結核病藥物副作用處理指引

台北醫學大學․市立萬芳醫院

胸腔內科 余明治醫師

台灣結核病診治指引(新病人的藥物選擇與治療時間)

•優先處方：INH + RMP + EMB + PZA 2個月，再INH + RMP + EMB 4個月

•其次處方： INH + RMP + EMB 9個月–嚴重痛風病人，或無法忍受pyrazinamide的病人

•尚未得知藥敏試驗結果，Ethambutol必須全程使用–避免產生抗藥

•治療過程中藥敏試驗如發現isoniazid及rifampin均有效時，可停止使用ethambutol– Ethambutol的使用與否並不影響治療的效果與治療所需的時間

Adding Moxifloxacin is Associated with a Shorter Time to Culture Conversion in Pulmonary Tuberculosis

Int J Tuberc Lung Dis 2010;14:65–71

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 Taiwan1957–2001

2008 > 65y/o: 52% J Formos Med Assoc 2006;105:25–30

Factors Influencing Time to Smear Conversion in Patients with Smear-positive Pulmonary Tuberculosis

Respirology 2009;14:1012–1019

Radiological Presentation of Pulmonary Tuberculosis Infectedby the W-Beijing Mycobacterium tuberculosis Strain

Int J Tuberc Lung Dis 2009;13:1387–1392

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

Tuberculosis ChemotherapyStill a Double-edged Sword

Am J Respir Crit Care Med 2003; 167: 1461–2

何種藥物會產生肝毒性？

• Rifater – Isoniazid 80 mg– Rifampin 120 mg– Pyrazinamide 250 mg

• Ethambutol

• AST: 228• ALT: 105

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; 50–64 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– 25 mg/day

Isoniazid

• Central nervous system effects– Reported but have not been quantified– 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

Isoniazid 副作用

• 肝炎– 約10-20%的病人血中轉胺酶(transaminase)值會暫時輕微升高

• 多發生於用藥後十週內，但也可能在治療中任何期間出現• 通常不需停藥即會恢復正常

– 嚴重肝炎發生率約0.1-0.15%• 多出現在投藥後三個月內• 發生率和年齡有關

– 35歲以下約為0.3%、35-49歲1.2%、50-64歲2.3%• 常停藥後即可恢復正常

Isoniazid 副作用

• 周邊神經炎– 最常見的症狀為對稱性肢端麻木或刺痛感– 孕婦或合併糖尿病、尿毒症、癲癇，酗酒或營養不良之患者

最好同時投予pyridoxine(一般不建議常規使用pyridoxine)• 過敏性反應如發熱、皮疹、Stevens-Johnson syndrome、

溶血性貧血、血管炎、白血球偏低，及消化道反應

• 其他較不常見的神經毒性包括痙攣、毒性腦病變、視神經炎及萎縮、記憶障礙與毒性精神病症

• 類狼瘡症候群 (Lupus-like syndrome); 發生率小於1%

Rifampin (RIF): Orange Discoloration of Bodily Fluids (sputum, urine, sweat, tears)

Rifampin (RIF)

• Hepatotoxicity– Transient asymptomatic hyperbilirubinemia– 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

0.07–0.3% of patients

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副作用

• 食慾不振、噁心、嘔吐、胃痛、下痢、皮疹、肝炎• 間歇治療時，若劑量大於10 mg/kg，偶有血小板減少、

感冒的症狀、溶血性貧血及急性腎衰竭等副作用

• RMP會加速肝臟對藥物的代謝，同時服用其他經肝代謝的藥物時，如– 口服避孕藥，RMP會降低避孕藥的效果，故服用RMP期間應改

用其他避孕方法

– 同時服用coumadin類抗凝血劑、口服糖尿病藥、副腎皮質賀爾蒙、毛地黃製劑，RMP會減弱其作用

何種藥物會導致痛風發作？

• Rifater – Isoniazid– Rifampin– Pyrazinamide

• Ethambutol

Pyrazinamide

• Hepatotoxicity: about 1%• Gastrointestinal symptoms: common• Asymptomatic hyperuricemia

– An expected effect of the drug– Generally without adverse consequence

• Nongouty polyarthralgia: may occur in up to 40% of patients– The pain usually responds to aspirin or other nonsteroidal

antiinflammatory agents• Acute gouty arthritis

– Rare except in patients with preexisting gout • Transient morbilliform rash: usually self-limited

Pyrazinamide副作用• 肝毒性，在高劑量(3 gm/day)較常發生，使用劑量小於

25 mg/kg，發生率低於5%，與INH及RMP同時使用會增加肝毒性的機會

• PZA會干擾尿酸代謝而導致高尿酸血症，血清尿酸濃度小於13 mg/dl時，通常不需要藥物治療

• 偶爾合併關節痛，以水楊酸劑(salicylates)即可緩解，急性痛風則較為少見

• 皮疹及胃腸不適

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

• Cutaneous reactions– Skin reactions requiring discontinuation of the drug

occur in 0.2–0.7 % of patients

Ethambutol 副作用

• 眼球後視神經炎– EMB最常見的副作用，腎衰竭的病人較易發生– 與劑量有關，每日劑量小於15 mg/kg時，其發生率小於1%

– 症狀包括視力模糊、中央盲點及紅綠色盲– 一旦發現視力減退，若立即停藥，可恢復視力

• 過敏性反應、皮膚炎、皮膚搔癢、食慾不振、噁心、嘔吐、胃腸不適、腹痛

Fixed-Dose Combination Preparations

• Reducing the risk of monotherapy

• The ease of administration• The potential for reducing

medication errors

• Fixed-dose combinations are highly recommended

Streptomycin

• Ototoxicity (vestibular and hearing disturbances)– Most important adverse reaction– The risk is increased

• Age • Increasing single doses • The cumulative dose (especially above 100–120 g)

• Neurotoxicity– Circumoral parasthesias immediately after injection

• Nephrotoxicity

Streptomycin 副作用

• 常見的副作用為耳毒性、暈眩或聽力障礙• 腎毒性偶亦發生• 耳毒性或腎毒性較易發生在高齡病人，且與累積劑量及最高血中藥物濃度有關

– 累積劑量最好不超過120 gm

GOT: 777 U/L GPT: 1333 U/L

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– CBC、AST/ALT、bilirubin、uric acid、BUN/Cre 、 Sugar

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依附醫囑性，診療醫師應鼓勵病人（尤其是痰塗片陽性病人）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

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

• Patients be clinically monitored during treatment so that adverse effects can be detected promptly and managed properly

– Routine laboratory monitoring is not necessary

•

Follow-Up Evaluations (3)

•使用藥物後的第2、4、8週均應追蹤檢查

Follow-Up Evaluations (4)

• 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 15--20 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

To Assess the Risk-Benefit of Anti-TB Drugs

Transmission

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: 1359-74

• Six-month regimens – 2HERZ/4HR

• Nine-month regimen – 2HER/7HR

ATS/CDC/IDSA Am J Respir Crit Care Med 2003;167: 603–62

Alternative Regimens (1A)

Alternative Regimens (1B)

Symptom-based Approach to Managing Side-effects of Anti-TB drugs

• Minor adverse effects– Continue the TB

treatment and be given symptomatic treatment

• Major side-effect– The treatment or the

responsible drug is stopped

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

• Most adverse reactions are attributable to a single drug– Can be resolved by designing a treatment regimen to exclude

that agent

The Management Approach to Adverse Drug Reactions (2)

• 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

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

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

Liver Disease Caused by the Anti-TB Drugs

• All drugs should be stopped• If the patient is severely ill with TB and it is considered

unsafe to stop TB treatment– A non-hepatotoxic regimen consisting of streptomycin,

ethambutol and a fluoroquinolone should be started• Once drug-induced hepatitis has resolved

– The drugs are reintroduced one at a time– If symptoms recur or liver function tests become abnormal as

the drugs are reintroduced, the last drug added should be stopped

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 UpsetNausea, 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

Drug Administration• The first-line anti-TB medications should be administered

together as single dose rather than in divided 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• 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

結核藥物副作用的處理原則

• 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

– 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

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

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作症狀處理

• 使用isoniazid病人的末梢神經麻木，可以pyridoxine緩解

應即停止用藥 (1)

• 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13 mg/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

應即停止用藥 (2)

• 結核病人於治療中如發生上述藥物副作用時，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, 56 y/o, Uremia

GOT: 1704 U/LGPT: 1481 U/L

結核病藥物副作用處理指引台灣結核病診治指引�(新病人的藥物選擇與治療時間)投影片編號 3投影片編號 4Adding Moxifloxacin is Associated with a Shorter Time to �Culture Conversion in Pulmonary Tuberculosis�Int J Tuberc Lung Dis 2010;14:65–71Risk Groups/Factors for Adverse Antituberculous Drug ReactionsAge Transition of Tuberculosis Patients in Taiwan�1957–2001Factors Influencing Time to Smear Conversion in Patients with Smear-positive Pulmonary Tuberculosis�Respirology 2009;14:1012–1019Radiological Presentation of Pulmonary Tuberculosis Infected�by the W-Beijing Mycobacterium tuberculosis Strain� Int J Tuberc Lung Dis 2009;13:1387–1392Male, 69 y/oTuberculosis Chemotherapy�Still a Double-edged Sword � Am J Respir Crit Care Med 2003; 167: 1461–2投影片編號 12投影片編號 13何種藥物會產生肝毒性？IsoniazidIsoniazid: Peripheral NeurotoxicityIsoniazidIsoniazid 副作用Isoniazid 副作用Rifampin (RIF): Orange Discoloration of Bodily Fluids (sputum, urine, sweat, tears)Rifampin (RIF)Rifampin (RIF)Rifampin (RIF)Rifampin副作用何種藥物會導致痛風發作？PyrazinamidePyrazinamide副作用何種藥物可能會導致病患�視力減弱，甚至完全喪失？EthambutolEthambutol 副作用Fixed-Dose Combination Preparations投影片編號 32StreptomycinStreptomycin 副作用投影片編號 35Baseline Evaluations Follow-Up Evaluations (1)Follow-Up Evaluations (2)Follow-Up Evaluations (3)Follow-Up Evaluations (4)To Assess the Risk-Benefit of Anti-TB DrugsTransmissionAnti-TB chemotherapy: Three Basic PrinciplesAlternative Regimens (1A)Alternative Regimens (1B)Symptom-based Approach to Managing Side-effects �of Anti-TB drugsThe Management Approach to Adverse Drug Reactions (1)The Management Approach to Adverse Drug Reactions (2)Management of Drug-related Hepatitis (1)Management of Drug-related Hepatitis (2)Management of Drug-related Hepatitis (3)Liver Disease Caused by the Anti-TB DrugsManagement of Drug-related Hepatitis (3)Gastrointestinal Upset�Nausea, Vomiting, Poor Appetite, Abdominal PainDrug AdministrationRash結核藥物副作用的處理原則嚴密觀察即可，不必停藥症狀治療緩解，不必停藥應即停止用藥 (1)應即停止用藥 (2)Male, 56 y/o, Uremia 投影片編號 63