Important renal safety information regarding the use of tenofovir and Truvada

13 April 2006. Related: Treatment alerts.

Dear Health Care Professional

Tenofovir (tenofovir disoproxil fumarate, Viread) and Truvada (fixed dose combination emtricitabine/tenofovir DF)

Following discussion with the European Medicines Agency scientific committee, the Committee for Medicinal Products for Human Use (CHMP), at which the Medicines and Healthcare products Regulatory Agency (MHRA) participates, Gilead is writing to ensure that you are aware of important renal safety information and recommendations in the current European Summary of Product Characteristics (SPC) for tenofovir and Truvada.

The tenofovir DF dose interval recommendations for tenofovir DF were the subject of a previous letter to Healthcare Professionals released in July 2003. However, Gilead has continued to receive reports of renal adverse reactions (e.g. renal failure including acute cases, tubulopathies including Fanconi syndrome, nephrogenic diabetes insipidus) in patients whose creatinine clearance was not established at baseline and in renally impaired patients who have not had their dosing interval adjusted in line with the guidance provided on the SPC.

It was therefore considered important to remind you of the SPC sections pertaining to renal monitoring and dose adjustments in case of renal impairment as follows:

• Monitoring of renal function (by measuring creatinine clearance and serum phosphate) is recommended before taking tenofovir DF, every four weeks during the first year, and then every three months for all patients. In patients at risk for, or with a history of renal dysfunction and patients with renal insufficiency, more frequent monitoring of renal function should be considered (see section 4.4 of the Truvada and tenofovir DF SPCs).
• If serum phosphate is <1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy), and the dose interval adjusted (see 4.2). Consideration should also be given to interrupting treatment with tenofovir DF in patients with creatinine clearance decreased to < 50 ml/min or decreases in serum phosphate to <1.0 mg/dl (0.32 mmol/l) (see section 4.4 of the Truvada and tenofovir Df SPCs).

Creatinine clearance for individual patients should be calculated according to the Cockroft-Gault formula:

Female:

Clearance: (ml/min) = (1.04 x (140-age) x weight (kg)) Creatinine (µmol/l)

Male:

Clearance: (ml/min) =(1.23 x (140-age) x weight (kg)) Creatinine (µmol/l)

Dosing interval adjustment is required in patients who receive tenofovir DF with pre-existing renal impairment, or in patients who develop renal insufficiency for any reason while on treatment, as summarised below.

VIREAD (see Viread SPC section 4.2):

TRUVADA (see Truvada SPC section 4.2):

– TRUVADA is not recommended for patients with severe renal impairment (creatinine clearance < 30 ml/min) and in patients who require haemodialysis since appropriate dose reductions cannot be achieved with the combination tablet.

The safety and efficacy of the dosing interval adjustment guidelines for tenofovir DF and Truvada have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.

Use of tenofovir DF should be avoided with concurrent or recent use of a nephrotoxic medicinal product. If concomitant use of tenofovir DF and nephrotoxic agents is unavoidable, renal function should be monitored weekly (see tenofovir DF SPC section 4.4 and Truvada SPC section 4.4 and 4.5).

The Company would also like to take this opportunity to request that physicians remind patients that they must not take Truvada (emtricitabine/tenofovir DF fixed combination) concurrently with Viread (tenofovir DF) or Emtriva (emtricitabine).

See currently approved Viread and Truvada SPCs (sections 4.2. Posology and method of administration, 4.4. Special warnings and special precautions for use, 4.5. Interaction with other medicinal products and other forms of interaction and 4.8. Undesirable effects).

Any suspected adverse reactions should be notified to the company and/or the MHRA in the usual way.

For further information please contact:

Medical Information, Gilead Sciences Limited. Tel. + 44 (0) 1223 897555; ukmedinfo@Gilead.com

Comment

The EMEA asked Gilead to issue this Dear Doctor Letter to medical professionals and community organisations concerning renal monitoring for patients on tenofovir (TDF) and Truvada (issued 10 March 2006). This emphases the importance of monitoring patients’ renal function (CrCL as per Cockroft-Gault) at least monthly for the first year and three-monthly thereafter.

The EMEA will not be issuing a public statement on their website as they are not seeing an increase in incidence. A similar letter was issued when TDF was first licensed.