tb_adverse_drug_management_อ_วิชัย

การประชุมวิชาการเรื่อง เภสัชบําบัดในผูปวยวัณโรค วันที่ 21 22 กรกฎาคม 2554วนท 21 - 22 กรกฎาคม 2554

ณ หองกัญญาลักษณ ชั้น 3 โรงแรมโฟรวิงส สุขุมวิท 26 กรุงเทพมหานคร

Prevention and Management ofPrevention and Management of Adverse drug reaction from

A ti t b l i DAnti-tuberculosis Drug

อ.ภก.ดร.วิชัย สันติมาลีวรกุลB. Pharm, M. Pharm, Ph.D. (Pharm Care),

Board Certified Pharmacotherapy

Prevention and Management of Adverse drug ti f A ti t b l i Dreaction from Anti-tuberculosis Drug

Isoniazid

Rifampicin

EthambutolEthambutol

Pyrazinamide


Isoniazid

RifampicinLiver injury

Cutaneous reactionsEthambutol

Pyrazinamide

Cutaneous reactions

Ocular toxicityy

Clinical presentation ?

Dose related ?

Risk factor ?

Duration related ?

Reversible ?

Managable ?


Liver injury

Cutaneous reactionsCutaneous reactions

Ocular toxicity


Liver injuryj y

Definition of hepatotoxicity according to the WHO Adverse Drug Reaction TerminologyWHO Adverse Drug Reaction Terminology

TABLE: CLINICAL HEPATITIS IN PERSONS TAKINGISONIAZID AND RIFAMPIN

D g N mbe of Patients Clinical

ISONIAZID AND RIFAMPIN

Drug Number of Studies

Patients Clinical hepatitis (%)

INH 6 38 257 0 6INH 6 38,257 0.6

INH plus other drugs, but not RIF

10 2,053 1.6but not RIF

INH plus RIF 19 6,155 2.7

RIF l th d 5 1 264 1 1RIF plus other drugs, but not INH

5 1,264 1.1

Chest 1991 Feb;99(2):465-71.

Figure: Isoniazid metabolismFigure: Isoniazid metabolism

Metabolism of isoniazid and its influence by alcohol and rifampicin.p

The management of anti-tuberculosis Drug induced hepatotoxicityDrug induced hepatotoxicity

INH, RIF, and PZA should be stopped immediately

Testing for h titi ihepatitis viruses

A, B, and C ?

E t thExposure to other possible

hepatotoxins ?

Two ormore antituberculosismedications without hepatotoxicity, p y,such as EMB, SM, amikacin/kanamycin, or a fluoroquinolone

First-line medications should be restarted in sequential fashion

The management of anti-tuberculosis Drug induced hepatotoxicity

Figure: Monitoring for hepatotoxicity during treatment of TB disease


Liver injuryj y

Treatment of tuberculosis: WHO guidelines

WHO Library Cataloguing inWHO Library Cataloguing-in-Publication Data:Treatment of tuberculosis:Treatment of tuberculosis: guidelines – 4th ed.WHO/HTM/TB/2009.420

Management of drug-induced hepatitisg g p

The reaction has resolved, rifampin may be restarted +/- ethambutol

After 3–7 days, isoniazid may be reintroduced

If symptoms recur or liver function tests become abnormal as the drugs are reintroduced the last drug added should be stoppeddrugs are reintroduced, the last drug added should be stopped

d b d d ld f hPyrazinamide can be reintroduced in a milder case of hepatotoxicity


A patient with liver injury

- All responsible anti-TB drugs must be stopped (isoniazid, rifampicin, pyrazinamide)( , p , py )

- A non-hepatotoxic regimen consisting of streptomycin, ethambutol and a fluoroquinolone should be startedq

- Wait for liver function tests to revert to normal and clinical symptoms (nausea, abdominal pain) to resolveclinical symptoms (nausea, abdominal pain) to resolve

- If do not resolve and the liver disease is severe, the non-hepatotoxic regimen consisting of streptomycin,hepatotoxic regimen consisting of streptomycin, ethambutol and fluoroquinolone for 18–24 months


A patient with liver injuryp j y

The reaction has resolved, reintroduce one by one (RFP)The reaction has resolved, reintroduce one by one (RFP)

After 3–7 days, isoniazid may be reintroducedAfter 3 7 days, isoniazid may be reintroduced

If symptoms recur or liver function tests become abnormalIf symptoms recur or liver function tests become abnormal as the drugs are reintroduced, the last drug added should be stopped


Rifampicin cannot be usedp

- Isoniazid, ethambutol and streptomycin for 2 months followed by 10 months of isoniazid and ethambutolfollowed by 10 months of isoniazid and ethambutol

Isoniazid cannot be used

- Rifampicin, pyrazinamide and ethambutol for 6–9 months

Isoniazid nor rifampicin can be used

Th h t t i i t t i th b t l- The non-hepatotoxic regimen: streptomycin, ethambutol and a fluoroquinolone for 18–24 months.


Hepatitis with jaundice during the intensive phase p j g p

Restart the same drugs EXCEPT pyrazinamide replace with fstreptomycin to complete the 2-month of initial therapy

rifampicin and isoniazid for the 6-month continuation phase.

Hepatitis with jaundice during the continuation phase:

Restart isoniazid and rifampicin to complete the 4-month continuation phase of therapy4-month continuation phase of therapy.


Hepatitis with jaundice during the continuation phase:Hepatitis with jaundice during the continuation phase:

Restart isoniazid and rifampicin to complete the 4-month continuation phase of therapy.


Liver injury

Management of drug-induced liver injuryg g j y

INH at dosage of 100 mg/day from day 1maximum dosage from day 4g y

If there is no further reaction standardh h b

RIF at dosage of 150 mg/day from day 8maximum dosage from day 11

chemotherapy can be continued and anyalternative drugs maximum dosage from day 11 introduced temporarilycan then be withdrawn

PZA at dosage of 500 mg/day from day 15i d f d 18maximum dosage from day 18


Liver injury

คูมืออบรม แนวทางมาตรฐานํ ิ ั โการดําเนินงานควบคุมวัณโรคสําหรับคลินิกวัณโรค

สํานักวัณโรค กรมควบคุมโรค 2552กระทรวงสาธารณสุข 2552

Management of drug-induced liver injury

มีอาการทางคลินกิ เชน คลื่นไส อาเจียน ตัวเหลือง ตาเหลือง

g g j y

AST > 5 เทา ของคาปกติพิกัดบน โดยไมตองมีอาการ

ประเมินอาการและตรวจ AST ถาไมเพิ่มหรือเล็กนอย Challenge ตอไป

Management of drug-induced liver injuryg g j y

ิ่ Ch ll R ึ่ ใ ใ ี ั ื ิ่จะเริม Challenge ยา R ซึงใชในแนวทางเดียวกนั คือ คอย ๆ เพิมขนาดยา R จนถึง Full dose ในเวลา 5 – 7 วัน

ประเมนิอาการและตรวจ AST ถาไมเพิ่มหรือเล็กนอยไมตอง Challenge ยา Z

ในระหวาง Challenge ยาตัวใดตัวหนึ่งแลวเกิดอาการคลื่นไส อาเจียนมาก C a e geตรวจ AST เพิ่มขึ้นชัดเจน หยุด Challenge ทันที รอจนอาการดีขึ้น เริ่ม Challenge ยาตัวถัดไป

Arm I: isoniazid, rifampicin, and pyrazinamide simultaneously at full dosagesimultaneously at full dosage

Arm II: based on the American Thoracic Society guidelinesArm III: based on British Thoracic Society guidelinesArm III: based on British Thoracic Society guidelines

Clinical Infectious Diseases 2010; 50:833–839

Table: Comparison of Maximum Derangement of Liver Function Test Results in the 3 Arms after Reintroduction of Anti-TuberculosisResults in the 3 Arms after Reintroduction of Anti Tuberculosis Drugs and Recurrent Rate of Drug-Induced hepatotoxicity


Concerned issues in liver injury management

- There are a few of clinical data to compare the safety among p y gstrategies

The incidences of liver injury in each drug from various- The incidences of liver injury in each drug from various regions are different

- The exact mechanism of liver injury is unknown

- The role of pyrazinamide for reintroduction is controversiale o e o py a a de o e t oduct o s co t o e s a


Liver injury


Ocular toxicity


Cutaneous reactions

Management of cutaneous reactionsa age e t o cuta eous eact o s

A ti t d l it hi ith t hA patient develops itching without a rash

- Treatment with antihistamines and skin moisturizing

- Continue TB treatment while observing the patient closely

A patient with skin rash

All esponsible anti TB d gs m st be stopped-All responsible anti-TB drugs must be stopped (isoniazid, rifampicin, pyrazinamide)

Th ti h l d i t d b-The reaction has resolved, reintroduce one by one,


starting with the drug least likely to be cause: RIF

A reaction afterA reaction after adding in a particular drug identifies

Full dose of isoniazid3 d identifies

that drug as causative agent

over 3 days

Then EMB, or PZA If no rash appears after the first three drugs have been restarted

Except mild case and the fourth

the first three drugs have been restartedthe fourth drug should not be restarted

drug is considered essential


Cutaneous reactions


A ti t d l it hi ith t hA patient develops itching without a rash

- Treatment with antihistamines and skin moisturizing

- Continue TB treatment while observing the patient closely

A patient with skin rash

- All responsible anti-TB drugs must be stopped (isoniazid, rifampicin, pyrazinamide)

- The reaction has resolved, reintroduce one by one, y


starting with the drug least likely to be cause (RFP or INH)

a small challenge dose, such as 50 mg isoniazidThe dose is gradually increased over 3 days.The dose is gradually increased over 3 days.

Full dose of the 1st drug, add in a new one

A reaction after adding in a particular drug identifies that drug as causative agentthat drug as causative agent


Cutaneous reactions


- หยุดยาทุกตัวทันที ิ ใ ั ื่ 3 ั ไป - พิจารณาใชยาตัวอืน อยางนอย 3 ตัวไปกอน

- เริ่ม Challenge ดวยยา (E, R, H และ Z) ทีละตัว ตัวละ 2 - 3 วัน- ถามี rash รนแรงขึ้นระหวาง Challenge หยดยาตัวลาสด- ถาม rash รนุแรงขนระหวาง Challenge หยุดยาตวลาสุด

วันที่ 1 ใหยา E ขนาด 400 มิลลิกรมัวนท 1 ใหยา E ขนาด 400 มลลกรม วันที่ 2 ใหยา E ขนาด 800 มิลลิกรมั วันที่ 3 ใหยา R ขนาด 300 มิลลิกรมั วันที่ 4 ใหยา R ขนาด 450 มิลลิกรมั วันที่ 5 ใหยา H ขนาด 100 มิลลิกรมั ั ี ่ 6 ใ H 300 ิ ิ ัวันที 6 ใหยา H ขนาด 300 มิลลิกรมั วันที่ 7 ใหยา Z ขนาด 500 มิลลิกรมั วันที่ 8 ใหยา Z ขนาด 1500 มิลลิกรมัวนท 8 ใหยา Z ขนาด 1500 มลลกรม


ี่ ั โ (ไ )ขอเสนอแนะของผูเชียวชาญวัณโรค (ไทย) 1 กรณีตับอักเสบ แนะนาํให Challenge ยา H Z และ R เพราะ1. กรณตบอกเสบ แนะนาให Challenge ยา H, Z และ R เพราะ

พบวา R เปนสาเหตุของอาการตับอักเสบ ตัวเหลือง ตาเหลือง บอยกวา Zบอยกวา Z

2. กรณีผื่นผิวหนงัให Challenge ยา E, R, H และ Z ตามลําดับ

Please carefully transfer this clinical data

t ti i l lif it tito practice in real life situation

Severe form of skin disorderStevens-Johnson syndrome

Severe form of skin disorderStevens-Johnson syndrome

Reintroducing antituberculosis therapy after Stevens-Johnson syndrome in human immunodeficiency virus y yinfected patients with tuberculosis: role of desensitization

- Eight patients, including six men who had developed SJS while on four-drug anti-TB therapy

- All patients were treated with dexamethasone 12 mg/day. After complete resolution, reintroduction of antitubercular drugs

International Journal of Dermatology 2001, 40, 472-484

Table: Reintroduction schedule

International Journal of Dermatology 2001, 40, 472-484

Concerned issues in cutaneous toxic management

- There are a few of clinical data to compare the safety among p y gstrategies

The exact mechanism of cutaneous is unknown- The exact mechanism of cutaneous is unknown

- The role of full or gradual dose not desensitized dose is not clear

- The role of pyrazinamide for reintroduction is controversial


Liver injury


Ocular toxicity

Figure: The mitochondrial pathway to apoptosis. Accumulation of reactive oxygen species (ROS) leads to a decrease in the electrical potential across the mitochondrial membrane, which allows for an opening of the mitochondrial permeability transition pore (MPTP) releasing cytochrome c (Cyt c) into the cytosol Cytochrome c binds topore (MPTP), releasing cytochrome c (Cyt c) into the cytosol. Cytochrome c binds to apoptosis activating factor-1 (APAF-1), which activates procaspase-9, which triggers the caspase cascade and apoptosis

J Neuro Ophthalmol, 2008;28(4) 265-268

Ethambutol induced occular toxicity

Clinical presentationClinical presentation

- Commonly, bilateral progression- Painless blurring of vision - Decreased colour perception- Central vision is most commonly affected- Classically, red-green colour changes

Hong Kong Med J 2006;12:56-60


Dose-related:Dose related:

The incidence of ethambutol-related optic neuritis

- > 35 mg/kg per day 18%- 25 mg/kg per day: 5 -6% - 15 mg/kg per day <1%

Risk factors:Risk factors:- Abnormal renal function - Diabetes mellitus- Diabetes mellitus - Smoking- Drinking alcoholg



Duration-relatedU ll d l d t l t 1 5 th ft t t t- Usually delayed, at least 1.5 months after treatment

- The mean interval between onset of therapy and toxic effects: 3-5 months- Manifestations of toxicity as late as 12 months after therapy- Manifestations of toxicity as late as 12 months after therapy

Reversibility- Classically, reversible on discontinuation of ethambutol - Permanent visual impairment without recovery has been reported within

f ll d ha follow-up period 6 months - 3 years - No risk factor was identified for the poor visual recovery

The statistically significant difference in visual recovery between patients- The statistically significant difference in visual recovery between patients aged >60 yrs and <60 yrs reported by 20% and 80%,respectively.



Management- Immediately discontinue- Refer to an ophthalmologist - Severe ocular toxicity: stop both isoniazid and ethambutol- If isoniazid is not stopped, stopp 6 weeks later if there is no

improvement in vision


Table: Dosing recommendations for adult patients with reduced renal function and for patients receiving hemodialysisreduced renal function and for patients receiving hemodialysis

Am J Respir Crit Care Med Vol 167. pp 603–662, 2003


Isoniazid

RifampicinLiver injury

Cutaneous reactionsEthambutol

Pyrazinamide

Cutaneous reactions

Ocular toxicityy

Clinical presentation ?

Dose related ?

Risk factor ?

Duration related ?

Reversible ?

Managable ?

Thank you for your attention

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tb_adverse_drug_management_อ_วิชัย

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