BMS advice on interaction between didanosine EC and tenofovir

11 July 2002. Related: Treatment alerts, Antiretrovirals.

Enteric coated didanoisine (Videx EC) is the version of didanosine (ddI) that provides certain advantages over standard buffered ddI tablets. Tenofovir DF (Viread), a nucleotide reverse transcriptase inhibitor (NtRTI), is the most recently approved drug for the treatment of HIV infection.

Enteric-coated didanosine (Videx EC; Bristol-Myers Squibb) is much gentler on the stomach than the original buffered tablet formulation of the nucleoside transcriptase inhibitor, study results indicate. Switching to Videx EC led to significant reductions in nausea, bloating, GI upset, diarrhoea, abdominal cramps and gas, according to patient symptom scores recorded in diaries.

The currently recommended doses of Videx EC or Videx TABS (buffered formulation) 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.

Following is a letter sent by Bristol-Myers Squibb to physicians and other healthcare professionals that related to a recent study of the Videx EC/Viread interaction.

Dear HIV treating professional:

Bristol-Myers Squibb Virology would like to make HIV clinicians aware of new pharmacokinetic (PK) data concerning the co-administration of Videx EC (ddI, 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 pharmacokinetics 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 300mg with a light meal, resulted in an approximate 46% increase in didanosine exposure relative to the administration 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.

Summarised below are the results from both the initial and new PK studies.

Light meal: 373 Kcal: 8.2 grams fat. * patient dose <60 kg weight ** patients >60 kg weight

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 hour before 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.
• Administration of Videx EC (didanosine) 400 mg QD (all subjects o60 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.
• Co-administration of Videx EC 400 mg QD (all subjects o60 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.

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 diarrhoea (57%), peripheral neurologic symptoms (25%), nausea (24%), headache (22%), rash (14%), and vomiting (14%).

Frequent side effects reported in Videx-containing regimens are diarrhoea (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 Videx EC (didanosine) and VIDEX (didanosine) full prescribing information.

Sincerely, Michael R Stevens, PharmD

Vice President, Virology Medical Affairs, 7 May 2002.

Source: Bristol-Myers Squibb

Comment

The issue with this particular interaction may be more complicated than the PK-data suggest. The relationship between plasma levels and intracellular levels/efficacy/adverse events is established for NNRTIs and PIs, but not for NRTIs. The activity of NRTIs is determined by the amount of triphosphate in the cell which seems to have a high interpersonal variability and is not linear to the plasma concentration.

To date a recommendation for the amount of dose reduction appears to be based more on gut feeling than data.