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1 結核病藥物副作用的處理 台北醫學大學 市立萬芳醫院結核病中心余明治醫師 Standard 8 All patients who have not been treated previously should receive an internationally accepted first-line treatment regimen using drugs of known bioavailability The initial phase should consist of two months of isoniazid, rifampicin, pyrazinamide, and ethambutol The preferred continuation phase consists of isoniazid and rifampicin given for four months 1

2 新病人的藥物選擇 使用劑量與治療時間 INH + RMP + EMB + PZA 2 個月, 再 INH + RMP + EMB 4 個月 一般使用劑量 ( 每日 ): Isoniazid: 通常給予 300 mg, 但如果體重過輕, 可依體重調整劑量, 大人為 5 mg/kg, 孩童為 mg/kg Ethambutol: 一般體重病人給予 800 mg Rifampin:50 kg 以上病人給予 600 mg,50 kg 以下病人給予 450 mg Pyrazinamide:45 kg 以下病人給予 1000 mg,46-75 kg 病人給予 1500 mg,76 kg 以上病人給予 2000 kg Rifater: 成人每 10 kg 給 1 錠, 至多給 5 錠 Rifinah: 成人 50 kg 以上給 Rifinah300 2 錠,50 kg 以下給 Rifinah150 3 錠 2

3 Risk Groups/Factors for Adverse Antituberculous Drug Reactions Advanced age Malnutrition Pregnancy Alcoholism Liver failure Chronic renal failure HIV infection Disseminated and advanced TB Atopy Anaemia Diabetes mellitus Family history of adverse anti-tb drug reactions Patients receiving irregular anti-tb treatment Patients receiving medication for other disorders, in addition to anti-tb drugs Age Transition of Tuberculosis Patients in Taiwan, >65y/o: 52% J Formos Med Assoc 2006;105:

4 Between July 2002 and December 2003 Male, 69 y/o Treatment regimen Rifater+ EMB Skin rash and itching GOT: 75 U/L, GPT:125 U/L Uric acid: 15.7 mg/dl 4

5 藥物劑量可能副作用藥物劑量可能副作用 Rifater(Rifampin 120mg, INH 80mg, Pyrazinamide 250mg) 衛肺特糖衣錠 Rifinah150 mg (Rifampin 150mg, INAH 100mg) 樂肺寧糖衣錠 150 Rifinah300 mg (Rifampin 300mg, INAH 150mg) 樂肺寧糖衣錠 300 Mide 500mg/tab (Pyrazinamide, PZA) 邁得錠 INAH 100mg/tab (Isoniazid) 肺速淨片 Rifampicin 150mg/cap (Rifampin, RIF) 立汎黴素膠囊 Myambutol 400mg/tab (Ethambutol, EMB) 孟表多錠 抗結核藥物 皮膚發疹或癢 腸胃不適 肢體麻刺感 肝功能異常 ( 食慾不振或黃疸 ) 關節酸痛 橙色尿 ( 正常現象 ) 皮膚發疹或癢 腸胃不適 肢體麻刺感 肝功能異常 ( 食慾不振或黃疸 ) 橙色尿 ( 正常現象 ) 皮膚發疹或癢 腸胃不適 肢體麻刺感 肝功能異常 ( 食慾不振或黃疸 ) 橙色尿 ( 正常現象 ) 肝功能異常 ( 食慾不振或黃疸 ) 關節酸痛 皮膚發疹或癢 腸胃不適 肢體麻刺感 肝功能異常 ( 食慾不振或黃疸 ) 食慾不振 皮膚發疹或癢皮膚發疹或癢 腸胃不適 肝功能異常 ( 食慾不振或黃疸 ) 橙色尿 ( 正常現象 ) 視覺模糊 皮膚發疹或癢 腸胃不適 Cycloserine (Cycloserine) 250mg 惠絲菌素膠囊 Cravit 500mg/tab (Levofloxacin) 可樂必妥 Tubax 250mg/tab (Prothionamide) 畢癆疾糖衣錠 PAS 500mg/tab (P-aminosalicylic acid) 鈣派斯膜衣錠 Avelox (Moxifloxacin, 400 mg) 威洛速錠 Streptomycin 1gm/vial (Streptomycin, SM) 鏈黴素 Kanamycin 1gm/vial (Kanamycin,KM) 健黴素 請勿自行停藥, 若有身體不舒服時, 敬請立即回診或聯絡醫師 護理師及藥師協助處理! 皮膚發疹或紅斑 情緒低落 頭暈 頭痛 倦怠 ( 少見 ) 誘發癲癇 ( 少見 ) 頭痛 ( 暈 ) 皮膚發疹或癢 腸胃不適 不可與胃藥 牛奶合用噁心 嘔吐 疲倦 頭痛 ( 暈 ) 肝功能異常 ( 食慾不振或黃疸 ) 肢體麻刺感 ( 少見 ) 情緒抑鬱 ( 少見 ) 視覺模糊( 少見 ) 噁心 嘔吐 皮膚發疹或紅斑 肝功能異常 ( 食慾不振或黃疸 ) 噁心 嘔吐 疲倦 虛弱 皮膚紅疹 關節腫脹疼痛 ( 肌腱發炎, 少見 ) 不可與胃藥合用 聽力受損 耳鳴 腎毒性 暈眩 聽力受損 耳鳴 腎毒性 暈眩 台北醫學大學 萬芳醫學中心 B 祝您早日康復! 結核病中心 / 藥劑部謹製 下列何種藥物會產生肝毒性? Rifater Isoniazid Rifampin Pyrazinamide Ethambutol GOT: 100 U/L GPT: 162 U/L 5

6 Isoniazid Asymptomatic elevation of aminotransferases Elevations up to five times the upper limit of normal: 10 20% Usually return to normal even with continued administration of the drug Clinical hepatitis: the risk increases Increasing age: < 20 y/o: uncommon; y/o: 2% Underlying liver disease Heavy alcohol consumption Fatal hepatitis Associated with continued administration of INH despite onset of symptoms of hepatitis Isoniazid: Peripheral Neurotoxicity Dose related Uncommon (< 0.2%) at conventional doses The risk is increased Associated with neuropathy Nutritional deficiency Diabetes HIV infection Renal failure Alcoholism Pregnant and breastfeeding women Pyridoxine supplementation 6

7 Isoniazid Central nervous system effects such as dysarthria, irritability, seizures, dysphoria, and inability to concentrate Lupus-like syndrome Hypersensitivity reactions: such as fever, rash, Stevens- Johnson syndrome, hemolytic anemia, vasculitis, and neutropenia are rare Rifampin (RIF): Orange Discoloration of Bodily Fluids (sputum, urine, sweat, tears) 7

8 Rifampin (RIF) Hepatotoxicity Transient asymptomatic hyperbilirubinemia May occur in 0.6% of patients More severe clinical hepatitis Typically: a cholestatic pattern Rifampin (RIF) Cutaneous reactions ( Pruritis with or without rash): 6% Generally self-limited Continued treatment with the drug may be possible More severe, occurring in % of patients 8

9 Rifampin (RIF) Gastrointestinal reactions (nausea, anorexia, abdominal pain) Rarely severe enough to necessitate discontinuation of the drug Flu-like syndrome More likely to occur with intermittent administration of a higher dose Severe immunologic reactions: (rare < 0.1%) Thrombocytopenia, hemolytic anemia, acute renal failure Rifampin (RIF) Drug interactions due to induction of hepatic microsomal enzymes Reductions in serum concentrations of common drugs Such as oral contraceptives, methadone, and warfarin Bidirectional interactions ti between rifamycins i and antiretroviral agents 9

10 下列何種藥物會導致痛風發作? Rifater Isoniazid Rifampin Pyrazinamide Ethambutol Pyrazinamide Hepatotoxicity: about 1% Gastrointestinal symptoms: common Nongouty polyarthralgia: may occur in up to 40% of patients The pain usually responds to aspirin or other nonsteroidal antiinflammatory agents Asymptomatic hyperuricemia An expected effect of the drug Generally without adverse consequence Acute gouty arthritis Rare except in patients with preexisting gout Transient morbilliform rash: usually self-limited 10

11 下列何種藥物可能會導致病患視力減弱, 甚至完全喪失? Rifater Isoniazid Rifampin Pyrazinamide Ethambutol Ethambutol Retrobulbar neuritis Decreased visual acuity or red-green color discrimination Dose related Minimal risk at a daily dose of 15 mg/kg In patients with renal insufficiency Peripheral neuritis A rare adverse effect Cutaneous reactions Skin reactions requiring discontinuation of the drug occur in % of patients 11

12 Fixed-Dose Combination Preparations Reducing the risk of monotherapy The ease of administration The potential for reducing medication errors 12

13 Streptomycin Ototoxicity (vestibular and hearing disturbances) Most important adverse reaction The risk is increased Age Increasing single doses The cumulative dose (especially above g) Neurotoxicity Circumoral parasthesias immediately after injection Nephrotoxicity GOT: 777 U/L GPT: 1333 U/L 13

14 Baseline Evaluations Measurements of AST, bilirubin, alkaline phosphatase, and serum creatinine and a platelet count should be obtained for all adults (uric acid and sugar) Testing of visual acuity and color vision should be performed when EMB is to be used All patients with tuberculosis have counseling and testing for HIV infection (U.S.) 使用藥物前應安排血液及生化檢查, 建議項目如下 : CBC AST/ALT Bilirubin Uric Acid BUN/Cre Follow-Up Evaluations (1) It is essential that patients have clinical evaluations at least monthly To identify possible adverse effects of the anti-tb medications To assess adherence 為能確實掌握病人服藥順服度, 診療醫師應鼓 為能確實掌握病人服藥順服度, 診療醫師應鼓勵病人接受 DOT, 觀察用藥, 尤其不應以開立慢性病連續處方箋的方式減少病人回診追蹤的頻率 14

15 Follow-Up Evaluations (2) It is not necessary to monitor liver or renal function or platelet count for patients being treated with first-line drugs unless there were abnormalities at baseline or there are clinical reasons to obtain the measurements Patients who have stable abnormalities of hepatic or renal function at baseline should have repeat measurements early in the course of treatment, then less frequently to ensure that there has not been worsening 使用藥物後的第 週均應追蹤檢查 Follow-Up Evaluations (3) Patients receiving EMB should be Questioned regarding visual disturbances at monthly intervals Monthly repeat testing of visual acuity and color vision is recommended for Receiving an EMB dose exceeding mg/kg Receiving the drug for more than 2 months 使用 Ethambutol 病人, 應按月檢查視力及辨色力 15

16 Tuberculosis Chemotherapy Still a Double-edged Sword Am J Respir Crit Care Med 2003; 167: Transmission 16

17 To Assess the Risk-Benefit of Anti-TB Drugs Anti-TB chemotherapy: Three Basic Principles Multiple drugs to which the organisms are susceptible The drugs must be taken regularly Therapy must continue for a sufficient period of time ATS/CDC Am J Respir Crit Care Med 1994; 149: Six-month regimens 2HERZ/4HR Nine-month regimen 2HER/7HR ATS/CDC/IDSA Am J Respir Crit Care Med 2003; 167:

18 Alternative Regimens (1) The potential role of a fluoroquinolone and optimal length of therapy have not been defined ATS/CDC/IDSA Am J Respir Crit Care Med 2003; 167: Building a Treatment Regimen for MDR-TB 18

19 Alternative Regimens (2) Treatment becomes greatly complicated when any of the first-line drugs cannot be used Must only be cared by specialist physicians If pyrazinamide (Z) cannot be used: 2HRE/7HR If isoniazid (H) cannot be used: 2REZ/10RE If rifampicin (R) cannot be used: 2HEZ(S)/10HE If ethambutol t (E) cannot be used: 2HRZS/4HR 各類結核病人的治療建議簡表 病人分類 建議治療方式 藥物抗藥或已知藥敏試驗結果之藥物副作用 單一藥物抗藥 1. INH 不能用 :EMB + RMP + PZA 6-9 個月 ( 治療 2 個月時痰培養陽性, 治療 9 個月 ) 2. RMP 不能用 :INH + EMB + PZA ± FQN/INH + EMB + FQN 18 個月 ( 其中 INH + EMB + PZA ± FQN 至少 2 個月 ) 3. EMB 不能用 : 優先 INH + RMP + PZA 2 個月 /INH + RMP 4 個月其次 INH + RMP 9 個月 4. PZA 不能用 :INH + RMP 9 個月二種以上藥物抗藥 1. INH + RMP 不能用 :EMB+PZA+FQN+TBN+SM 至少 6 個月 /EMB + PZA + FQN + TBN 個月 2. INH + RMP + EMB/PZA/SM 不能用 :FQN+TBN+ PAS/CS + KM/AM, 加 EMB/PZA 中可用者至少 6 個月, 再 FQN + TBN + PAS/CS, 加 EMB/PZA 中可用者 個月 3. INH + EMB 不能用 :RMP + PZA + FQN 9 個月 4. RMP + EMB 不能用 :INH + PZA + FQN + SM 6 個月 /INH + PZA + FQN 12 個月 5. EMB + PZA 不能用 :INH + RMP 9 個月 6. INH + PZA 不能用 :RMP + EMB + FQN 9 個月 7. RMP + PZA 不能用 :INH + EMB + FQN + SM 6 個月 /INH + EMB + FQN 12 個月 19

20 Management of Common Adverse Effects Attuned to the potential for adverse effects First-line drugs not be stopped without adequate justification Mild adverse effects Can generally be managed with symptomatic therapy More severe effects Drugs must be discontinued The Management Approach to Adverse Drug Reactions (1) With regards to the anti-tb treatment regimen following an adverse reaction As many first-line drugs should be tried as possible More effective and less toxic than the second-line agents Early detection is essential Clearly affect the associated morbidity and mortality Clearly affect the associated morbidity and mortality Most adverse reactions are attributable to a single drug Can be resolved by designing a treatment regimen to exclude that agent 20

21 The Management Approach to Adverse Drug Reactions (2) Evaluating the severity of the adverse reaction and establishing whether it is dose dependent Making the necessary dose adjustments Mild or moderate adverse reactions To provide symptomatic treatment for the reaction, adjust the drug dose, or change the timing of administration If these measures prove to be unsuccessful, suspension of treatment should then be considered A serious adverse reaction All treatment should be suspended Management of Drug-related Hepatitis (1) The first-line antituberculosis drugs, INH, RIF, and PZA, can cause drug-induced liver injury An asymptomatic increase in AST concentration occurs in nearly 20% of patients treated with the standard four-drug regimen In most patients asymptomatic aminotransferase elevations In most patients, asymptomatic aminotransferase elevations resolve spontaneously In addition to AST elevation, occasionally there are disproportionate increases in bilirubin and alkaline phosphatase This pattern is more consistent with rifampin hepatotoxicity 21

22 Management of Drug-related Hepatitis (2) If AST levels are more than five times the upper limit of normal (with or without symptoms) or more than three times normal in the presence of symptoms hepatotoxic drugs should be stopped immediately and the patient evaluated carefully Drug-induced hepatitis is usually a diagnosis of exclusion Serologic testing for hepatitis A, B, and C should be performed Carefully regarding symptoms suggestive of biliary tract disease Exposures to other potential hepatotoxins, particularly alcohol and hepatotoxic medications Management of Drug-related Hepatitis (3) To give at least three nonhepatotoxic anti-tb drugs Until the specific cause of hepatotoxicity can be determined and an appropriate longer term regimen begun Restarted one at a time After the AST concentration returns to less than two times the upper limit of normal In patients with elevated baseline AST from preexisting liver disease, drugs should be restarted when the AST returns to near baseline levels RIF: restarted first 22

23 Management of Drug-related Hepatitis (3) 治療改為併用 SM EMB 或 Quinolone 等兩種以上抗結核藥物 肝功能恢復後, 依 INH RMP PZA 順序, 再重新進行小量漸進式給藥試驗 If RIF and INH are tolerated, and hepatitis was severe, PZA should be assumed to be responsible and should be discontinued Gastrointestinal Upset Nausea, Vomiting, Poor Appetite, Abdominal Pain Many of the antituberculosis drugs can cause gastrointestinal upset Particularly in the first few weeks of therapy Serum AST and bilirubin should be measured The initial approach to gastrointestinal intolerance, not associated with hepatic toxicity To change the hour of drug administration and/or to administer the drugs with food 23

24 Drug Administration The first-line anti-tb medications should be administered together th as single dose rather than in divided id d doses Ingestion with food delays or moderately decreases the absorption of anti-tb drugs The effects of food are of little clinical significance The wide therapeutic margin of the first-line agents Epigastric distress or nausea with the first-line drugs Dosing with food is recommended Preferable to splitting a dose or changing to a second-line drug Antacids have minimal effects on the absorption of the first-line anti-tb drugs Rash All drugs used in treating tuberculosis can cause a rash All drugs used in treating tuberculosis can cause a rash The rash may be minor (affecting a limited area or being predominantly manifested as itching) Antihistamines should be given for symptomatic relief All anti-tb medications can be continued If there is a generalized erythematous rash (especially if it is associated with fever and/or mucous membrane involvement) All drugs should be stopped immediately When the rash is substantially improved The medications can be restarted one by one 24

25 發生結核藥物副作用的處理原則 (1) 結核藥物副作用無法獲得妥善處理是病人不能按規服藥的主要原因 診療醫師如對其副作用掉以輕心 或草率處理, 往往會使病人對治療失去信心 斷續用藥, 導致續發性抗藥性菌株的產生, 後果非常嚴重 因此病人抱怨的副作用, 無論如何微不足道 對身體無傷 ; 無論多麼千奇百怪 匪夷所思, 只要足以影響病人服藥意願, 診療醫師即應認真面對 發生結核藥物副作用的處理原則 (2) 該副作用是否嚴密觀察即可, 不必停藥? 無症狀 AST/ALT 5 倍以內的輕度上昇, 或血球輕微減少 輕微的皮膚搔癢 初用藥時的全身倦怠, 可予心理支持, 或改睡前服藥 血清尿酸濃度在 13 mg/dl 以下時, 請病人多喝水, 暫不停藥, 也不用降尿酸藥物 25

26 發生結核藥物副作用的處理原則 (3) 該副作用可否症狀治療緩解, 不必停藥? 病人發生腸胃不適症狀, 可將藥物改飯後服用, 或併用 Primperan 等來緩解 輕度皮膚搔癢, 可開立長效抗組織胺劑來緩解 輕度痛風 關節酸痛, 先以短暫非類固醇抗發炎藥物 (NSAID) 作症狀處理 使用 Isoniazid 病人的末梢神經麻木, 可以 Pyridoxine 緩解 發生結核藥物副作用的處理原則 (4A) 下列副作用應即停止用藥 : 下列副作用應即停止用藥 有肝炎症狀 AST/ALT 3 倍以上的上昇, 或無肝炎症狀 AST/ALT 5 倍以上的上昇 嚴重之貧血 血小板下降 泛血球寡少症, 及急性腎功能受損 紫斑 嚴重無法緩解之痛風症狀 或血清尿酸值高於 13mg/dL 無法改善 或高血清尿酸症併急性腎功能惡化 嚴重無法緩解之皮疹搔癢或併發 St Jh d 嚴重無法緩解之皮疹 搔癢 或併發 Steven-Johnson syndrome 視力模糊 其他任何導致病人無法規則服藥的副作用 或不適反應 26

27 發生結核藥物副作用的處理原則 (4B) 結核病人於治療中如發生此類藥物副作用時 除非該副作用非常明確是由某一特定結核藥物所致 ( 如視力模糊之於 Ethambutol 高血清尿酸之於 Pyrazinamide), 可以直接停止該藥 建議先停止所有可能造成此副作用之結核藥物, 俟副作用消失後, 以逐一緩慢嘗試用藥方式 (Rechallenge) 找出導致此副作用之藥物 Male, 63 y/o, DM (1) DST: all susceptible Treatment HERZS+Rifabutin +Moxifloxacin Skin rash, fever and liver function abnormalities??? 27

28 95/10/19 Isolation Symptomatic treatment 95/10/23: INH 100 mg qd 95/10/24: INH 300 mg qd 95/10/26: PZA 500 mg qd 95/10/28: PZA 1500 mg qd 95/10/31: RIF 150 mg qd 95/11/1: RIF 450 mg qd Male, 63 y/o, DM (2) 95/10/19 95/11/6 95/11/1095/11/17 GOT GPT /12/1 96/1/26 96/3/23 96/5/18 GOT GPT Male, 56 y/o, Uremia GOT: 1704 U/L GPT: 1481 U/L 28

29 Male, 56 y/o, Uremia Thank You for Your Attention! 29