Definitions - I

Adverse drug
reaction


Adverse drug event


Causal

Causality assessment


Dechallenge



Rechallenge
A response to a medicine which is noxious and unintended,
and which occurs at doses normally used in man

Any untoward medical occurrence that may present during
treatment with a pharmaceutical product, but which does
not necessarily have a causal relationship with this treatment

The medicine has contributed to or caused the event

The evaluation of the likelihood that a medicine was the
causative agent of an observed adverse reaction

The withdrawal of a drug from a patient; the point at which
the continuity, reduction or disappearance of adverse effects
may be observed

The voluntary or inadvertent re-administration of a medicine
suspected of causing an adverse reaction. The point at which
a drug is again given to a patient after its previous
withdrawal

Definitions - II
Relationship
assessment





Risk factor



Serious Reaction
The objective evaluation of the relationship between the
administration of a medicine and a health event, taking into
consideration duration of therapy to onset of event, response
to dechallenge and rechallenge (if performed) and the
presence of other diseases or medicines that could have
caused the event. This process stops short of attempting to
establish a causal relationship, but is an essential preliminary.

A characteristic associated with an increased probability of
occurrence of an event. In the presence of a risk factor, a
patient is more likely to develop an adverse reaction.

A serious reaction is an adverse drug reaction which involves any of
the following:
- death or a life-threatening experience;
- hospitalization or prolongation of hospitalization;
- persistent significant disability;
- congenital anomaly
Major Clinical Categories in Events Dictionary
Accidents
Alimentary
Associations (of concomitant
medicines & events)
Autonomic
Circulatory
Died
Device
Endocrine / metabolic
Ear, Nose & Throat
Eyes
Haematological
Hepatobiliary

Immunological
Infections
Lactation exposure
Musculoskeletal
Neoplasms
Neurological
Poisoning
Pregnancy register
Mental health disorders
Reproductive organs
Respiratory
Skin
Surgery
Unclassified
Urological
Individual medicines for TB therapy (alphabetical)
Am amikacin Lfx levofloxacin
Amx/Clv amoxicillin/clavulanate Lzd linezolid
Cm capreomycin Mfx moxifloxacin
Cfx ciprofloxacin Ofx ofloxacin
Clr clarithromycin PAS p-aminosalicylic acid
Cfz clofazimine Pto protionamide
Cs cycloserine Z pyrazinamide
E ethambutol Rfb rifabutin
Eto ethionamide R rifampicin
Gfx gatifloxacin S streptomycin
Ipm imipenem Trd terizidone
H isoniazid Thz thioacetazone
Km kanamycin
Antituberculosis drugs (by group)
Group Description Drug Abbreviation
1. First-line oral antituberculosis drugs isoniazid
rifampicin
ethambutol
pyrazinamide
rifabutin
H
R
E
Z
Rfb
2. Injectable antituberculosis drugs kanamycin
amikacin
capreomycin
streptomycin
Km
Amk
Cm
S
3. Fluoroquinolones levofloxacin
moxifloxacin
ofloxacin
Lfx
Mfx
Ofx
4. Oral bacteriostatic second-line
antituberculosis drugs
ethionamide
protionamide
cycloserine
terizidone
p-aminosalicylic acid
Eto
Pto
Cs
Trd
PAS
5. Antituberculosis drugs with unclear
efficacy or unclear role in MDR-TB treatment
(not recommended by WHO for routine use
in MDR-TB patients)
clofazimine
linezolid
amoxicillin/clavulanate
thioacetazone
clarithromycin
imipenem
Cfz
Lzd
Amx/Clv
Thz
Clr
Ipm

ADRs commonly associated with anti-TB drugs
First-line drugs* Second-line drugs**
Hepatitis Nausea/vomiting
Nausea/vomiting/GI upset Diarrhoea
Rash Arthralgia
Weakness/fatigue Dizziness/vertigo
Arthralgia Hearing disturbances
Fever Headache
Pruritus Sleep disturbances
Headache Electrolyte disturbances
Vertigo/tinnitus Abdominal pain
Visual disturbances Anorexia
Paraesthesia Gastritis
Anorexia/weight loss Peripheral neuropathy
Abdominal pain Depression
Swelling Tinnitus
Palpitations Allergic reaction
Dyspnoea Rash
Seizures Visual disturbances
Neutrophilia Seizures
Hypothyroidism
Psychosis
Hepatitis
Renal failure/nephrotoxicity
Potentially overlapping toxicities of antiretrovirals and anti-
tuberculosis agents
Potential toxicity Antiretroviral therapy Anti-tuberculosis therapy
Peripheral neuropathy stavudine
didanosine
cycloserine
isoniazid
ethambutol
fluoroquinolones
streptomycin
kanamycin
amikacin
capreomycin
viomycin
ethionamide/prothionamide
linezolid
Psychiatric symptoms efavirenz cycloserine
isoniazid
fluoroquinolones
ethionamide/prothionamide
Hepatitis nevirapine
ritonavir-boosted protease inhibitors
efavirenz
etravirine
maraviroc
pyrazinamide
isoniazid
rifampicin/rifabutin
p-aminosalicylic acid
ethionamide/prothionamide
fluoroquinolones
Potential toxicity Antiretroviral therapy Anti-tuberculosis therapy
Gastrointestinal intolerance zidovudine
protease inhibitors didanosine
ethionamide/prothionamide
p-aminosalicylic acid
pyrazinamide
isoniazid
rifampicin
ethambutol
clofazimine
Renal toxicity

tenofovir
indinavir
streptomycin
kanamycin
capreomycin
amikacin
viomycin
rifampicin
Bone marrow toxicity zidovudine linezolid
rifampicin/rifabutin
Lactic acidosis

stavudine
didanosine
zidovudine
linezolid
StevensJohnson syndrome

nevirapine efavirenz
etravirine
thioacetazone
cycloserine
linezolid ethambutol
streptomycin
Arrhythmias / QT prolongation atazanavir/ritonavir
saquinavir/ritonavir
lopinavir/ritonavir
fluoroquinolones
Rash / pruritus nevirapine efavirenz
etravirine
abacavir
rifampicin/rifabutin
pyrazinamide
Grade of toxicity
Grade Toxicity
GRADE 1
Mild
Transient or mild discomfort; no limitation in activity;
no medical intervention or therapy required
GRADE 2
Moderate
Mild to moderate limitation in activity some
assistance may be needed; no or minimal medical
intervention or therapy required
GRADE 3
Severe
Marked limitation in activity, some assistance usually
required; medical intervention or therapy required,
hospitalization possible
GRADE 4
Life-
threatening
Extreme limitation in activity, significant assistance
required; significant medical intervention or therapy
required, hospitalization or hospice care probable
Adverse reaction Symptoms and signs Usual drug responsible
Audiovestibular
manifestations
Hearing loss, vertigo, new-onset tinnitus Aminoglycosides, capreomycin
Blood sugar
abnormalities
Dizziness, sweating, fainting, poor response
to infections
Fluorquinolones (FQ), rifampicin
(R), pyrazinamide (Z)
Dermatitis (2) Itching, rash, hives, fever, petechial rash Z, rifamycins; thiacetazone & HIV
Gastro-intestinal (1) Anorexia, nausea, vomiting, epigastric pain Z, rifamycins; PAS
Haematology Leucopenia, thrombocytopenia, anaemia,
eosinophilia
R (intermittent); linezolid, H,
capreomycin
Hepatitis (3) Anorexia, nausea, vomiting, jaundice,
abdominal pain
RHZ(E)
Hypothyroidism Fatigue, weight gain, depression PAS, pro/etionamide
Joint, tendon Gout-like manifestations; SLE;
tendinopathies
Z; H (rarely R); FQ;
Neuro/psychiatric Headaches, depression, agitation;
suicidal ideation
H, FQ; cycloserine
Peripheral neuropathy Numb feet or hands H, linezolid; cycloserine,
aminoglycosides
Renal impairment Uraemia; haematuria Aminoglycosides, capreomycin;
rifampicin (intermittent)
Visual Vision loss and colour blindness; uveitis E, linezolid; rifabutin, rifapentane;
Major adverse reactions
Adverse reaction Probable cause Action
Skin rash with or without itching Streptomycin, isoniazid,
rifampicin, pyrazinamide
Stop anti-TB drugs
Deafness (no wax on otoscopy) Streptomycin Stop streptomycin
Dizziness (vertigo and
nystagmus)
Streptomycin Stop streptomycin
Jaundice (other causes
excluded), hepatitis
Isoniazid, pyrazinamide,
rifampicin
Stop anti-TB drugs
Confusion (suspect drug-
induced acute liver failure if
there is jaundice)
Most anti-TB drugs Stop anti-TB drugs
Visual impairment (other causes
excluded)
Ethambutol Stop ethambutol
Shock, purpura, acute renal
failure
Rifampicin Stop rifampicin
Decreased urine output Streptomycin Stop streptomycin
Minor adverse reactions
Adverse reaction Probable cause Action
Nausea, anorexia RHZ Anti-emetic; with a small meal
Joint pains Z NSAIDs (vitamin D?)
Drowsiness H Take at bed-time
Itching R Anti-histamine
Drug interactions
Alcohol
Anticoagulation

Opiates
Oral contraceptive


RHZ
R

R
R

Avoid or limit intake
Daily heparin
(danger if double dose of warfarin)
Double dose
Alternative contraception
Cessation of a single drug
Adverse event Drug to stop
Deafness
Vertigo and nystagmus
Renal impairment
Streptomycin
Visual impairment
(exclude other causes)
Ethambutol
Flu like syndrome with
shock
purpura
acute renal impairment
Rifampicin
Management of cutaneous reactions
Itching without a rash and there is no other obvious cause
- symptomatic treatment with antihistamines and skin moisturizing,
- continue TB treatment while observing the patient closely.

If a skin rash develops
- all anti-TB drugs must be stopped.
- Once the reaction has resolved, anti-TB drugs are reintroduced one by
one, starting with the drug least likely to be responsible for the reaction
(rifampicin or isoniazid) at a small challenge dose, such as 50 mg isoniazid.
- The dose is gradually increased over 3 days.
- This procedure is repeated, adding in one drug at a time.
A reaction after adding in a particular drug identifies that drug as the one
responsible for the reaction !
- The alternative regimens are applicable when a particular drug cannot be
used because it was implicated as the cause of a cutaneous reaction.
Drug-induced hepatitis
Diagnosis
AST/ALT > 3-5x upper limit of normal
Rise in bilirubin above normal
Action
Stop RHZ
If treatment required SEFq
Re-introduction of TB drugs (1)
LFTs normal or AST/ALT <2x upper limit
If LFTs due to EtOH (or not due to TB drugs)
restart RHZ together
If bilirubin and ALP
rifampicin most likely
start HE
add Z 1 week later if OK
If OK, use S (+Fq)

Re-introduction of TB drugs (2)
ATS : R RH RHE (2RHE/7RH)
Common: H RH RHE (2RHE/7RH)
NYBTC: E ER REZ (2REZ/7RE)
If R the problem, 2SHEZ/10HE
If H the problem, 2REZ/7RE
If Z the problem, 2SHE(Fq)/10HE

Second line drugs
Minor adverse effects treat symptomatically
Major adverse effects
stop drug if possible (except hypothyroidism PAS, Eto/Pto)
drug treatment of symptoms if essential
anticonvulsants
amitriptyline or gabapentin for peripheral
neuropathy
amiloride or spironolactone if K
+
or Mg
2+

antipsychotics (may be effective treatment!)
avoid PPIs (pyrazinamide)
avoid aspirin NSAIDs (efflux)
Monitoring and recording adverse effects
Most TB patients complete their treatment without any significant
adverse drug effects. However, a few patients do experience adverse
effects.
Important that patients be clinically monitored during treatment so
that adverse effects can be detected promptly and managed properly.
Routine laboratory monitoring is not necessary.
Method:
- teaching patients how to recognize the symptoms of common effects,
- urging them to report if they develop such symptoms
- asking about symptoms when patients come to collect drugs.
Adverse reactions to drugs should be recorded on
the TB Treatment Card under Observations.
Ask
If this is first visit:
Review the patients past medical history,
including their past history of TB treatments.
For all visits:
How have you been?
Have you needed urgent medical care?
If yes, ask for record/diagnosis.
Have your TB symptoms improved?
Cough? Sputum?
Difficult breathing?
Fever/night sweats?
Weight loss?
Have you had any side-effects?
Nausea/vomiting?
Fatigue?
Skin rash?
Tingling in hands or feet?
Deafness? Ringing of ears?
Headache?
Seizures? Loss of consciousness?
Feeling anxious? Feeling sad or unhappy?
What problems have you had taking the
medicines?
Have you missed any doses?
Have you had any problems with your
treatment supporter?
What else do you want to talk about?
Look
In all patients:
Weigh the patient. Calculate weight gain or loss.
Record. If weight loss, ask about food intake
Measure temperature
Count respiratory rate
Look for pallor. If pallor, check haemoglobin
Look at whites of the eyeyellow?
Look for thrush
If any new symptoms:
Do further assessment of symptoms.
Clinical review of symptoms and
signs, medication use, side-effects, complications
Monitoring during treatment of DR-TB
Monitoring evaluation Recommended frequency
Evaluation by clinician At baseline, and at least monthly until conversion, then
every 23 months
Screening by DOT worker At every DOT encounter
Sputum smears and
cultures
Monitor smears and cultures monthly throughout treatment. (Note:
programmes with limited resources may choose to do smears
monthly but cultures only every other month)
Weight

At baseline and then monthly
Drug susceptibility At baseline in programmes doing individualized treatment
Chest radiograph At baseline, and then every 6 months
Serum creatinine At baseline, then monthly if possible while receiving an
injectable drug. Every 13 weeks in HIV-infected patients,
diabetics and other high-risk patients
Serum potassium Monthly while receiving an injectable agent. Every 13
weeks in HIV-infected patients, diabetics and other high-risk
patients
Monitoring evaluation Recommended frequency
Thyroid stimulating hormone
(TSH)
Every 6 months if receiving ethionamide/protionamide
hormone and/or PAS; and monitor monthly for
signs/symptoms of hypothyroidism. TSH is sufficient for screening for
hypothyroidism; it is not necessary to measure hormone thyroid levels
Liver serum enzymes Periodic monitoring (every 13 months) in patients
receiving pyrazinamide for extended periods or for patients
at risk for or with symptoms of hepatitis. For HIV-infected
patients, do monthly monitoring
HIV screening At baseline, and repeat if clinically indicated
Pregnancy tests At baseline for women of childbearing age, and repeat if
indicated
Haemoglobin and
white blood count
If on linezolid, monitor weekly at first, then monthly or as
needed based on symptoms; there is little clinical experience
with prolonged use
For HIV-positive patients on an ART regimen that includes AZT,
monitor monthly initially and then as needed based on symptoms
Lipase

Indicated for work up of abdominal pain to rule out
pancreatitis in patients on linezolid, D4T, ddI, ddc.
Lactic acidosis Indicated for work up of lactic acidosis in patients on linezolid or ART
Serum glucose If receiving gatifloxacin, monitor glucose frequently (weekly) and educate patient
on signs and symptoms of hypoglycaemia and hyperglcycaemia
Prevention of adverse effects of drugs

Some drug-induced side-effects can be prevented!
Eg: isoniazid / cycloserine / terizidone - induce peripheral neuropathy:
numbness or a tingling or burning sensation of the hands or feet
Occurs more commonly in:
- pregnant women
- people with the following conditions: HIV infection, alcohol dependency,
malnutrition, diabetes, chronic liver disease, renal failure.
These patients should receive preventive treatment with
pyridoxine, 10 mg/day along with their anti-TB drugs
(other guidelines recommend 25 mg/day)
Commonly used ancillary medications
Indication Drug
Nausea, vomiting, upset stomach Metoclopramide, dimenhydrinate, prochlorperazine,
promethazine, bismuth subsalicylate
Heartburn, acid indigestion, sour stomach, ulcer H2-blockers (ranitidine, cimetidine, famotidine, etc.),
proton pump inhibitors (omeprazole, lansoprazole, etc.)
Avoid antacids because they can decrease absorption
of flouroquinolones
Oral candidiasis (non-AIDS patient) Fluconazole, clotrimazole lozenges
Diarrhoea Loperamide
Depression Selective serotonin reuptake inhibitors (fluoxetine,
sertraline), tricyclic antidepressants (amitriptyline)
Severe anxiety Lorazepam, diazepam, clonazepam
Insomnia Dimenhydrinate
Psychosis Haloperidol, thorazine, risperidone (consider
benzotropine or biperiden to prevent extrapyramidal
effects)
Indication Drug
Seizures Phenytoin, carbamazepine, valproic acid, phenobarbital
Prophylaxis of neurological complications of
cycloserine
Pyridoxine (vitamin B6)

Peripheral neuropathy Amitriptyline
Vestibular symptoms Meclizine, dimenhydrinate, prochlorperazine,
promethazine
Musculoskeletal pain,
arthralgia, headaches
Ibuprofen, paracetamol, codeine
Cutaneous reactions, itching Hydrocortisone cream, calamine, caladryl lotions
Systemic hypersensitivity reactions Antihistamines (diphenhydramine, chlorpheniramine,
dimenhydrinate), corticosteroids (prednisone,
dexamethasone)
Bronchospasm Inhaled beta-agonists (albuterol, etc.), inhaled
corticosteroids (beclomethasone, etc.), oral steroids
(prednisone), injectable steroids (dexamethasone,
methylprednisolone)
Hypothyroidism Levothyroxine
Electrolyte wasting Potassium and magnesium replacement