure relative to the adminis-tration of VIDEX EC alone in the fasted state. Co-administration of VIDEX EC 400 mg QD (all subjects≥60 kg) and tenofovir DF 300 mg with a light meal, resulted in an approximate 60% increase in didanosine exposure relative to the administration of VIDEX EC alone in the fasted state. Summarized below are the results from both the initial and new PK studies.
 
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  Co-administration of didanosine either as chewable tablets or enteric coated beadlets had no effect on the area under the curve (AUC) of tenofovir DF. However, use of VIDEX EC or VIDEX TABS with tenofovir DF in various fasting and fed states results in a mean increase in the didanosine AUC ranging from approximately 44% to 60%. Based on the results of these studies, the currently recommended doses of VIDEX EC or VIDEX TABS used in tenofovir DF-containing regimens may result in higher plasma levels of didanosine, with the potential for increased dose-related toxicities, including but not limited to peripheral neuropathy and pancreatitis. As such, patients taking tenofovir DF and standard doses of VIDEX EC or VIDEX TABS concomitantly should be monitored for didanosine-associated adverse events.
 
Summary
 
  • Administration of VIDEX TABS (didanosine) 400 mg QD (250 mg QD if <60 kg) one houbefore tenofovir DF 300 mg QD (both in the fasting state) results in an approximate 44% increase in didanosine exposure relative to the administration of VIDEX TABS 400 mg alone in the fasted state.

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  • Administration of VIDEX EC (didanosine) 400 mg QD (all subjects ⋅60 kg) two hours before tenofovir DF 300 mg with a light meal, results in an approximate 46% increase in didanosine exposure relative to the administration of VIDEX EC alone in the fasted state.

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  • Co-administration of VIDEX EC 400 mg QD (all subjects ⋅60 kg) and tenofovir DF 300 mg with a light meal, results in an approximate 60% increase in didanosine exposure relative to the administration of VIDEX EC alone in the fasted state.

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Bristol-Myers Squibb will be evaluating the issue further. Patients taking tenofovir DF and standard doses of VIDEX EC or VIDEX TABS concomitantly should continue to be monitored for didanosine-associated adverse events.
 
Fatal and non-fatal pancreatitis have occurred with didanosine. Didanosine should be suspended in suspected cases of pancreatitis and discontinued in confirmed cases. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Fatal lactic acidosis has occurred in pregnant women receiving the combination of didanosine and stavudine. This combination should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk.
 
Important toxicities include retinal changes, optic neuritis and peripheral neuropathy. The risk for pancreatitis, peripheral neuropathy and hepatotoxicity may be increased for patients treated with didanosine in combination with stavudine.
 
Frequent side effects reported in VIDEX EC-containing triple combination regimens are diarrhea (57%), peripheral neurologic symptoms (25%), nausea (24%), headache (22%), rash (14%), and vomiting (14%).
 
VIDEX EC 400 mg Capsule (60 kg) or 250 mg Capsule (<60 kg)
 
Frequent side effects reported in VIDEX-containing regimens are diarrhea (70%), nausea (53%), headache (46%), rash (30%), vomiting (30%) and neuropathy (26%). All didanosine formulations should be administered on an empty stomach.
 
VIDEX EC should only be administered once daily.
 
We appreciate your interest in Bristol-Myers Squibb Virology products and hope you find this information helpful. If you would like to receive additional information on this issue, please contact our Medical Department at 1-800-426-7644. Please see the enclosed VIDEX EC (didanosine) and VIDEX (didanosine) full prescribing information.
 
Sincerely,
Michael R. Stevens, PharmD
Vice President, Virology Medical Affairs
 
 
 
 
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