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      Division of Infectious Diseases
          Department of Pediatrics
Queen Sirikit National Institute of Child Health
   Children usually have low organism numbers.
   Cavitating disease is relatively rare
(about 6% of cases or fewer in those under 13 years of age)

   In contrast, children develop extrapulmonary TB
    more often than adults do.Severe and
    disseminated TB occur especially in young
    children (less than 3 years old).
   Treatment outcomes in children are generally
    good, low risk of adverse events associated with
    use of the recommended treatment regimens.
First - Line Treatment of Tuberculosis (TB) for Drug-Sensitive TB
   Because of the high risk of disseminated tuberculosis in
    infants and children younger than 4 years of age,
    treatment should be started as soon as the diagnosis of
    tuberculosis is suspected.
   In general, the regimens recommended for adults are
    also the regimens of choice for infants, children, and
    adolescents with tuberculosis, with the exception that
    ethambutol is not used routinely in children.
   When clinical or epidemiologic circumstances suggest
    an increased probability of INH resistance, EMB can be
    used safely at a dose of 15--20 mg/kg per day, even in
    children too young for routine eye testing. Streptomycin,
    kanamycin, or amikacin also can be used as the fourth
    drug, when necessary.
Treatment of Tuberculosis, Morbidity and Mortality Weekly Report, June 20, 2003.
       Antituberculosis treatment in
   The main objectives of anti-TB treatment are :
   1. Cure the patient of TB (by rapidly eliminating
     most of the bacilli)
   2. prevent death from active TB or its late effects
   3. prevent relapse of TB (by eliminating the
     dormant bacilli)
   4. prevent the development of drug resistance (by
     using a combination of drugs)
   5. decrease TB transmission to others

Guidance for national tuberculosis programmes on the management of tuberculosis in children :
World Health Organization, 2006.
     Recommended treatment regimens
    Anti-TB treatment is divided into two phases:

   1. Intensive phase
          The purpose : to rapidly eliminate the majority of organisms and to
      prevent the emergence of drug resistance.
          uses a greater number of drugs

   2. Continuation phase
          The purpose : to eradicate the dormant organisms.
          fewer drugs because the risk of acquiring drug resistance is low, as
           most of the organisms have already been eliminated.

   In either phase, treatment can be given daily or three times

Guidance for national tuberculosis programmes on the management of tuberculosis in children :
World Health Organization, 2006.
     In general, extrapulmonary tuberculosis in
    children can be treated with the same regimens
    as pulmonary disease.
    Exceptions are disseminated tuberculosis and
    tuberculous meningitis : 9--12 months of
    treatment is recommended.

     The optimal treatment of pulmonary tuberculosis in
    children and adolescents with HIV infection is unknown.
    The American Academy of Pediatrics recommends that
    initial therapy should always include at least three drugs,
     and the total duration of therapy should be at least 9
    months, although there are no data to support this

Treatment of Tuberculosis, Morbidity and Mortality Weekly Report, June 20, 2003.
     The recommended treatment regimens
     for children.

Guidance for national tuberculosis programmes on the management of tuberculosis in
children : World Health Organization, 2006.
Guidance for national tuberculosis programmes on the management of tuberculosis in
children : World Health Organization, 2006.
N Engl J Med, Vol. 345, No. 3. July 19, 2001.
             Table - Drug side effects

     Baseline and Follow-Up Evaluations
At the time treatment is initiated

   appropriate specimens collected for microscopic exam and
    mycobacterial culture.
     three sputum specimens should be obtained 8--24 hours apart.
     Susceptibility testing for INH, RIF, and EMB should be performed on
     an initial positive culture
     Second-line drug susceptibility testing should be done only in
     reference laboratories and be limited to specimens from patients
     who have had prior therapy, have been in contact of a patient with
     known drug resistance, have demonstrated resistance to rifampin or
     two other first-line drugs, or who have positive cultures after more
     than 3 months of treatment.
   Measurements of AST, bilirubin, alkaline phosphatase,
    and serum creatinine and a platelet count
   Testing of visual acuity (Snellen chart) and color vision
    (Ishihara tests) should be performed when EMB is to be
   In addition, it is recommended that all patients with
    tuberculosis have counseling and testing for HIV
   Patients with epidemiologic factors suggesting a risk for
    hepatitis B or C, for example, injection drug use, birth in
    Asia or Africa, or HIV infection, should have serologic
    tests for these viruses
During treatment
    a sputum specimen for AFB smear and culture should be obtained at
     monthly intervals until two consecutive specimens are negative on

    For patients who had positive AFB smears at the time of diagnosis,
     follow-up smears may be obtained at more frequent intervals (e.g., every
     2 weeks until two consecutive specimens are negative) to provide an
     early assessment of the response to treatment, especially for patients in
     situations in which the risk of transmission is high.

    a repeat chest radiograph at completion of 2 months of
     treatment may be useful but is not essential

     As a routine, it is not necessary to monitor liver or renal
    function or platelet count unless there were abnormalities
    at baseline or there are clinical reasons to obtain the
   Patients who have stable abnormalities of hepatic or
    renal function at baseline should have repeat
    measurements early in the course of treatment

   Patients receiving EMB should be questioned regarding
    visual disturbances at monthly intervals; monthly repeat
    testing of visual acuity and color vision is recommended
    for patients receiving an EMB dose exceeding 15--20
    mg/kg (the recommended range) and for patients
    receiving the drug for more than 2 months.
     Definition of Completion of Therapy

   Treatment for a defined duration without
    accounting for the number of doses taken can
    result in undertreatment. Therefore, the
    determination of whether or not treatment has
    been completed is based on the total number of
    doses taken---not solely on the duration of
   In some cases, either because of drug toxicity or
    nonadherence to the regimen, the specified
    number of doses cannot be administered within
    the targeted time period
           Adverse drug reactions

   Adverse events caused
    by anti-TB drugs are
    much less common in
    children than in adults.

   Mild adverse effects can
    generally be managed
    with symptomatic therapy,
    whereas with more
    severe effects the
    offending drug or drugs
    must be discontinued.
Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003.
Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003.
Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003.
    Adverse drug reactions
   Gastrointestinal upset :
    nausea, vomiting, poor appetite, abdominal pain
   Rash
   Drug fever
   Hepatitis
   Miscellaneous :
     Arthalgias (joint pain)
    Flushing reactions
    Influenza Syndrome
    Optic Neuritis (vision)
Gastrointestinal upset :
nausea, vomiting, poor appetite, abdominal pain
   Gastrointestinal reactions are common, particularly in the first few weeks of
   Many of the antituberculosis drugs can cause gastrointestinal upset
   In the presence of gastrointestinal symptoms serum AST and bilirubin should
    be measured.
        If the AST level is less than three times the upper limit of normal, the symptoms
         are assumed not to be due to hepatic toxicity.

   The initial approach to gastrointestinal intolerance, not associated with
     hepatic toxicity, is to change the hour of drug administration and/or to
     administer the drugs with food.
   If patients are taking daily DOT, the timing of the drug administration should
    be altered, preferably to be closer to mealtime.
   Alternatively, food can be taken at the time of DOT administration.
   Patients receiving self-administered therapy can take the medications at
    bedtime. If gastrointestinal intolerance persists it may be best for all
    medications to be taken with meals.
   All drugs used in treating tuberculosis can cause a rash.
   The response to a patient with a rash depends on its
   The rash may be minor, affecting a limited area or being
    predominantly manifested as itching,
       antihistamines should be given for symptomatic relief, but all
        antituberculosis medications can be continued.

   A petechial rash may suggest thrombocytopenia in
    patients taking RIF.
       The platelet count should be checked and, if low, RIF
        hypersensitivity should be presumed to be the cause.
       RIF should be stopped and the platelet count monitored until it
        returns to baseline; RIF should not be restarted.
   a generalized erythematous rash, especially if it is
    associated with fever and/or mucous membrane
    involvement, all drugs should be stopped immediately.
           If the patient has severe tuberculosis, three new drugs
        (e.g., an aminoglycoside and two oral agents) should be

   When the rash is substantially improved the medications
    can be restarted one by one, at intervals of 2-3 days.

   RIF should be restarted first (because it is the least likely
    to cause rash, and it is the most important agent),
    followed by INH, and then EMB or PZA.

   If the rash recurs the last drug added should be stopped.
                                             drug rash

Figure 1 & 2: Pruritic erythematous maculopapular lesions over the abdomen
    Thrombocytopenia--a rare but potentially serious
    side effect of initial daily and interrupted use of
  usually occurs during high-dose intermittent treatment.
 About 6 percent of patients receiving high-dose twice-weekly
 rifampicin develop thrombocytopenia. only a few cases of
 thrombocytopenia develop during daily treatment or after
 administration of rifampicrn following an interruption of therapy.
 diagnosed by the temporal relationship between the start of drug
 administration and the onset ofthrombocytopenia, and confirmed by
 recovery after the cessation of the drug.
 platelet count usually returns to normal range within 36 hours
 might be explained by the existence of IgG and IgM antibodies to
 These antibodies could fix a complement on the platelets in th
 presence of rifampicin, resulting in platelet destruction.

                                                Chest 1989;96;202-203.
                               Drug fever
    Recurrence of fever in a patient who has been receiving therapy for
    several weeks should suggest drug fever, especially if the patient is
    showing microbiological and radiographic improvement.

    The clinical hallmark of drug fever is that the patient
    looks and feels well despite having a high fever
    (often greater than 39ºC) , no specific pattern to the fever.
    Eo may or may not be present.
    The first step in management
        To ensure that there is no superinfection or worsening of
        If these potential causes are excluded all drugs should be
       stopped, fever usually will resolve within 24 hours.
         Patients with severe TB should be given at least 3 new drugs in the
       interim. Once the fever has resolved, the same protocol as described
        above for restarting drugs in the presence of a rash should be followed.
 Three of the first-line antituberculosis drugs, INH, RIF,
 and PZA, can cause drug-induced liver injury
 INH + rifampin > INH alone >> pyrazinamide alone >
  rifampin alone > ethionamide

          AST level three or more times the upper limit of normal
       in the presence of symptoms                     or
           five or more times the upper limit of normal in the absence of

•     If the AST level < 5 times : mild toxicity
          AST level 5-10 times : moderate toxicity
          AST level > 10 times : severe toxicity *

    Toxic hepatitis with isoniazid and rifampin: a meta-analysis. Chest 1991;99:465–471.
    an asymptomatic increase in AST concentration occurs in
     nearly 20% of patients treated with the standard four-drug
    In the absence of symptoms, therapy should not be altered
     but the frequency of clinical and laboratory monitoring
     should be increased.
                 In most patients, asymptomatic aminotransferase elevations resolve
     However, if AST levels > 5 times the upper limit of normal
     (with or without symptoms) or > 3 times normal in the
     presence of symptoms, hepatotoxic drugs should be
     stopped immediately and the patient evaluated carefully.

    *Toxic   hepatitis with isoniazid and rifampin: a meta-analysis. Chest 1991;99:465–471.
    In addition to AST elevation, occasionally there are
    disproportionate increases in bilirubin and alkaline
    phosphatase. This pattern is more consistent with
    rifampin hepatotoxicity

    Patients should be screened for other causes of
     hepatitis (Serologic testing for hepatitis A, B, and C),
    questioned carefully regarding symptoms suggestive of
    biliary tract disease, exposures to other potential
    hepatotoxins, particularly alcohol and hepatotoxic
     If treatment for TB needs to be continued for severe
    forms of TB, nonhepatotoxic anti-TB drugs should be
    introduced (at least 3 drugs e.g. ethambutol,
     aminoglycoside and fluoroquinolone)

     The suspect antituberculosis medications should be
    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.)

    Because RIF is much less likely to cause
     hepatotoxicity than is INH or PZA and is the most
     effective agent, it should be restarted first.

            RIF → INH → PZA
               ( every 1 week if AST does not increase)

     If symptoms recur or AST increases the last drug added
    should be stopped. If RIF and INH are tolerated, and hepatitis was
    severe, PZA should be assumed to be responsible and should
    be discontinued.
    In this last circumstance, depending on the number of doses of PZA
    taken, severity of disease, and bacteriological status, therapy might
    be extended to 9 months.
     Risk factors for hepatotoxicity from
     antituberculosis drugs: a case- control study
     A case-control study was undertaken to assess the role of age, sex, disease extent,
    nutritional status, past history of liver disease, infection with hepatitis viruses,
    acetylator status, and high alcohol intake as risk factors in the development of
    hepatotoxicity in patients with pulmonary tuberculosis receiving antituberculosis.
     METHODS: The cases comprised 86 consecutive patients who were diagnosed as
    having hepatitis induced by antituberculosis drugs and who were negative for any of
    the hepatitis markers. The control group comprised 406 consecutive patients
    who completed antituberculosis treatment without developing hepatitis.
     RESULTS: The cases were older and their serum albumin levels were lower than in
    the control group. High alcohol intake was more common among the cases, they had
    more extensive disease radiologically, and the proportion of slow acetylators was
    higher. No differences were observed between the two groups in the other risk
    factors analysed.
    CONCLUSIONS: only advanced age, hypoalbuminaemia, high alcohol intake,
    slow acetylator phenotype, and extensive disease were risk factors for the
    development of hepatotoxicity. The risk of hepatitis in the presence of one or
    more of these risk factors may be increased.

                                              JN Pande et al.Thorax, Vol 51, 132-136.
VOL.II, No.1, FEBRUARY, 2006.
           Risk factors for hepatotoxicity
 1.     hypoalbuminaemia *
 2.     advanced age * ****
 3.     high alcohol intake   * , ****

 4.     slow acetylator phenotype *
 5.     extensive disease    *, **, ***
 6.     Female ** ***
 7.     Poor nutritional status     **, *** , ****

 8.     chronic viral infection with HBV, HCV ****
 9.     HIV ****

* Thorax, Vol 51, 132-136.
*** Ann Pharmacother 2004; 38(6): 1074-9.
**** Indian J Exp Biol 2003; 41(11):1226-32.
   A study from Nepal reported the incidence of
    hepatotoxicity as 8%..

   The mild elevation of transaminases seen in as
    many as 20% of patients who are treated during the first
    2 months of therapy
   The more severe hepatitis seen in up to 1% of adults
    who are treated may be a consequence of the
    production of more reactive species by the cytochrome
    P-450 enzyme system
              Incidence of hepatotoxicity due to antitubercular
               medicines and assessment of risk factors. Ann
               Pharmacother 2004; 38(6): 1074-9
     The biochemical mechanism of isoniazid hepatotoxicity
     remains incompletely defined.

    The most widely accepted theory is that isoniazid
     metabolism produces reactive metabolites that bind to
     and damage cellular macromolecules in the liver.

    some studies suggest that people who are slow acetylators are at
     greater risk, suggesting that slow
     metabolism results in diversion of isoniazid metabolism to an
     alternate (eg, cytochrome P-450–mediated)
     pathway that may produce a toxic metabolite.

     Recent studies show that polymorphism of N-acetyl transferase 2
    (NAT2) genes and glutathione-s-transferase (GST) are the major
    susceptibility risk factors for ATT induced hepatitis. Slow acetylators
    of NAT2 develop more severe hepatotoxicity than rapid acetylators
    making it a significant risk factor.

        Antituberculosis drug-induced hepatitis: risk factors, prevention and management.
        Indian J Exp Biol 2003; 41(11):1226-32.
Antituberculosis Drugs and Hepatotoxicity VOL.12 NO.1 JANUARY 2007.
    Grading of adverse drug events (2)
Grading of adverse drug events (1)
      Grading of adverse drug events (2)

Guidelines on co-trimoxazole prophylaxis for HI V-related infections among children,
adolescents and adults, World Health Organization 2006.
   Miscellaneous Adverse Effects :
       Arthalgias (joint pain)
Arthalgias Type 1
 pyrazinamide>>ethambutol>isoniazid
 pain and tenderness of joints: fingers, shoulders, knees,
   etc. (usually mild)
 TB medications do not require discontinuation
 low dose nonsteroidal antiinflammatory agents (NSAIDS)
  can be used for pain relief as needed
 if symptoms persist, consider referral for rheumatologic
Arthalgias Type 2 (Gouty Arthritis)

 pyrazinamide>>ethambutol
 pain, tenderness and swelling of joints: fingers,
  shoulders, knees, etc.
 symptoms are usually severe
 signs: elevated serum uric acid concentrations
 TB medications usually do not require discontinuation
 If acute swelling is present, the affected joint should be
  aspirated and examined for urate crystals to confirm the
  diagnosis of acute gouty arthritis.
 Drug : nonsteroidal antiinflammatory agents, colchicine
 Consider referral for rheumatologic evaluation for acute
  gouty arthritis attacks
              Flushing reactions
 flushing and/or itching of the skin with or without a rash
 hot flashes, palpitations,headache and/or increased
 blood pressure
 usually involves the face and scalp; may cause
 redness/watering of the eyes
 usually occurs 2-3 hours after drug ingestion

Reaction : rifampin, pyrazinamide
       : isoniazid + tyramine containing foods (cheese,
        red wine) or certain fish (tuna, skipjack)
 flushing is usually mild and resolves without therapy
 if flushing is bothersome to the patient, an antihistamine
  may be administered to treat
              Influenza Syndrome
 rifampin > rifabutin (intermittent regimens > daily
 fever, headache, bone pain
 usually occurs 1-2 hours after drug administration
 usually resolves within 12 hours of drug administration
 switch from intermittent therapy to daily dosing
 (7 days/week)
 symptomatic therapy may be required when switching
  from intermittent to daily therapy to prevent the reaction
  with initial doses
Neurotoxicity : Peripheral Neuropathy
   INH>>>ethambutol
   prickling, tingling or burning sensation of the
     fingers and/or toes
   usually occurs in a stocking glove distribution
   rarely occurs in children unless severe
     malnutrition is present.
   uncommon if the patient is receiving pyridoxine
     (vitamin B6)

   Treatment : pyridoxine 100-200mg po q day
          while the patient is receiving INH.
    Nervous System Effects in Children
   INH ***
   Clinical Presentation : drowsiness or hyperactivity
            dizziness, tonic/clonic seizures (rare)


1. Drowsiness
 a. make sure the dose does not exceed 10 mg/kg/d
 b. add pyridoxine 50mg to the regimen
 c. administer medications around afternoon naps or at
2. Hyperactivity
a. make sure the dose does not exceed 10mg/kg/d
b. switch to twice weekly dosing as soon as possible
1) if the child becomes hyperactive only on the days of
  medication administration, then the medication is the
2) add pyridoxine 50mg daily for 6 weeks, then twice
  weekly for the remainder of therapy

3. Dizziness
a. make sure the dose does not exceed 10mg/kg/d

4. Tonic/clonic seizures
a. hospitalize the child and administer isoniazid to
  document the reaction
b. if a seizure occurs, discontinue isoniazid and add an
   alternative agent to the regimen
                       Optic Neuritis (vision)

     ethambutol >>INH
     Clinical Presentation :
          blurred vision (decrease in the “sharpness” of objects)
          “spots” present in patient’s field of vision
          red/green color blindness
   optic neuritis has not been documented in
   discontinue drug

Guidelines for the Management of Adverse Drug Effects of Antimycobacterial Agents,
Lawrence Flick Memorial Tuberculosis Clinic Philadelphia Tuberculosis Control Program
November 1998.
                            Isoniazid (INH)
   A prospective cohort study of 11,141 patients receiving INH preventive
    therapy reported a rate of hepatitis lower than that previously
    reported. Of these, 11 patients (0.10% of those starting, and 0.15% of
    those completing therapy) developed clinical hepatitis.
            Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with
             isoniazid preventive therapy: a 7-year survey from a Public Health
             Tuberculosis Clinic. JAMA 1999; 281(11):1014-8.
   Hepatotoxicity is rare in children receiving INH. In a 10-year
    retrospective analysis, the incidence of hepatotoxicity in 564 children
    receiving INH (10 milligrams per kilogram per day (mg/kg/day) to a
    maximum of 300 mg/day) for the prophylactic treatment of
    tuberculous was 0.18%.
                  Incidence of hepatotoxicity in children receiving isoniazid chemoprophylaxis.
                   Pediatr Infect Dis J 1989; 8:649-50.
    However, the incidence of hepatotoxicity in children receiving INH
    and rifampicin for TB was 3.3% in another retrospective study (14 of 430
            Hepatotoxicity from isoniazid and rifampin among children treated for
             tuberculosis. Pediatrics 1983; 72:491-9.
   The most common adverse effect of this drug is
    hepatotoxicity. Hepatotoxicity is dose related and may
    occur any time during therapy.
   In the Centre for Diseases Control (CDC) update, 48
    cases of hepatotoxicity were reported in association with
    a 2-month regimen of Rifampin-pyrazinamide for the
    treatment of latent tuberculosis between October 2000 and
    June 2003. Thirty-seven patients recovered and 11 died of
    liver failure. Of the 48 reported cases, 33 (69%) occurred in
    the second month of therapy.
           CDC: Update: Adverse event data and revised American Thoracic
            Society/CDC recommendations against the use of rifampin and
            pyrazinamide for treatment of latent tuberculosis infection-United
            States, 2003. MMWR 2003; 52 (31):735-9.
   Strategies to minimize the occurrence of
   Liver function tests are to be done before the
    start of treatment and monitored every 2 weeks
    during the initial two months in the risk groups
    like patients with pre-existing liver disorders,
    alcoholics, the elderly and the malnourished.
    Close clinical and biochemical monitoring is to
    be done in hepatitis B carriers also as there is
    higher incidence of liver dysfunction and
    symptomatic hepatitis.
          Antituberculosis drug-related liver dysfunction in chronic
           hepatitis B infection. Hepatology 2000; 3: 201-6.

   There are fewer reports of hepatotoxicity with
    Ethambutol in the treatment of TB. Abnormal
    liver function tests have been reported in some
    patients taking ethambutol; however, these
    patients were also taking other antiTB drugs
    known to cause liver dysfunction.
          The management of anti-tuberculosis drug-induced
           hepatotoxicity. Int J Tuberc Lung Dis 2001; 5 (1): 65-9.
   Rifampicin
   Transient abnormalities in liver function are common in the initial
    stages of therapy. But in some cases it may cause severe
    hepatotoxicity, more so in those with pre-existing liver disease,
    forcing the physician to change treatment and opt for liver friendly
   Rifampicin causes transient elevations in hepatic enzymes usually
    within the first 8 weeks of therapy in 10% to 15% of patients, with less
    than 1% of the patients demonstrating overt rifampicin-induced
    hepatotoxicity. The occurrence of mortality associated with
    hepatotoxicity has been reported to be 16 in 500,000 patients receiving
    rifampicin. A higher incidence of hepatotoxicity has been reported in
    patients receiving rifampicin with other anti TB agents, and is
    estimated to be fewer than 4%.
            McNeill L, Allen M, Estrada C, et al: Pyrazinamide and rifampin vs isoniazid
             for the treatment of latent tuberculosis: improved completion rates but more
             hepatotoxicity. Chest 2003; 123:102-6
          Manifestations of rifampicin-induced
    The side effects of rifampicine due to an immunoallergic mechanism are
     rare and usually observed during discontinued treatment or administration of
      high doses. OBSERVATIONS: An immediate hypersensitivity reaction with
     anaphylactic manifestations and increase in IgE occurred in a 39 year-old
     man suffering from resistant tuberculosis. The reaction occurred within the
     first hour following a low dose of rifampicin administered in a desensitisation
     attempt, the outcome of which was favourable after administration of
     corticosteroids and antihistamines. A type II hypersensitivity reaction
     occurred in a 76 year-old male patient in the form of thrombopenia on D76
     of a twice weekly treatment, diagnosed because of hemoptysis with
     normalisation of platelet level on withdrawal of rifampicin. An immune
     complex hypersensitivity reaction was responsible for hepato-renal failure
     on D68 of twice weekly treatment and required permanent withdrawal of
     rifampicin and dialysis, which led to subsequent improvement.
    COMMENTS: These clinical cases illustrate the variability of the
     hypersensitivity mechanisms observed with rifampicin, the difficulty in
     imputability tests and methods for immunological confirmation, the interest
     of continuous treatment which avoids a certain number of these accidents,
     and that of desensitisation during immediate hypersensitive reactions which
     permits the continuation this major anti-tuberculosis drug.

                                        Presse Med. 2003 Jul 26;32(25):1167-9.
   Education of caregivers regarding sign
    and symptom of potential A/E is

   or more severe liver injury may occur from
   one week to many months after the initiation of
   isoniazid therapy; however, the majority_of cases of
   isoniazid-pssociated hepatitis occur within the first
   three months of treatment, In most
   occurs shortly after isoniazid has been
   discontinu&cLıpd is almost always complete. Monitoring
   liver enzymes has not proved useful in
   associated hepatitis except in those patients
   who report gastrointestinal symptoms such as
   anorexia, nausea, vomiting or jaundice.

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