Is anemia a known side effect of Reumacon (CPH-82)?/nA woman with rheumatoid arthritis has been tre

Fråga: Is anemia a known side effect of Reumacon (CPH-82)?

A woman with rheumatoid arthritis has been treated with Reumacon 200-300 mg daily for 3-4 years. In addition to Reumacon she also takes Prednisolon (prednisolone), Orudis Ret. (ketoprofen), Seloken (metoprolol), Losec (omeprazole), Cytotec (misoprostol) and Somadril (carisoprodol). In October 2000 she visited Vietnam and after that she had a persistent diarrhoea. In January 2001 she deteriorated with severe diarrhoea and was submitted to a hospital but recovered after treatment with metronidazole. During the time in the hospital a hemoglobin (Hb) value of 90 g/l was observed. The patient´s habitual Hb is around 110-115 g/L. The Hb value fell gradually during two months to 60 g/L. A bone marrow sample was suggestive of myelodysplastic syndrome (MDS) and there were no signs of peripheral hemolysis. The white cell count was unaffected as was the thrombocyte count. Reumacon has been discontinued. The Hb value has not yet normalised.

Sammanfattning: There are a few reports of anemia during CPH-82 treatment. One of the cases includes a positive de- and rechallange. In the present case, a casual relationship would be strengthened if the Hb value returns to normal after withdrawal of the drug.

Svar: CPH-82 is a semisynthetic podophyllotoxin derivate (a mixture of two benzyledinated podofyllotoxin glycosides) that is used for treating rheumatoid diseases (1). Not much is known about the pharmacokinetics of the two active components of CPH-82. All information that is available is unpublished data supplied by the manufacturer (2). The mechanism of action is only partially known, but CPH-82 influences the cell cycle and cell proliferation. It also inhibits the release of IgA, IgG, IgM, and the cytokines IL-6 and TNF-alfa (3). At least 6000 patients have been treated with CPH-82 during the last 15 years. The drug is in clinical use in the Scandinavian countries and, to a lesser extent, in Germany and Switzerland (2). The most common side effects involve the alimentary system with symptoms such as diarrhoea, abdominal pain and nausea (4).

Epipodophyllotoxins- etoposide and teniposide- are also podophyllotoxin derivates. Epipodophyllotoxins reduce the rate of mitosis and are important components in chemotherapy protocols for hematological malignancies (5). Several studies have reported leukaemias after treatment with podophyllotoxincontaining regimens, and it is clear that epipodophyllotoxins carry a small but definite risk of secondary leukaemia. Since the patients with secondary leukaemia have been exposed to multiple chemotherapeutic agents, the development of secondary leukaemias might be a combined effect rather than the result of podophyllotoxin treatment alone. In the vast majority of cases of acute leukaemia after treatment with epidophyllotoxins, the MDS phase is brief or absent with rapid conversion to acute leukaemia (6).

There is one published case report of leukaemia during CPH-82 treatment in a patient with juvenile chronic arthritis (1). It concerns a woman who had been treated with CPH-82 for 21 months. She had also received chlorambucil, azathioprine and mercaptopurine in addition to CPH-82 and thus the causal effect of single/combination drug treatment on the development of leukaemia cannot be determined.

According to the manufacturer there are three reports of anemia during CPH-82 treatment (2). All three are Swedish reports. The first concerns a 74-year-old man who was treated with CPH-82 200 mg/day. After 4 months treatment elevated liver enzymes and anemia were noticed. The treatment with CPH-82 was stopped. However, no information on the outcome is available. The second report concerns a woman with polyarthritis. After two months treatment with CPH-82 the hemoglobin value had decreased from 90 g/L to 61 g/L. In addition to CPH-82 she also received treatment with prednisolone, diclofenac, ASA, codeine and chloroquine phosphate. The treatment with CPH-82 was stopped and her hemoglobin value normalised within a few months. CPH-82 treatment was started again and the anemia relapsed. The third case concerns a woman with a history of tuberculosis, who suffered from rheumatoid arthritis. She had treatment with CPH-82. During the period of treatment she developed aplastic anemia and died. At autopsy it was shown that she suffered from miliary tuberculosis. The physician in charge was not of the opinion that the treatment with CPH-82 had contributed to the course of events.

In Swedis there are two reports of anemia during treatment with CPH-82 (7). In one of the reports the causal relationship is considered possible. This report refers to the same patient as the second case reported by the manufacturer (summarised above). In the second case reported to Swedis, the causal relationship is considered unlikely.

In the WHO database, there is one report of anemia and one report of marrow depression during treatment with CPH-82 (8).

In a clinical study of CPH-82 vs methotrexate in early rheumatoid arthritis one patient treated with CPH-82 developed transient mild anemia and leucopenia during treatment (9). The study was a 24-week, double-blind, randomised study of 100 patients with active rheumatoid arthritis.

According to the manufacturer, animal studies on CPH-82 using much higher doses than clinical ones have not shown any toxic effect on erythropoiesis (2).

We recommend this case to be reported to the Swedish Adverse Drug Reaction Committee (SADRAC).