Transcript Adverse Drug Reactions to Anti-TB drugs by Dr

Adverse Drug Reactions to
Anti-TB drugs
Dr M A Jalil Chowdhury
Professor 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
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•
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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:
Mild or no symptom; less increase in liver
enzymes (< 5 times). No clinical jaundice
# Continue the Anti-TB drugs and Monitor
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 restarted 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).
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 reintroduced, 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 diseases
a) 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 reintroducing 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
Drug
Challenge doses
Day 1
Day 2
Day 3
50mg
300mg
300mg
Rifampicin
75mg
300mg
Full dose
Pyrazinamide
250mg
1gm
Full dose
Ethambutol
100mg
500mg
Full dose
125mg
500mg
Full dose
Isoniazid
Streptomycin
Least likely
Most likely
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.