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Management of
adverse drug events
Graham Bothamley
Homerton University Hospital
NHS Foundation Trust, London; UK
Elmira Ibrahim
Marius Nasta Institute, National Tuberculosis Program
Bucharest; Romania
Christoph Lange
Clinical Infectious Diseases, Research Center Borstel
University of Lübeck; Germany
Definitions - I
Adverse drug
reaction
A response to a medicine which is noxious and unintended,
and which occurs at doses normally used in man
Adverse drug event
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
Causal
The medicine has contributed to or caused the event
Causality assessment
The evaluation of the likelihood that a medicine was the
causative agent of an observed adverse reaction
Dechallenge
The withdrawal of a drug from a patient; the point at which
the continuity, reduction or disappearance of adverse effects
may be observed
Rechallenge
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
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.
Risk factor
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.
Serious 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
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Accidents
Alimentary
Associations (of concomitant
medicines & events)
Autonomic
Circulatory
Died
Device
Endocrine / metabolic
Ear, Nose & Throat
Eyes
Haematological
Hepatobiliary
•
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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 antituberculosis 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
Stevens–Johnson 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
Lifethreatening
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 druginduced acute liver failure if
there is jaundice)
Most anti-TB drugs
Stop anti-TB drugs
Visual impairment (other causes Ethambutol
excluded)
Stop ethambutol
Shock, purpura, acute renal
failure
Rifampicin
Stop rifampicin
Decreased urine output
Streptomycin
Stop streptomycin
Minor adverse reactions
Adverse reaction
Nausea, anorexia
Probable cause Action
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 Mg2+
» 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”.
Clinical review of symptoms and
signs, medication use, side-effects, complications
Ask
If this is first visit:
• Review the patient’s 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 eye—yellow?
• Look for thrush
If any new symptoms:
• Do further assessment of symptoms.
Monitoring during treatment of DR-TB
Monitoring evaluation
Recommended frequency
Evaluation by clinician
At baseline, and at least monthly until conversion, then
every 2–3 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 1–3 weeks in HIV-infected patients,
diabetics and other high-risk patients
Serum potassium
Monthly while receiving an injectable agent. Every 1–3
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 1–3 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