New European recommendations regarding the co-administration of ddI (Videx) and tenofovir DF (Viread)

2 March 2005

Dear Health Care Professional

Following discussion with the European Medicines Agencies scientific committee, the Committee for Medicinal Products for Human Use (CHMP), Bristol-Myers Squibb and Gilead Sciences International Limited are writing to inform you of new European recommendations regarding the co-administration of didanosine and tenofovir DF.

• Co-administration of didanosine and tenofovir disoproxil fumarate is not recommended, especially in patients with high viral load and low CD4 cell counts.
• If co-administration of this combination is judged to be strictly necessary, patients should be carefully monitored for efficacy and didanosine-related adverse events.

These new European recommendations have been developed in view of the efficacy and safety issues outlined below.

Efficacy issue:

A high rate of early virological failure and emergence of resistance has been observed in several clinical studies in which didanosine and tenofovir DF were co-administered with a non-nucleoside reverse transcriptase inhibitor (NNRTI) in antiretroviral-naïve HIV-1 infected adults with high baseline viral loads and low CD4 cell counts. [1-3]

Similar findings had previously been reported in the context of triple combination involving didanosine and tenofovir DF with another nucleoside reverse transcriptase inhibitor (NRTI).[4]

Although all these reports have been reported in specific situations (i.e. antiretroviral naïve patients and co-administration with NRTI or NNRTI), it could not be ruled out that such worrying findings could be observed in other contexts (such as in antiretroviral experienced patients and/or in combination with protease inhibitors).

Therefore, co-administration of didanosine and tenofovir DF is not recommended within any antiretroviral treatment regimen unless judged strictly necessary.

Safety issue:

Separate pharmacokinetic studies showed that co-administration of didanosine and tenofovir DF resulted in 40-60% increase in systemic exposure to didanosine that may increase the risk for didanosine-related adverse events. Rare cases of pancreatitis and lactic acidosis, sometimes fatal, have been reported.

The European Summary of Product Characteristics (SmPC) for ddI (Videx) and tenofovir DF (Viread) are currently being updated with these new recommendations.

New information to be included in Sections 4.4 (Special Warnings and Special Precautions for use) and 4.5 (Interactions with other medicinal products) is summarised in the attachment to this letter.

Bristol-Myers Squibb and Gilead are committed to providing you with current product information for the management of your patients for HIV infection. You can assist us by monitoring the safety of our products and reporting adverse reactions, which should be sent to the local representatives listed below or to the Medicines and Healthcare products Regulatory Agency (MHRA).

For further information, please contact:

Medical Information Department
Bristol-Myers Squibb Pharmaceuticals Ltd
141 – 149 Staines Road
Hounslow, Middlesex
TW3 3JA

Gilead Sciences Ltd
Flowers Building, Granta Park
Abington, Cambridge
CB1 6GT
0800 7311736
01223 897555

References:

1. Podzamczer D, Ferrer E, Gatell JM et al. Early virologic failure with a combination of tenofovir, didanosine and efavirenz. Antiviral Therapy 10: 171-177, 2005.
2. Moyle G, Maitland D, Hand J et al. Early virological failure in persons with viral loads >100,000 copies/mL and CD4 counts <200/mm3 receiving didanosine/tenofovir/efavirenz as initial therapy: 12 week results from a randomized comparative trial [poster]. 44th ICAAC; 2004 October 30-November 2; Washington, DC, USA. Poster H-566.
3. Leon A, Martinez E, Malloloas J et al.Early virological failure in treatment-naive HIV-infected adults receiving didanosine and tenofovir plus efavirenz or nevirapine. AIDS 19(2): 213-215, 2005.
4. Jemsek J, Harper E, Hutcherson P. Poor virologic responses and early emergence of resistance in treatment-naive, HIV-infected patients receiving a once-daily triple nucleoside regimen of didanosine, lamivudine, and tenofovir DF [oral presentation]. 11th CROI; 2004. February 8-11; San Francisco, California, USA. Oral Presentation 51.

Summary of new recommendations regarding the co-administration of didanosine and tenofovir disoproxil fumarate that will be included in the EU Summary of Product Characteristics (SmPC) for Videx and Viread:

SmPC Section 4.4 (Special Warnings and Special Precautions for use):

Co-administration of tenofovir disoproxil fumarate and didanosine results in a 40-60% increase in systemic exposure to didanosine that may increase the risk for didanosine-related adverse events (see 4.5). Rare cases of pancreatitis and lactic acidosis, sometimes fatal, have been reported.

A reduced didanosine dose (250 mg) has been tested to avoid over-exposure to didanosine in case of co-administration with tenofovir disoproxil fumarate, but this has been associated with reports of high rate of virological failure and of emergence of resistance at early stage within several tested combinations. Co-administration of tenofovir disoproxil fumarate and didanosine is therefore not recommended, especially in patients with high viral load and low CD4 cell count. If this combination is judged strictly necessary, patients should be carefully monitored for efficacy and didanosine related adverse events.

SmPC Section 4.5 (Interactions with other medicinal products):

When didanosine gastro-resistant capsules were administered 2 hours prior to or concurrently with tenofovir disoproxil fumarate, the AUC for didanosine was on average increased by 48% and 60% respectively. The mean increase in the AUC of didanosine was 44% when the buffered tablets were administered 1 hour prior to tenofovir. In both cases the pharmacokinetic parameters for tenofovir administered with a light meal were unchanged. The co-administration of tenofovir disoproxil fumarate and didanosine is not recommended (see 4.4).