includes detaled adverse effect of first line Anti-TB Drugs

1. ADVERSE EFFECTS
OF
ANTI-TB DRUGS
JAINISH PATEL
14
PHARM D 3rdYEAR

2. DRUGS USED INTREATMENT OFTB
• FIRST LINE DRUGS :-
• Isoniazide (INH)
• Rifampin
• Rifapentine
• Pyrazinamide (PZA)
• Ethambutol
• Streptomycin
• SECOND LINE DRUGS :-
• Amikacin
• Capreomycin
• Clofazimine
• Cycloserine
• Ethionamide
• Kanamycin
• Levofloxacin
• Ofloxacin
• Para amino salicylic acid
• Rifambustin

4. DERMATOLOGICAL ADVERSE EFFECTS
Mild “Flushing” Reactions(two different types of reactions )
1. REACTION 1 :-
• Flushing and /or itching with or without rash.
• Usually includes FACE , SCALP and may cause redness/watering of eyes.
• Obsevered after 2-3 hrs of drug admistration.
CAUSATIVE DRUGS:
• Seen most frequenty in Rifampin and Pyrazinamide

5. Management:
• Flushing is mild and resolves without therapy.
• if flushing is bothersome to the patient, an antihistamine may be
administered to treat or prevent the reaction.

6. 2. REACTION 2 :-
• Flushing and /or itching of skin with or without rash + Hot flashes ,
palpitations ,headache and/or increase in blood pressure.
• Occurs immediately after ingestion of certain food with the anti-TB drug.
• Ussualy resoves within 2 hrs.
CAUSATIVE AGENTS :-
• Isoniazide(INH) + tyramine containing food ( cheese, red wine ) or certain
fish like – tuna , skipjack
MANAGEMENT :-
• Advice the patient not to ingest tyramine containing food while receiving
INH.

7. •Moderate/severe hypersensitivity (immune) reactions
• Clinical Presentation hives (raised, itchy rash) with or
without fever
• Drug Rash with Eosinophilia and Systemic Symptoms
(DRESS) syndrome is a life-threatening adverse drug
reaction that is distinct from other drug-related
reactions.
•Causative Agents
•INH < rifampin < PZA < ethionamide < cycloserine < ethambutol <
para-aminosalicylic acid < streptomycin
•NOTE:in children, viral infections (e.g. Epstein-Barr and Herpes
Simplex) commonly result in hives that may be confused with a drug
reaction.

8. •Children
1. Discontinue all drugs
2. Rule out a viral infection
a. full physical exam
b. complete blood count (examine for lymphocytosis)
• If a viral infection is present, restart all of theTB medications

9. Adults
•Discontinue all drugs until the reaction resolves
•Identify the causative drug by rechallenging (restarting) each drug every 4 days according toTable 1 (example
follows on next page).
Table 11
begin the rechallenge with INH 50mg on day 1
1) if the original reaction was severe, begin the rechallenge with 1/10 the day 1 dose listed inTable 1 (e.g. INH
5mg)
1.if a reaction does not occur after the day 1 dose, increase the INH to 300mg on day 2
2.if a reaction does not occur after the day 2 dose, continue INH 300mg q day
3.continue to add drugs in the order and doses specified on Table 1 every 4 days
a.if the original reaction was severe, begin the rechallenge with 1/10 the day 1 dose listed in Table 1
b.if the day 2 dose is less than the normal recommended dose based on the patient’s weight, increase
to the appropriate dose on day 3
(i)example for ethambutol dosing in a 70kg person: day 1=100mg, day 2=500mg, and day
3=1000mg
•If a reaction occurs during drug rechallenge and the causative drug can not be discontinued, drug desensitization
will be necessary.

10. Drug Rechallenge Protocol
Drug Challenge Doses
Day 1 Day 2
isoniazid 50mg 300 mg
rifampin 75mg 300 mg
pyrazinamide 250mg 1.0 gm
ethionamide 125mg 375 mg
cycloserine 125mg 250 mg
ethambutol 100mg 500 mg
para-aminosalicylic acid
(PAS)
1.0gm 5.0 gm
streptomycin 125mg 500 mg

11. Gastrointestinal symptoms (nausea and
vomiting)
• CAUSATIVE AGENTS:
•+++++ clofazimine, ethionamide, para-aminosalicylic acid (PAS)
•++++ rifampin
•+++ rifabutin, isoniazid (twice and thrice weekly dosing)
•++ ethambutol, pyrazinamide, ofloxacin, levofloxacin
•Gastrointestinal symptoms may be due to the bulk of drugs. Patients who complain
of nausea or vomiting can be advised to take drugs embedded in a banana.

12. • MANAGEMENT:
• if vomiting persists, drugs will be administered one hour after one tablet of
Domperidone and/or a course of proton pump inhibitor (Omeprazole) or H2
receptor inhibitor (Famotidine, Ranitidine);
• other antacids are usually not given, since they interfere with absorption of FQ;
• in case of severe vomiting, the hydration status of the patient should be
monitored and rehydration therapy initiated if required;
• • if the offending drug is Ethionamide, the drug is more acceptable if administered
with milk, or after milk, or at bedtime to avoid nausea;
• • if vomiting is severe, drugs can be withheld temporarily and tests can be
conducted to rule out other causes of vomiting like hepatitis;
• • assess for danger signs including dehydration, electrolyte disturbance and
hepatitis. Initiate rehydration therapy if indicated and correct any electrolyte
disturbance. If there is blood in the vomit, check haemoglobin and treat for
possible bleeding ulcers

13. • NOTE:
• Although nausea and vomiting are uncommon adverse effects of the
aminoglycosides (streptomycin, amikacin, kanamycin) and capreomycin, it
may be an indication of vestibular toxicity (inner-ear toxicity). If this occurs,
contact aTB Control physician.

14. Gastrointestinal symptoms (gastritis &
abdominal pain)
• Abdominal pain is often associated with serious adverse effects, such as
pancreatitis (Linezolid,Bedaquiline), lactic acidosis and hepatitis. If any of
these are suspected, it is important to obtain appropriate laboratory tests to
confirm and suspend the suspected agent.
• CAUSATIVE AGENTS:PAS, Ethionamide , protionamide ,INH, rifampin

15. • MANAGEMENT:
• if symptoms are associated and consistent with gastritis (epigastric
burning or discomfort, sour taste in mouth associated with reflux) initiate
medical therapy with the
• use of H2-blockers (ranitidine 150 mg twice daily or 300 mg once daily) or
proton-pump inhibitors (omeprazole 20 mg once daily). Avoid use of
antacids as they decrease absorption of FQ;
• for severe abdominal pain, stop suspected agent(s) for short periods of
time (1-7 days);
• lower the dose of the suspected agent, if this can be done without
compromising the regimen; and
• discontinue suspected agent if this can be done without compromising the
regimen.

16. Gastrointestinal Adverse Effects
Diarrhea
• Clinical Presentation
• ≥ 3 loose bowel movements per day
• Causative Agents
• +++++ clofazimine, ethionamide, para-aminosalicylic acid (PAS)
• +++ rifampin
• ++ rifabutin, ofloxacin, levofloxacin
• + isoniazid, ethambutol, pyrazinamide, rifapentine, cycloserine, aminoglycosides,
capreomycin

17. • MANAGEMENT:
• encourage fluid intake;
• treat uncomplicated diarrhoea (no blood in stool and no fever) with
loperamide 4 mg by mouth initially followed by 2 mg after each loose stool
to a maximum of 10 mg per 24 hours;
• check serum electrolytes (especially potassium) and dehydration status if
diarrhoea is severe; and
• fever and diarrhoea and/or blood in the stools indicate that diarrhoea may
be secondary to something other than the simple adverse effect of anti-TB
drugs

18. Hepatotoxicity (Hepatitis)
•Causative Agents
•INH + rifampin > INH alone >> pyrazinamide∗ alone > rifampin alone >
ethionamide

22. •Routine Monitoring for Hepatotoxicity in Adults
1. Obtain baseline liver function tests (LFTs) 8,9
a. serum transaminase enzymes
1) aspartate aminotransferase (AST) [normal 0-40 u/l]
2) alanine aminotransferase (ALT) [normal 0-40 u/l]
b. alkaline phosphatase [normal 25-115 u/l]
c. gamma glutamyl transpeptidase (GGTP) [normal 10-50 u/l]
d. total bilirubin [normal 0.2-1.5 mg/dl]

23. •Management in Adults
1. Asymptomatic patients with an increase in LFTs from baseline:
a. if the increase in LFTs is < 3-5x normal: continue the current regimen and monitor for
symptoms of liver dysfunction
• for asymptomatic patients, if the serum transaminases increases > 3-5x normal: hold
INH until levels return to baseline
1) if the patient is receiving a two drug regimen, substitute at least one other drug (e.g. ethambutol)
until the INH is restarted
2) if the transaminases increase with rechallenge of INH, discontinue INH, substitute
•another drug (e.g. ethambutol) and adjust the treatment duration as
required
• if the serum total bilirubin increases: therapy usually does not require modification
rifampin competes with bilirubin for elimination resulting in increased serum
bilirubin initially; bilirubin levels usually return to normal with continued therapy

24. • Symptomatic patients
• Hold all drugs and obtain LFTs
• If LFTs are within the normal ranges, refer to the Management of Nausea/Vomiting section
(pages 7-9)
• If LFTs are elevated, hold drugs until symptoms resolve and the transaminases decreases to
< 2x normal3 , 6
• ethambutol and pyrazinamide should be started if drug therapy can not be held secondary to the
patient’s clinical condition
• use streptomycin if pyrazinamide is suspected to be the cause of hepatotoxicity
• rechallenge the patient after resolution of signs and symptoms by adding drugs to the regimen
every 4 days6:
• rifampin for 3 days, if patients remains asymptomatic then add
• INH for 3 days, if patients remains asymptomatic then add
• pyrazinamide (15-20mg/kg/d) for 3 days
• if signs and symptoms recur with rechallenge, discontinue the responsible drug and modify the
regimen and/or duration of therapy as required

25. Miscellaneous Adverse Effects
Arthalgias (joint pain)
• ArthalgiasType 1
• Causative Agents1 , 2 pyrazinamide>>ethambutol>isoniazid
• Clinical Presentation pain and tenderness of joints: fingers, shoulders, knees, etc. (usually mild)
• Management
• 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 evaluation

26. Arthalgias Type 2 (Gouty Arthritis)
• Causative Agents1 , 2 pyrazinamide>>ethambutol
• Clinical Presentation symptoms: pain, tenderness and swelling of
joints: fingers, shoulders, knees, etc.
•symptoms are usually severe
•signs: elevated serum uric acid concentrations

27. • Management
• 1.TB medications usually do not require discontinuation
• 2.If acute swelling is present, the affected joint should be aspirated and examined for urate crystals to confirm the
diagnosis of acute gouty arthritis.
• 3.Therapy
• a.nonsteroidal antiinflammatory agents include:
• indomethacin (Indocin®) 50 mg tid-qid until pain relief, then 25mg tid-qid
• ibuprofen (Motrin®, Advil®) 800 mg tid
• naproxen (Naprosyn®) 750 mg x1, then 250mg q 8 hour
• b.colchicine is an alternative to NSAIDS
• 1)dose: 0.5-1.2 mg x1, then 0.5-0.6 mg q 1-2 hours until joint pain is relieved or nausea, vomiting or diarrhea
occurs
• 2)pain usually resolves after 4-8 mg cumulative dose 3) maximum dose: 8mg
• d. a steroid taper may be required for severe attacks
• 4.Recurrent episodes may occur while the patient remains on pyrazinamide or ethambutol.
• a.consider using prophylactic colchicine
• 1)0.6 mg one to two times daily
• 2)continue until causative agent is discontinued
• 5.Consider referral for rheumatologic evaluation for acute gouty arthritis attacks

28. Miscellaneous Adverse Effects
“Influenza Syndrome”
Causative Agents2 rifampin > rifabutin (intermittent
regimens > daily regimens)
Management
•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 ( i.e. oseltamivir and
zanamivir)

29. Neurotoxicity (Nervous System)
•Causative Agents1 , 2
•INH>>>ethambutol
• patients with comorbid
disease (diabetes, HIV, alcohol
depaendence) may be more
likely to develop peripheral
neuropathy, but these
conditions are not
• contraindications to the use of
agents listed here

30. •Management
•peripheral neuropathy rarely occurs in children unless severe
malnutrition is present if peripheral neuropathy occurs, it can be
treated with pyridoxine (vitamin B6) 100-200mg po q day
•while the patient is receiving INH
•- therapy with tricyclic antidepressants such as amitriptyline (start with
25 mg at bedtime, the dose may be increased to a maximum of 150 mg)
can be tried. Do not use tricyclic antidepressants with selective serotonin
reuptake inhibitors and antidepressant drugs;
 rarely, medication may be discontinued, but only if an alternative drug is available and
the regimen is not compromised.
• a

31. Seizures
• Causative agents :
• INH, FQ ,cycloserine

32. • initiate anticonvulsant therapy (carbamazepine, phenytoin or valproic acid
are most commonly used);
• increase pyridoxine to maximum daily dose (200 mg per day);
• check serum electrolytes including potassium, sodium, bicarbonate, calcium,
magnesium and chloride; and
• when seizures have resolved, restart medication, one at a time. Cs should not
be restarted unless it is absolutely essential to the regimen. If Cs is
reinitiated, start a dose one weight band lower.

33. Nephrotoxicity (renal toxicity)
• CAUSATIVE AGENTS:streptomycin,amikacin,kanamycin,capriomycin
• management strategies
• discontinue the suspected agent;
• consider using Cm if an aminoglycoside had been the prior injectable drug in
the regimen;
• consider other contributing etiologies (non-steroidal anti-inflammatory
drugs, diabetes, other medications, dehydration, congestive heart failure,
urinary obstruction, etc.,) and address as indicated;
• follow creatinine (and electrolyte) levels closely, every 1-2 weeks;

34. • consider dosing the injectable agent 2-3 times a week if the drug is essential
to the regimen and the patient can tolerate (close monitoring of creatinine).
If creatinine continues to rise despite twice/thrice a week dosing, suspend
the injectable agent; and
• adjust allTB medication according to creatinine clearance in consultation
with nephrologist. Also, note that renal impairment may be permanent

35. Vestibular toxicity (tinnitus and dizziness)
• CAUSATIVE AGENTS:INZ,streptomycin,kanamycin,FQ,ethionamides
• If early symptoms of vestibular toxicity appear, there may be a need to change
dosing of the injectable agent to twice/thrice a week.
• if tinnitus and unsteadiness worsen with the above adjustment, stop the injectable
agent. This is one of the few adverse reactions that may cause permanent
intolerable toxicity and can necessitate discontinuation of a class of agents.

36. Optic Neuritis (vision)
• blurred vision, vision disorder, inability to distinguish certain colours, partial loss of
vision, or vision loss
• CAUSATIVE AGENTS:ethambutol>>INH
• Management:
••discontinue drug and don’t start again.

37. QT prolongation
• CAUSATIVE AGENTS:bedaquline,delamanid,FQ,INH
• Management:
• any patient found to have a QT value greater than 500ms,stop all suspected QT
prolonging drugs;
• repeat ECG and confirm the prolongation;
• check potassium, calcium and magnesium levels;
• electrolyte levels should be maintained in the normal range in any patient with an
elevated QT interval;
• avoid other drugs that increase the QT interval. Monitor the patient’s renal and
hepatic function and adjust the dose of FQ if impairment is present;
• consider suspension of FQ if risk of torsades de pointes outweighs benefits of the
drug; and
• also see relevant section for more information on QT interval monitoring with Bdq
and Dlm.

39. 1) J.G., the 32-year-old wife of H.G., and her children are tested to determine
whether they have been infected with M. tuberculosis. For his wife, the
induration from 5TU of PPD was 12 mm, which is reported as positive. J.G.
states that she has never received the BCG vaccine. After 2 months of
isoniazid therapy, J.G. was found to have an aspartate aminotransferase
(AST) of 150 international units/L. Discuss the presentation, prognosis, and
mechanism of isoniazid-induced hepatitis. What are the risk factors for
developing hepatitis? Should isoniazid be discontinued to prevent further
liver damage?

40. • High-risk patients should be followed with routine monitoring of LFTs.
These patients include those who consume alcohol daily, persons older than
35 years of age, those taking other hepatotoxic drugs, those with pre-
existing liver disease, intravenous drug users, black and Hispanic women,
and all postpartum women. In these high-risk patients, isoniazid should be
discontinued if the AST level exceeds three to five times the upper limit of
the normal value.61 Because J.G.’s AST is greater than three times the
upper range ofthe normalvalue, isoniazid should be discontinued
temporarily until the AST returns to normal. At that time, isoniazid should
be resumed, and her LFTs rechecked. Ifthe AST increases again, the drug
should be discontinued, and J.G. should be followed frequently for
development ofactiveTB.

41. 2) C.M., a 50-kg, 35-year-old woman, is being treated for activeTB disease
with isoniazid 1,200 mg and rifampin 600 mg twice weekly. Is 1,200 mg of
isoniazid twice weekly an appropriate dose for a 50-kg patient? What isoniazid
side effects, other than hepatotoxicity, should be anticipated?
• PERIPHERAL NEUROPATHY:
uncommon at the recommended daily and intermittent doses, isoniazid can
cause a peripheral neuropathy by interfering with pyridoxine (vitamin B6)
metabolism.30,45 As many as 20%ofpatientsmayexperience this problemwith
isoniazid doses greater than 6 mg/kg/day. Numbness or tingling in the feet or
hands are the most common neuropathic symptom. In patients with medical
conditions inwhich neuropathy is common,including diabetes mellitus,
alcoholism, HIV infection, malnutrition, and renal failure, supplemental
pyridoxine 25 mg/day should be given with isoniazid.

42. • ALLERGIC AND OTHER REACTIONS:
Allergic reactions consisting of arthralgias, skin rash, swelling of the tongue,
and fever have also been reported. Isoniazid has been associated with arthritic
symptoms and systemic lupus erythematosus; approximately 20% of patients
receiving isoniazid develop antinuclear antibodies.30 Other less common
reactions reported with isoniazid are dry mouth, epigastric distress, CNS
stimulation and depression, psychoses, hemolytic anemia, pyridoxine-
responsive anemia, and agranulocytosis.

43. 3) One month after beginning her twice-weekly DOT regimen, C.M. exhibited
symptoms of myalgias, malaise, and anorexia. Laboratory data were normal except
for a slightly decreased platelet count. Could C.M.’s symptoms be related to her drug
therapy? What adverse reactions other than hepatotoxicity should be anticipated in a
patient receiving rifampin?
• FLULIKE SYNDROME:
A flulike syndrome has been reported in about 1% ofpatients
receiving intermittent rifampin administration.This syndrome is rarely seen with usual
doses of600 mgtwiceweekly, but the incidence increases with twice-weekly doses
greater than 900 mg.The incidence also increases ifthe dosing interval is increased to
1 week or longer.122,123 Unless the symptoms are severe, discontinuation of the drug
is unnecessary. Because C.M. is receiving rifampin 900 mg twice weekly, her dose
should be reduced to 600 mg and administered daily until the symptoms subside.The
temporary administration of a nonsteroidal anti-inflammatory drug has been used to
alleviate the flulike symptoms

44. • On occasion, rifampin can cause hepatocellular injury and potentiate
hepatotoxicity of other antituberculosis drugs.111Although elevations
ofliver enzymes are seen on occasion, rifampin is more likely to produce
cholestasis, as manifested by increases in alkaline phosphatase
andhyperbilirubinemiawithout hepatocellular injury.111 Elevations ofall liver
function tests may be seen transiently during the first month of rifampin
therapy, but they are usually benign.
• THROMBOCYTOPENIA:
Thrombocytopenia is more frequently associated with intermittent or
interrupted rifampin administration, likely caused by production
ofimmunoglobulinG and immunoglobulin M antibodies to rifampin.These
antibodies likely fix complement onto the platelets, resulting in platelet
destruction

45. • ACUTE RENAL FAILURE:
Acute renal failure has been reported rarely with rifampin.30This
hypersensitivity reaction may occur with both intermittent and daily
administration and may last as long as 12 months.122 Rifampin should be
discontinued, and other drugs (e.g., pyrazinamide and ethambutol) should be
given.The dose ofethambutol should be adjusted for renal dysfunction. Both
rifampin and isoniazid may, however, be given in normal dosages to patients
with pre-existing renal failure.
DISCOLORATION OF BODYFLUIDS
Another important characteristic ofrifampin relates to its chemical makeup. It
is an orange-red crystalline powder that is distributed widely in body fluids. As
a result, it can discolor saliva, tears, urine, and sweat.30 Patients using
rifampin should be warned ofthis effect and cautioned not to use soft contact
lenses because of possible discoloration.

46. 4)Will the combination of isoniazid and rifampin increase the risk of hepatotoxicity in
C.M. to a greater extent than either drug alone?
• Some initial evidence suggested that the concomitant use of
isoniazid and rifampinwas associated with a greater incidence of hepatotoxicity.The
mechanism was thought to be attributable to rifampin induction of the metabolism
of isoniazid to either monoacetylhydrazine or to other hepatotoxic products
ofhydrolysis. Steele et al.117 performed a meta-analysis reviewing the incidence of
hepatitis using regimens that contained isoniazid without rifampin, rifampin without
isoniazid, and regimens containing both drugs.They found the incidence ofclinical
hepatitis was greater in regimens containing both isoniazid and rifampin (2.7%)
versus regimens of isoniazid alone (1.6%), but this effect was additive, not synergistic,
and therefore expected.117The use ofthe two drugs together, therefore, is not
contraindicated, but caution should be used in high-risk groups such as the elderly,
alcoholics, those receiving concomitant hepatotoxic agents, and those with pre-
existing liver disease.

47. 5) .E., a 65-year-old woman, was placed on isoniazid 300 mg/day, rifampin 600
mg/day, pyrazinamide 900 mg/day, and ethambutol 1,200 mg/day for initial
treatment of active pulmonaryTB.Two months after the initiation of therapy,
she began to complain of blurred vision. A routine eye examination and visual
field tests yielded a diagnosis of optic neuritis. No evidence was seen of
glaucoma, cataracts, or retinal damage. Laboratory tests were within normal
limits except for an elevated serum uric acid (9.7 mg/ dL) and a slightly
elevated serum creatinine (1.6 mg/dL). No symptoms of joint pain were
associated with the elevated serum uric acid, and there was no history of gout.
Her calculated creatinine clearance based on her weight of 65 kg was 36
mL/minute. Could the visual problem and increased uric acid levels be related
to her medications?

48. • .E.’s decrease in visual acuity is compatible with ethambutolinduced optic
neuritis.This condition is characterized by central scotomas, loss of red-
green color vision, or less commonly, a peripheral vision defect.The
intensity of these ocular effects is related to the duration of continued
therapy after decreased visual acuity is first noted.
• Optic neuritis manifested in S.E. is probably caused by the
• use of an increased ethambutol dose (18.5 mg/kg) in a patient with impaired
renal function. Because ethambutol adds no additional benefit to isoniazid
and rifampin after the first 2 months for susceptible organisms, it can be
discontinued. Ethambutol is excreted by the kidney (50%–80%), and her
ethambutol dosage interval (or dosage) should have been increased based
on the decline in creatinine clearance

49. Reference
• https://www.google.co.in/search?q=isoniazid+tyramine&source=lnms&tbm=isch&sa=X&ve
d=0ahUKEwiRwrDQsePdAhVMKY8KHcX1AJEQ_AUIDigB&biw=1350&bih=640#img
• https://www.researchgate.net/publication/246757792_Hyperuricemia_and_Arthralgias_Dur
ing_Pyrazinamide_Therapy_in_Patients_With_Pulmonary_Tuberculosis
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940184/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940184/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940184/
• http://truvenhealth.com/Products/Micromedex/Quick-Reference/Mobile
• https://www.drugs.com/sfx/rifampin-side-effects.html
• Koda Kimble AndYoung’s – AppliedTherapeutics
the clinical use of drugs (tenth edition )