Méthothrexate: décès par surdosage. Rappel des effets indésirables listés aux Etats-Unis

Je relaie une information reçue le 12 juillet du Centre régional de pharmacovigilance de Toulouse (Service de pharmacologie du Pr Jean-Louis Montastruc), puis cite plusieurs références et renvoie au RCP (résumé des caractéristiques du produit) états-unien, et notamment aux sections « mises en garde et précautions d’emploi » et « effets indésirables ».

A noter que dans son numéro de mai 2007, la revue Prescrire s’est insurgée « que des patients meurent encore d’erreurs de dose de méthotrexate, alors que ces erreurs sont connues depuis longtemps et sont évitables », avec ces précisions :

« Le méthotrexate est un médicament cytotoxique utilisé en cancérologie, rhumatologie et dermatologie. Ses effets indésirables, parfois graves, voire mortels, touchent divers organes. Ils augmentent avec la dose et en cas d’insuffisance rénale. Des troubles tels qu’une fièvre et des ulcérations buccales peuvent révéler l’apparition d’effets indésirables. La revue Prescrire souligne que des centaines de cas d’effets indésirables graves de ce médicament ont été collectés dans le monde entier depuis les années 1980, dont des dizaines de cas mortels, souvent dus à des erreurs. » Voir aussi l’article « Méthotrexate par voie orale : prévenir les surdoses par erreur » Rev Prescrire 2007 ; 27 (283) : 352-355.

A noter aussi un article de S. Reutenauer et al paru en octobre 2009 sous le titre « Surdosage au méthotrexate : complications, prise en charge et prévention » dans la revue Réanimation, vol. 18, N° 7 : 654-658.

La revue allemande Arznei-Telegramm a abordé a plusieurs reprises les effets indésirables, les interactions médicamenteuses et le surdosage du méthothrexate (Novatrex, Imeth, Methotrexate Bellon, etc.).

*

Voici l’information reçue du CHU de Toulouse :

« Le méthotrexate par voie orale est notamment indiqué en France dans le traitement de la polyarthrite rhumatoïde active, le psoriasis de l’adulte et le traitement d’entretien des leucémies aigues lymphoblastiques. Quelle que soit l’indication, la prise de méthotrexate par voie orale s’effectue en une prise unique par semaine, et la posologie s’exprime en mg/semaine.
Il est demandé au prescripteur de préciser sur l’ordonnance le jour de la semaine où le médicament doit être administré afin d’éviter toute confusion pouvant entraîner un surdosage accidentel.

L’Afssaps rappelle la nécessité d’être vigilant lors de toute prescription, délivrance ou administration de méthotrexate par voie orale, et demande aux professionnels de santé d’insister auprès des patients sur la prise hebdomadaire de ces médicaments et les risques inhérents à un surdosage.
Depuis 2007, l’Afssaps a été destinataire de signalements d’erreurs par prise quotidienne au lieu d’hebdomadaire de ces médicaments. Ces erreurs ont le plus souvent été associées à des effets indésirables graves et certaines ont été d’issue fatale, en raison notamment de la toxicité hématologique du méthotrexate en cas de surdosage.
Malgré la mise en oeuvre de ces mesures, l’Afssaps a eu connaissance, depuis le début de l’année 2011, de 4 cas de surdosage par prise quotidienne du traitement dont 2 ont entraîné le décès du patient. Deux de ces surdosages, consécutifs à une erreur de prescription ont conduit à :

• une aplasie médullaire d’issue fatale à la suite d’une prescription de 3 comprimés par jour au lieu de 3 par semaine ;
• une neutropénie et une cytolyse hépatique conduisant au décès du patient, à la suite d’une prescription de 6 comprimés par jour au lieu de 6 par semaine ;

Dans le 3e cas, la prescription était incomplète (absence de précision sur le rythme de prise). Le patient, qui a ainsi reçu un comprimé par jour de méthotrexate pendant 10 jours, n’a pas développé d’effet indésirable.
Enfin, en mai 2011, l’Afssaps a été informée de l’hospitalisation d’une patiente pour aplasie médullaire, d’évolution favorable, liée à une mauvaise compréhension du schéma d’administration de son traitement qu’elle a pris quotidiennement.

Vous trouverez plus d’informations sur le site www.bip31.fr et sur le site www.afssaps.sante.fr.

N’oubliez pas par ailleurs de déclarer au Centre Midi-Pyrénées de PharmacoVigilance, de PharmacoEpidémiologie et d’Information sur le médicament les effets indésirables « graves » ou encore « inattendus » : ceci nous permettra d’approfondir chaque jour, avec vous, pour nos malades, le rapport bénéfice/risque des médicaments. »

Elisabeth Gorsse

Secrétariat du Service de Pharmacologie médicale et clinique du CHU de Toulouse

*

Section « mises en garde et précautions d’emploi » du RCP états-unien, repris sur RxList (site qui recueille les RCT des médicaments d’ordonnance)

WARNINGS:

“METHOTREXATE SHOULD BE USED ONLY BY PHYSICIANS WHOSE KNOWLEDGE AND EXPERIENCE INCLUDE THE USE OF ANTIMETABOLITE THERAPY.

BECAUSE OF THE POSSIBILITY OF SERIOUS TOXIC REACTIONS (WHICH CAN BE FATAL):

METHOTREXATE SHOULD BE USED ONLY IN LIFE THREATENING NEOPLASTIC DISEASES, OR IN PATIENTS WITH PSORIASIS OR RHEUMATOID ARTHRITIS WITH SEVERE, RECALClTRANT, DISABLING DISEASE WHICH IS NOT ADEQUATELY RESPONSIVE TO OTHER FORMS OF THERAPY. DEATHS HAVE BEEN REPORTED WITH THE USE OF METHOTREXATE IN THE TREATMENT OF MALIGNANCY, PSORIASIS, AND RHEUMATOID ARTHRITIS.

PATIENTS SHOULD BE CLOSELY MONITORED FOR BONE MARROW, LIVER, LUNG AND KIDNEY TOXICITIES. (See PRECAUTIONS.)

PATIENTS SHOULD BE INFORMED BY THEIR PHYSICIAN OF THE RISKS lNVOLVED AND BE UNDER A PHYSICIAN’S CARE THROUGHOUT THERAPY.

Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, it is not recommended for women of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant women with psoriasis or rheumatoid arthritis should not receive methotrexate. (See CONTRAINDICATIONS.)

Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration.

Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs). (See PRECAUTIONS: DRUG INTERACTIONS.)

Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population. (See PRECAUTIONS, Organ System Toxicity, Hepatic.)

Methotrexate-induced lung disease is a potentially dangerous lesion, which may occur acutely at any time during therapy and which has been reported at doses as low as 7.5 mg/week. It is not always fully reversible. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.

Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.

Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted.

Like other cytotoxic drugs, methotrexate may induce « tumor lysis syndrome » in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.

Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy. (See PRECAUTIONS, Organ System Toxicity, Skin.)

Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy.

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

SIDE EFFECTS

« IN GENERAL, THE INCIDENCE AND SEVERITY OF ACUTE SIDE EFFECTS ARE RELATED TO DOSE AND FREQUENCY OF ADMINISTRATION. THE MOST SERlOUS REACTIONS ARE DISCUSSED ABOVE UNDER ORGAN SYSTEM TOXICITY IN THE PRECAUTION SECTION. THAT SECTION SHOULD ALSO BE CONSULTED WHEN LOOKING FOR INFORMATION ABOUT ADVERSE REACTIONS WITH METHOTREXATE.

The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.

Other adverse reactions that have been reported with methotrexate are listed below by organ system. In the oncology setting, concomitant treatment and the underlying disease make specific attribution of a reaction to methotrexate difficult.

Alimentary System: Gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis.

Blood and Lymphatic System Disorders: Suppressed hematopoiesis causing anemia, aplastic anemia, leukopenia and/or thrombocytopenia. Hypogammaglobulinemia has been reported rarely.

Cardiovascular: Pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus).

Central Nervous System: Headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis, and convulsions have also occurred following administration of methotrexate. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.

Infection: There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis carinii penumonia was the most common infection. Other reported infections included sepsis, nocardiosis; histoplasmosis, cryptococcosis, Herpes zoster, H. simplex hepatitis, and disseminated H. simplex.

Musculoskeletal System: Stress fracture.

Ophthalmic: Conjunctivitis, serious visual changes of unknown etiology.

Pulmonary System: Respiratory fibrosis, respiratory failure, interstitial pneumonitis deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred.

Skin: Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration, and exfoliative dermatitis.

Urogenital System: Severe nephropathy or renal failure, azotemia, cystitis, hematuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal defects.

Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, reversible lymphomas, tumor lysis syndrome, soft tissue necrosis and osteonecrosis. Anaphylactoid reactions have been reported.

Adverse Reactions in Double-Blind Rheumatoid Arthritis Studies:

The approximate incidences of methotrexate-attributed (i.e., placebo rate subtracted) adverse reactions in 12 to 18 week double-blind studies of patients (n=128) with rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week) pulse methotrexate, are listed below. Virtually all of these patients were on concomitant nonsteroidal anti-inflammatory drugs and some were also taking low dosages of corticosteroids. Hepatic histology was not examined in these short-term studies. (See PRECAUTIONS).

Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%.

Incidence 3% to 10%: Stomatitis, thrombocytopenia, (platelet count less than 100,000/mm³).

Incidence 1% to 3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (WBC less than 3000/mm³), pancytopenia, dizziness.

Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on 7.5 mg – 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of 1%. (see PRECAUTIONS).

Other less common reactions included decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, and vaginal discharge.

Adverse Reactions in Psoriasis:

There are no recent placebo-controlled trials in patients with psoriasis. There are two literature reports (Roenigk, 1969 and Nyfors, 1978) describing large series (n=204, 248) of psoriasis patients treated with methotrexate. Dosages ranged up to 25 mg per week and treatment was administered for up to four years. With the exception of alopecia, photosensitivity, and « burning of skin Iesions » (each 3% and 10%), the adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis studies. Rarely, painful plaque erosions may appear (Pearce, HP and Wilson, BB: Am Acad Dermatol 35:835-838, 1996).

Adverse Reactions in JRA Studies: [JRA = arthrite rhumatoïde juvénile]

The approximate incidences of adverse reactions reported in pediatric patients with JRA treated with oral, weekly doses of methotrexate (5 to 20 mg/m²/wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids); elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%, dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to 30 mg/m²/wk in JRA, the published data for doses above 20 mg/m²/wk are too limited to provide reliable estimates of adverse reaction rates. »

*

Elena Pasca