Adverse Drug Reactions to Anti-TB drugs Dr M A Jalil Chowdhury Professor of Medicine Bangabandhu...
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Transcript of Adverse Drug Reactions to Anti-TB drugs Dr M A Jalil Chowdhury Professor of Medicine Bangabandhu...
Adverse Drug Reactions toAnti-TB drugs
Dr M A Jalil ChowdhuryProfessor of Medicine
Bangabandhu Sheikh Mujib Medical University
Adverse Drug Reaction“Any response to a drug which is noxious and unintended, and which occurs at a doses used in man for prophylaxis, diagnosis, or treatment”-----WHO
• An exaggerated drug response
• an untoward effect on an organ system, different
from that being treated
• an allergic or hypersensitivity reaction
and idiosyncratic reaction
• a drug interaction that causes either an increased or
diminished response. contd
Adverse Drug Reactions
• Jaundice- Hepatitis
• Rash- Hypersensitivity reaction
Anti-tuberculosis drug-induced hepatotoxicity: concise up-to-date review.Tostmann A ,et al. J Gastroenterol Hepatol
2008:23;192-202
Anti-tuberculosis drug induced hepatitis
varied between 2% to 28%.
Hepatotoxicity of Anti-TB Drugs
Potentially Hepatotoxic Drugs Less Hepatotoxic
First Line ATDs INH (H) = 3 times Rifampicin (R) = 1 PZA (Z )= 10 times
First Line ATDs Aminoglycosides (AG) - SM, Ak, Km Capreomycin (Cm) Ethambutol (E)
Second Line ATDs Ethionamide (Eto) Prothionamide (Pto) PAS Rifabutin
Second Line ATDs Fluoroquinolones (FQs)
(Ofloxacin, Levofloxacin, Ciprofloxacin, Moxifloxacin)
Cycloserine (Cs)
Potential Risk Factors for Hepatotoxicity
• Increasing age• Malnutrition• Pre-existing CLD/ Elevated base line ALT• HIV infection• Pregnancy or post partum• Other hepatotoxic drugs• PZA in the regimen• Alcoholics• Slow acetylators
Drug-induced Hepatitis (DIH)
• Increase in AST/ALT > 3 times the ULN in presence of symptoms
OR
• Increase in AST/ALT > 5 times the ULN in the absence of symptoms
OR
• Serum bilirubin > 2 time the ULN or if clinically icteric
Scenario 1:
# Continue the Anti-TB drugs and Monitor
Mild or no symptom; less increase in liver enzymes (< 5 times). No clinical jaundice
Scenario 2: Developed jaundice and TB treatment can be deferred
It is very difficult to find out the cause. Anti-TB drugs
should be stopped until liver functions have returned to
normal. If liver function tests cannot be done, wait two
weeks after the jaundice has disappeared before
recommencing anti-TB treatment. It is strange, but
fortunate enough that in most cases, even in drug
induced hepatitis, the same drugs can be re-started
without return of hepatitis [TB/HIV–A Clinical Manual.
WHO 2nd ed.]. This can be done either gradually one by
one or all at once (if the hepatitis was mild). Contd.
Rechallenge schedule (ATS guideline)
• After ALT returns to less than 2 times the ULN >>> Rifampicin restarted with or without Ethambutol.>>>
• After 3 to 7 days, Isoniazid may be re-introduced, subsequently rechecking ALT.
• If symptom recurs or ALT increases, the last drug added should be stopped.
• PZA??
Scenario 3: Severely ill with Tuberculosis having mild/moderate to severe jaundice
A severely ill TB patient with drug induced
(or viral hepatitis) may die without anti-TB
drugs. In this case the patient should be
treated with a non-hepatotoxic regimen
consisting of SM, E ± fluoroquinolone(SE/SEQ) contd.
Scenario 3 contd.
• If the hepatitis has resolved the patient can then receive a continuation phase of 6-9 months of isoniazid and rifampicin (6HR).
• If hepatitis has not resolved SEQ should be continued for a total of 18-24 months.
Scenario 4: Acute Viral Hepatitis During Treatment of TB
• TB treatment should be deferred until the acute hepatitis has resolved. Re-start standard anti-TB regimen after resolution of acute hepatitis
• When it is necessary to treat during acute hepatitis: start with SM and E for 3 months
• If the hepatitis has resolved within 3 months then continue HR for 6 months (3 SE/6HR)
• If hepatitis has not fully resolved 12 SE
Scenario 5: Patient with pre-existing chronic liver disease
• Patient with established liver disease
should not receive pyrazinamide.
• Can receive the standard regimen
(2HRZE/4HR) provided no s/s or
laboratory evidence of active disease.
contd
Possible alternative Anti-TB drug regimens in liver
diseasesa) Two hepatotoxic drugs
• 9HRE
• 2 SHRE/6HR
• 6-9RZE
b) One hepatotoxic drug
• 2SHE/10HE
• 9 RE
c) No hepatotoxic drug
• 18-24SEQ
Management of Skin itching and rash/ Hypersensitivity reaction
(regime not containing thioacetazone)
They are commonest in the second to fourth week of treatment and rarely in the first week. Common with streptomycin ( & Th), less common with isoniazid, rifampicin, and ethambutol.
Management of Skin itching and rash/ Hypersensitivity reaction
• Itching –> exclude other obvious cause
• Antihistamine—> itching resolves
Continue Anti-TB drugs
Contd.
Management of Skin itching and rash/ Hypersensitivity reaction
• Itching not resolved+/ rash develops &/ fever—>STOP anti-TB drugs
• Wait for rash &/ fever to resolve
• Severe reaction –> supportive treatment
What next?
Management of Skin itching and rash/ Hypersensitivity reaction
The problem now is re-introducing TB treatment when we don’t know which anti-TB drug was responsible for the reaction. The table shows the standard approach to re-introducing anti-TB drugs one by one after a drug reaction.
Re-introduction of anti-TB drugs
The idea of drug challenging is to identify the drug responsible for the reaction.
Contd.
Re-introduction of anti-TB drugs
Give 2 anti-TB drugs which the patient has
not previously received.
Drug challenge starts with the anti-TB least
likely to be responsible for the reaction i.e.,
isoniazid. Thiacetazone and streptomycin
are the most likely to produce the reaction,
so test them last.
contd
Re-introduction of anti-TB drugs
Start with a small challenge dose/test dose as shown in table….If a reaction occurs to a small dose, it will not be such a bad reaction as to a full dose. There is usually a slight skin rash or fever within 2-3 hours. You can therefore test two doses a day, at 12-hour intervals, if the patient is in hospital. Gradually increase the dose over 3 days.
contd.
Challenging dose for detecting hypersensitivity reaction to anti-TB drugs/ Re-introduction of Anti-TB
drugs following drug reaction
Likelihood of causing a reaction
Challenge doses
Drug Day 1 Day 2 Day 3
Isoniazid Least likely 50mg 300mg 300mg
Rifampicin 75mg 300mg Full dose
Pyrazinamide 250mg 1gm Full dose
Ethambutol 100mg 500mg Full dose
Streptomycin Most likely 125mg 500mg Full dose
Re-introduction of anti-TB drugs
Repeat the procedure, adding in one drug at
a time. A reaction after adding a particular
drug identifies that drug as the one
responsible for the reaction.contd.
Re-introduction of anti-TB drugs
If the drug responsible for the reaction is pyrazinamide, Ethambutol, or streptomycin, resume anti-TB treatment without the offending drug. If possible, replace the offending drug with another drug. It may be necessary to extend the treatment regimen as a new start of treatment. This prolongs the total time if treatment, but decreases the risk of recurrence.
contd.
DESENSITIZATION
Rarely, patients develop hypersensitivity reactions to the 2 most potent ant-TB drugs, isoniazid and rifampicin. These drugs form the corner-stone of SCC. If an HIV-negative patient has had a reaction (but not a sever reaction) to isoniazid or rifampicin, it may be possible to desensitize the patient to the drug. However, never attempt desensitization in TB/HIV patients because of the high risk of serious toxicity. contd.
DESENSITIZATION• When starting to desensitize it is usually safer to
begin with a tenth of the normal dose. Then increase the dose b y a tenth each day, until the patient has the full dose on the tenth day. If the patient has a mild reaction to a dose, give the same dose instead of higher dose next day. If there is no reaction, go on increasing by a tenth each day. If the reaction is severe (which is unusual) go back to a lower dose and increase the doses more gradually.
• If the patient is in hospital, which should be, you can give the doses twice a day and save time.
contd.
DESENSITIZATION
• Once drug sensitization is over, give the drug as apart of the usual treatment regimen. If possible, while carrying out desensitization, give the patient 2 anti-TB drugs which the patient has not had before so as to prevent drug resistance.
• There is no evidence that challenge process gives rise to drug resistance. But desensitization process does give rise to the risk of resistance.