Wyeth-Ayerst, USA. The manufacturers of pharmaceutical products containing methotrexate, Lederle Pharmaceuticals and Lederle Parenterals, have issued a "Dear Doctor" letter to provide important new information to physicians so that they can make informed prescribing and treatment decisions regarding methotrexate (Rheumatrex^® Dose Pack, Methotrexate Sodium Tablets, Methotrexate Sodium for Injection, and Methotrexate Sodium Injection).

The following information has been received:

• Reports of bone and soft tissue necrosis following radiation therapy.

• Rare reports of painful plaque erosions when methotrexate has been used for the treatment of psoriasis.

• Reports that the combination of methotrexate with other potentially hepatotoxic agents may increase the risk of hepatotoxicity. The risk, if any, of such combination therapy has not been systematically evaluated.

• Urgent treatment of methotrexate overdose is sometimes necessary. Routine haemodialysis and haemoperfusion are ineffective in lowering methotrexate blood levels. A recent report indicates that high-flux dialysis equipment can acutely lower methotrexate blood levels.

In the light of the above information, the following statement has been added to the "Warnings" section of the prescribing information:

• Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

The "General" subsection of the "Precautions" section has been revised to include the following underlined text:

• Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent haemodialysis with a high-flux dialyser.

The same text has been added to the sections on "Overdosage" and to the "Guidelines for methotrexate therapy with leucovorin rescue".

The "Adverse Reactions in Psoriasis" section has been amended to include the following text:

• Rarely, painful plaque erosions may appear.

The "Drug Interactions" subsection has been modified to include the following paragraph:

• The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (e.g. azathioprine, retinoids, sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity.

References:

1) "Dear Doctor" letter, Wyeth-Ayerst Laboratories, June 1999.
[http://www.fda.gov/medwatch/safety/1999/methot.htm]

2) Turner SL et al: Radical external beam radiotherapy for 333 squamous carcinomas of the oral cavity - Evaluation of late morbidity and a watch policy for the clinically negative neck. Radiotherapy & Oncology 41:21-29, 1996.

3) Pearce HP and Wilson BB: Erosion of psoriatic plaques: An early sign of methotrexate toxicity. American Academy of Dermatology 35:835-838, 1996.

4) Data on file (spontaneous adverse event reporting system), Wyeth-Ayerst Laboratories.

5) Wall, SM et al: Effective clearance of methotrexate using high-flux haemodialysis membranes. American Journal of Kidney Disease 28(6):846-854, 1996.