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Lamictal (lamotrigine): Drug Safety Communication - Serious Immune System Reaction


AUDIENCE: Health Professional, Patient, Pharmacy

ISSUE: The FDA is warning that the medicine Lamictal (lamotrigine) for seizures and bipolar disorder can cause a rare but very serious reaction that excessively activates the body's infection-fighting immune system. This can cause severe inflammation throughout the body and lead to hospitalization and death, especially if the reaction is not diagnosed and treated quickly. As a result, we are requiring a new warning about this risk be added to the prescribing information in the lamotrigine drug labels.

BACKGROUND: The immune system reaction, called hemophagocytic lymphohistiocytosis (HLH), causes an uncontrolled response by the immune system. HLH typically presents as a persistent fever, usually greater than 101℉, and it can lead to severe problems with blood cells and organs throughout the body such as the liver, kidneys, and lungs.

Lamotrigine is used alone or with other medicines to treat seizures in patients two years and older. It may also be used as maintenance treatment in patients with bipolar disorder to help delay the occurrence of mood episodes such as depression, mania, or hypomania. Stopping lamotrigine without first talking to a prescriber can lead to uncontrolled seizures, or new or worsening mental health problems. Lamotrigine has been approved and on the market for 24 years, and is available under the brand name Lamictal and as generics.

RECOMMENDATION: Healthcare professionals should be aware that prompt recognition and early treatment is important for improving HLH outcomes and decreasing mortality. Diagnosis is often complicated because early signs and symptoms such as fever and rash are not specific. HLH may also be confused with other serious immune-related adverse reactions such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

Evaluate patients who develop fever or rash promptly, and discontinue lamotrigine if HLH or another serious immune-related adverse reaction is suspected and an alternative etiology for the signs and symptoms cannot be established. Advise patients to seek immediate medical attention if they experience symptoms of HLH during lamotrigine treatment. A diagnosis of HLH can be established if a patient has at least five of the following eight signs or symptoms:

• fever and rash
• enlarged spleen
• cytopenias
• elevated levels of triglycerides or low blood levels of fibrinogen
• high levels of blood ferritin
• hemophagocytosis identified through bone marrow, spleen, or lymph node biopsy
• decreased or absent Natural Killer (NK) Cell activity
• elevated blood levels of CD25 showing prolonged immune cell activation

Patients or their caregivers should contact their health care professionals right away if they experience any symptom of HLH while taking lamotrigine. HLH can occur within days to weeks after starting treatment. A physical examination and specific laboratory blood tests and other evaluations are used to diagnose HLH. Signs and symptoms of HLH include but are not limited to:

• fever
• enlarged liver; symptoms may include pain, tenderness, or unusual swelling over the liver area in the upper right belly
• swollen lymph nodes
• skin rashes
• yellow skin or eyes
• unusual bleeding
• nervous system problems, including seizures, trouble walking, difficulty seeing, or other visual disturbances

Read the patient Medication Guide, which explains the benefits and risks of lamotrigine, every time you get a new prescription because the information may change. Do not stop taking lamotrigine without talking to your health care professional first as doing so can cause serious problems.

Read the MedWatch Safety Alert, including a link to the FDA Drug Safety Communication, at: https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm605628.htm

Lamotrigine可單用或與其他藥物併用,以治療2歲以上病人之癲癇(seizures)發作;亦可用於躁鬱症(bipolar disorder)病人的維持治療,以幫助延緩情緒(如:憂鬱、狂燥或輕度狂燥)發作。美國FDA發布藥物安全警訊,LamictalR(lamotrigine)會引起罕見但嚴重的反應,過度激活免疫系統,其免疫反應稱為噬血球性淋巴組織球增生症(hemophagocytic lymphohistiocytosis, HLH)。HLH常見症狀為持續發燒,通常高於華氏101℉(38.3℃),且可能導致血球細胞和器官(如肝臟、腎臟和肺部)出現嚴重問題。若未即時診斷治療,亦可能導致住院和死亡。因此,美國FDA要求新增此安全警訊於仿單中。

醫療專業人員應了解及時診斷和早期治療對於改善HLH及降低死亡率非常重要。由於HLH之早期表徵和症狀(如發燒和皮疹)無特異性,故其診斷通常很複雜。HLH也可能與其他嚴重的免疫相關不良反應混淆,如Drug Reaction with Eosinophilia and Systemic Symptoms(DRESS)。若病人出現發燒或皮疹且懷疑有HLH或其他嚴重的免疫相關不良反應,無法確認有其它病因,請立即停止lamotrigine治療。如果病人在使用lamotrigine治療過程中出現HLH症狀,建議病人立即就醫。如果病人有以下症狀的五種以上,則可確診為HLH:

1. 發燒和皮疹(fever and rash)
2. 脾臟腫大(enlarged spleen)
3. 血球減少(cytopenias)
4. 高三酸甘油脂血症(elevated levels of triglycerides) 或低纖維蛋白原血症( low blood levels of fibrinogen)
5. 血漿中儲鐵蛋白高於標準值(high levels of blood ferritin)
6. 骨髓、脾臟或淋巴切片見到噬血症(hemophagocytosis identified through bone marrow, spleen, or lymph node biopsy)
7. 自然殺手細胞(natural killer, NK)活性很低或缺失(decreased or absent NK Cell activity)
8. 血中CD25較高,顯示免疫細胞活化(elevated blood levels of CD25 showing prolonged immune cell activation)

若病人或其照顧者發現病人服用lamotrigine時出現HLH症狀,應立即聯繫醫療專業人員。 HLH可能出現於開始治療後的幾天到幾週內發生,可透過理學檢查、血液檢查及其他評估確診。HLH的可能症狀包括:

1. 發燒
2. 肝腫大; 症狀包含疼痛、壓痛或右上腹之肝臟區域異常腫脹
3. 淋巴結腫大
4. 皮膚疹
5. 皮膚或眼睛變黃
6. 不尋常的出血
7. 神經系統相關問題,例如:癲癇、行走困難、看不清楚等相關視力問題




[Posted 04/25/2018]