antituberculosis adverse drug reactions

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Adverse drug reactions to Antituberculosis Drugs Presented by Wat Mitthamsiri, MD November 22, 2013

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Page 1: Antituberculosis Adverse Drug Reactions
Page 2: Antituberculosis Adverse Drug Reactions

Current Items and Regimens

Epidemiology of Anti-TB ADR

ADR of Specific Items

Management of Anti-TB ADR

Desensitization Protocols

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Yee, Valiquette, Pelletier, et al., Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003

•Objective: • To estimated the incidence and risk factors, of major side effects from 1st-line anti-TB drugs among 430 patients treated at the Montreal Chest Institute between 1990 and 1999

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Yee, Valiquette, Pelletier, et al., Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003

•Characteristics of patients

Page 13: Antituberculosis Adverse Drug Reactions

Yee, Valiquette, Pelletier, et al., Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003

•Characteristics of patients

Page 14: Antituberculosis Adverse Drug Reactions

Yee, Valiquette, Pelletier, et al., Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003

•Characteristics of patients

Page 15: Antituberculosis Adverse Drug Reactions

Yee, Valiquette, Pelletier, et al., Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003

Page 16: Antituberculosis Adverse Drug Reactions

Yee, Valiquette, Pelletier, et al., Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003

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• A 5-month regimen in 78 patients was evaluated for treatment of drug addicts and prisoners in Hong Kong with pulmonary TB

• Regimen: Daily Rx of 3HRZES+3HRZE • Ethambutol 25 mg/kg/day x2 months, then 15 mg/kg/day • Streptomycin 750 mg/day x3 months.

Hong Kong Chest Service/British Research Council Study, Tubercle 1983; 64: 265-74.

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• ADR required modification of the regimens occured in 8 (10%) patients

• Cutaneous reactions 1 patient • Vestibular 3 patients • Gastrointestinal 1 patient • Abnormal liver functions 3 patients • Hepatitis 1 patient • Arthralgia 3 patients • Headache 1 patient

Hong Kong Chest Service/British Research Council Study, Tubercle 1983; 64: 265-74.

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• 627 patients from Hong Kong were studied • All patients also received streptomycin. • During the first 2 months

• 40% of patients in both groups complained of adverse effects • Only 5% required termination of drugs

• 4% from the combined group • 7% from the separate formulations group

Hong Kong Chest Service/British Research Council, Am Rev Respir Dis 1991; 143: 700-6.

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• 5 different 6-month regimens were compared in randornised trials in Hong Kong

• (1) E3H3R3Z3S3 • (2) S3H3R3Z3 • (3) S3E3R3H3 • (4) E3H3R3Z3 • (5) EHRZ numbers = weekly frequency of drug administration

Hong Kong Chest Service/British Research Council, Tubercle 1982; 63: 89-98.

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• ADR: • (1) E3H3R3Z3S3: 35% of 244 patients • (2) S3H3R3Z3: 34% of 243 patients • (3) S3E3R3H3: 18% of 238 patients • (4) E3H3R3Z3: 26% of 241 patients • (5) EHRZ: 25% of 239 patients

Hong Kong Chest Service/British Research Council, Tubercle 1982; 63: 89-98.

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• Majority of ADR: Mild GI disorders not requiring alteration of treatment • 2nd majority of ADR: Mild cutaneous reactions • Only 50 patients (4% of 1205 patients) had a significant ADR -> termination of >/= 1 drugs

• 14 in regimen 1 • 15 in regimen 2 • 6 in regimen 3 • 7 in regimen 4 • 8 in regimen 5

Hong Kong Chest Service/British Research Council, Tubercle 1982; 63: 89-98.

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• Hepatic reactions (abnormal LFT, regardless of symptoms, leading to

modification of regimen): 21 (1.7%) patients • 3, 2, 0, 3 and 13 patients, from regimens 1 to 5, respectively • 16 patients had no symptoms, 3 patients had jaundice • 15 patients can resumed Rx once their LFT had returned to normal • In all regimens, there was a slight increase of ALT during the early treatment with subsequent decline at 2 months and after.

Hong Kong Chest Service/British Research Council, Tubercle 1982; 63: 89-98.

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• Hepatic reactions • No statistically significant difference between the 4 intermittent regimens • No evidence that PZA-containing regimens were associated with greater hepatic toxicity • In 195 patients on the daily regimen with normal LFT before treatment, 31 % subsequently had one or more abnormal results compared with 22% of the 187 patients on the corresponding intermittent regimen (EHRZ)

Hong Kong Chest Service/British Research Council, Tubercle 1982; 63: 89-98.

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• Hepatic reactions • No hepatic reactions in the 238 patients with H3R3E3S3 regimen (the only non-PZA regimen) • ALT level measured serially

• Tended to be higher on the daily regimen compared with the intermittent regimens (small differences and not statistically significant) • No difference between various intermittent regimens

Hong Kong Chest Service/British Research Council, Tubercle 1982; 63: 89-98.

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• 530 patients were treated

• Using 5 regimens of 6 months duration

• The initial phase was 2 months of SHRZ or EHR

•Followed by, 4H2R2 or 4HRE or 4H1R1E1 or 4H2R2E2 First number = treatment duration in months Subscript numbers = weekly frequency of drug administration

Hong Kong Chest Service/British Research Council, Am Rev Respir Dis 1991; 143: 700-6.

Page 27: Antituberculosis Adverse Drug Reactions

• ADR occurred in 66 patients (12.4%) • Liver toxicity 48 patients (9%) ,mostly mild and transient • Flu-like syndromes 2 patients both on RFP 600 mg/day • The use of PZA in the initial phase of all the regimens did not increase the ADR incidence • 56% of patients receiving PZA had raised serum uric acid levels but without arthralgia • Only 10 patients (1.8%) did ADR lead to alteration or withdrawal of treatment

Hong Kong Chest Service/British Research Council, Am Rev Respir Dis 1991; 143: 700-6.

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• Common manifestation: • Red itchy rash (papular or macular), usually involves the trunk more than the extremities • Periorbital swelling • Conjunctivitis • Rigor • Malaise • Vomiting • Aching limbs

Anil M. et al., Drug Safety 12 (1): 1-25,1995

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• Common manifestation: • Headache • Generalised lymphadenopathy • Albuminuria • Hepatosplenomegaly and occasionally jaundice

• •Rare manifestation

• Exfoliative dermatitis or SJS can occur • Especially following thioacetazone

Anil M. et al., Drug Safety 12 (1): 1-25,1995

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• Timing • Usually occur within the first 2 months • Commonly in the first 4 weeks

• Anaphylactic reactions can occur if a drug is given to a patient after a previous hypersensitivity reaction

Anil M. et al., Drug Safety 12 (1): 1-25,1995

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• Major target organ • Liver • Kidneys • Eyes • Vestibular system • Nervous systems

Anil M. et al., Drug Safety 12 (1): 1-25,1995

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• Hepatitis • Usually develop within the first 3 months of treatment • More likely to occur in combination regimens • In 230 patients in Singapore who on 2SHRZ/HRZ or 2SHRZ/HR, hepatitis developed in 11 (3%) patients

Singapore Tuberculosis Service/British Medical Research Council., Am Rev Respir Dis 1979; 119: 579-85

• In 604 patients taking daily SHRZ, jaundice occurred in 44 patients (7%)

• Significantly more frequent than 2 patients (1% )in 304 patients taking SHZ (no RFP)

Tuberculosis Research Centre, Madras, and National Tuberculosis Institute, Bangalore., Am Rev Respir Dis 1986; 134: 27-33

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• Hepatitis

• A meta-analysis of 34 studies of patients taking INH and/or RFP. Hepatoxicity occurred:

• 0.6% in 38 257 patients receiving INH alone • 1.6% of 2053 patients taking INH but not RFP • 1.1 % of 1264 patients receiving RFP but not INH • 2.55% of 6105 patients on both INH and RFP

Steele MA, et al., Chest 1991; 99: 465-71

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EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Hepatitis • Deaths due to hepatitis occur infrequently • More likely to occur with combination therapy • But the increase in risk is so small and not outweight benefits of combination regimen • Hepatitis is more common in the elderly • Pre-existing liver disease does not contraindicate the use of anti-TB drugs but necessitates careful review and biochemical monitoring

Anil M. et al., Drug Safety 12 (1): 1-25,1995

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Yee, Valiquette, Pelletier, et al., Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003

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• Synthesised in 1912 • Most potent early bactericidal antituberculosis agent • Metabolised by two pathways

• Direct pathway • Nonsignificant in fast acetylators • Accounts for some of metabolism of slow acetylators

• Indirect pathway • Favored by fast acetylators

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Presenter
Presentation Notes
fast acetylators (higher N-acetyltransferase enzyme activity), slow acetylators (lower N-acetyltransferase enzyme activity)
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Senousy, B. E. et al. Nat. Rev. Gastroenterol. Hepatol. 7, 543–556 (2010)

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Senousy, B. E. et al. Nat. Rev. Gastroenterol. Hepatol. 7, 543–556 (2010)

Indirect pathway

Favored by fast acetylator

Direct pathway

Account for some slow acetylator

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• 90% of Orientals are fast acetylators • 45% of black and white populations are fast acetylators Major toxicities of INH

• Hepatic • Dermatological • Allergic • Neurological

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Risk factors • Advance age • Liver transplant • Previous elevation of transaminases • Previous liver damage • Excessive alcohol consumption

• Hepatitis B carriers: No elevated risk • Unclear evidence of HIV-positive patient as higher risk population

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Pregnancy and postpartum states seem to be a period of particular risk • Timing: Drug-induced hepatitis usually occurs within the first 3 months of treatment but can occur at any time during treatment

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Asymptomatic elevation in liver enzymes will be seen in 10 – 22% • These elevation usually resolve, despite drug continuation • About 1/5 may persistently have elevated transaminases, which return to normal only after stopping the medication

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Overall incidence has been estimated at 5.4% • Mostly: urticaria, angioneurotic oedema and morbiliform eruptions • Up to 1.2% of patients develop erythema • Other reactions:

• Acne • Xerostomia • Nonthrombocytopenia purpura • Striae cutis atropica • Pruritis

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 48: Antituberculosis Adverse Drug Reactions

• Other reactions: (continued) • Lupus erythematous-like syndrome • Exfoliative dermatitis • TEN/SJS • Bullous disease • Generalised pustular dermatosis • Pellagra-like syndrome • Anagen effluvium • Associated lichenoid eruption • Alopecia

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 49: Antituberculosis Adverse Drug Reactions

• Chills or fever • Sustained or recurrent • Alone or as part of a hypersensitivity reaction with rash • Occurring 10 – 20 days after starting treatment • Quickly resolve once the medication is withheld • Reappear with rechallenge

• This reaction may even present as anaphylaxis

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Pyridoxine responsive anaemia • Agranulocytosis • Neutropenia • Coombs-positive haemolytic anaemia • Disseminated intravascular coagulation • Pure red cell aplasia • Hemophagocytic syndrome

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• INH binds to pyridoxine and depletes pyridoxine supplies

• Pyridoxine is required by GABA transaminase and glutamic acid decarboxylase which synthesise GABA • Pyridoxine deficiency -> Decreased levels of brain GABA -> INH-induced seizures • Pyridoxine is also involved in the metabolism of neurotransmitters such as dopamine, serotonin and tryptamine

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Peripheral neurotoxicity • Dose-related • Seen in <0.2%–1.2% of patients at conventional doses • Usually appear after six months of treatment • Can appear earlier at higher doses

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 53: Antituberculosis Adverse Drug Reactions

• Peripheral neurotoxicity • Risk factors:

• Increases with age • Slow acetylator status • Malnutrition • Diabetes • Renal failure • Alcoholism • Pregnancy and breastfeeding • Evidence that HIV is a risk factor is inconsistent

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 54: Antituberculosis Adverse Drug Reactions

• Peripheral neurotoxicity • Paresthesias

• Burning sensation, pricking pain, numbness or tingling • Start in the feet and can climb up to the hands and arms (in a stocking-glove distribution)

• Accompanied by muscle aches, occasionally muscular weakness • Can progress to more severe symptoms such as cerebellar ataxia

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Peripheral neurotoxicity • Neurological examination findings:

• Loss of sensory modalities • Light touch • Pain • Position • Vibration

• Areflexia • Muscle weakness • Atrophy

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 56: Antituberculosis Adverse Drug Reactions

• Peripheral neurotoxicity • Usually reversible with withdrawal of the medication • Except for cases that progressed to obvious muscle weakness

• Prevention: • Pyridoxine 25 – 50 mg once a day • Recommended for high risk groups

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Other adverse neurological effects: • Dysarthria • Irritability • Dysphoria • Inability to concentrate • Seizures (INH lowers the seizure threshold) • Hallucinosis • Psychosis

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Other adverse neurological effects: (continued) • Memory loss • Confusion • Altered mental status • Ototoxicity • Optic neuropathy • Other cranial neuropathies

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Symptoms: • N/V, visual disturbances, dizziness and slurred speech • Progression to stupor and seizures • Occurrence: 0.5 – 2 hr after ingestion • Progression to coma, hypotension and death in up to 21% of cases

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• PE: • Fever • Tachycardia • Hypotension • Oliguria and anuria

• Lab: • Hyperglycaemia • High anion gap metabolic acidosis • β-hydroxybutyric acidosis

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Initial management • Decontamination • Neurological, respiratory and cardiovascular support • Fluids and bicarbonate should be given • Correct metabolic acidosis • Forced diuresis • IV pyridoxine: Dosage of 1:1 with the estimated amount of ingested INH • Co-ingestion of pyridoxine may prevent serious ADR

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Initial management • Anticonvulsants (benzodiazepines or barbiturates) may be used to treat seizures • INH-induced seizures may respond to pyridoxine alone • Peritoneal or haemodialysis should be considered • Prevention measures should be applied

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Drug interactions • INH inhibits mainly CYP 2C19 and CYP 3A

• Lupus-like syndrome: rare (< 1%) • Lupus pleuritis • Lupus nephritis

• Histamine poisoning syndrome: Rare • Flushing of head and neck • Generalised throbbing headache • Rapid heart beat • Trembling

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Presenter
Presentation Notes
INH is a known inhibitor of histaminase. Specific Rx of histamine poisoning: Avoidance of the culprit foods (Swiss/strong cheddar cheese, wine, skipjack fish, hurulla fish and tuna fish)
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• Occupational asthma • Acute worsening of severe asthma • Ocular lens dislocation secondary to hyperhomocysteinemia • Pancreatitis • Hypoglycemia in a newborn

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 65: Antituberculosis Adverse Drug Reactions

• Synthesised in 1966 • Semisynthetic antibiotic which inhibits DNA-dependant RNA polymerase • A hepatic enzyme inducer -> reduce the serum concentration and efficacy of multiple other drugs • Causes orange discoloration of tears, sweat and urine

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 66: Antituberculosis Adverse Drug Reactions

• Synthesised in 1966 • Semisynthetic antibiotic which inhibits DNA-dependant RNA polymerase • A hepatic enzyme inducer -> reduce the serum concentration and efficacy of multiple other drugs • Causes orange discoloration of tears, sweat and urine.

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 67: Antituberculosis Adverse Drug Reactions

• ADR from RIF alone for LTBI in various populations • Rates of 22 – 26% • Discontinuation of therapy by 1 – 14%

• In multi-drug regimens • ADR leading to drug discontinuation is 1.7 – 3.3%

• Most common ADR to daily treatment: • Cutaneous • Hepatic • Hypersensitivity reactions

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Transient increased serum bilirubin on the 1st day of treatment

• But normalise within 2 weeks • May induce hepatocellular dysfunction early in the treatment

• Resolves without drug discontinuation • Risk factors:

• Increased risk in alcohol abuse and prior liver disease • No data of using RFP alone in HIV or HCV patients • Equivocal evidence in HBV patient

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 69: Antituberculosis Adverse Drug Reactions

• Most common RFP ADR • Common presentation:

• Flushing of the face and neck • Sometimes with pruritis or a rash • Occur in 0.3 – 10% of patients and is often transient • Usually occur within a few hours after ingestion, early in the course of treatment

• Dose-dependant • Occur more frequently in intermittent regimens

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 70: Antituberculosis Adverse Drug Reactions

• Other manifestation: • Urticaria • Maculopapular lesions • Pemphigus and pemphigus foliaceus • Porphyria cutanea tarda • Chronic papular acneiform lesions • Generalised burning sensation • Alopecia areata • Ocular symptoms: Exudative conjunctivitis • Stevens-Johnson syndrome may also occur

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 71: Antituberculosis Adverse Drug Reactions

• Reports of Rash, fever, lymphadenopathy, hepatosplenomegaly and elevated transaminases • Desensitisation may be successful • Just case reports of:

• Anaphylaxis • Lupus erythematosus • Red-man syndrome

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 72: Antituberculosis Adverse Drug Reactions

• Thrombocytopenia: Most common • 0.08% of patients on a daily regimen • 1 – 6% of patients on a twice-weekly regimen • Happens within 3 h after a dose • Platelet counts return to normal within 36 h • Mechanism?

• Intravascular immune phenomenon • Associated with antirifampin Ab • Platelet-membrane GPIb/IX complex: Target for the drug-dependent Ab

• Reversible if the RFP is withdrawn EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Other presentations: • Haemolytic anaemia • Neutropenia (rare) • Hypoprothrombinemia

• RFP interferes with vitamin K absorption and metabolism

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 74: Antituberculosis Adverse Drug Reactions

• Common presentations: • Loss of appetite • Nausea, vomiting and diarrhoea • Mild abdominal pain • Lead to regimen modification in up to 9% of patients • Can appear at any time in the course of treatment • More common with the intermittent regimens

• Rare presentations: • Eosinophilic colitis • Pseudomembranous colitis • Pill-induced oesophagitis

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 75: Antituberculosis Adverse Drug Reactions

• Presentations: • Fever • Chills • Headache • Dizziness • Bone pain • Shortness of breath: Rare • Occasionally, progress to hypotension and shock • Begin 1 – 2 h after each dose of RFP • Can last up to 8 h

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 76: Antituberculosis Adverse Drug Reactions

• Presentations: • Typically appears after the 3rd month of therapy • Dose-related • Higher incidence in longer intervals between doses • Evidence points to an Ab-mediated cause • Rx:

• Stop RFP: rarely needed • Temporary interruption of therapy • Dose reduction • Change to daily regimen

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Acute tubular necrosis • S/S: Fever, nausea, vomiting, diarrhoea, abdominal pain, haemolytic anaemia and thrombocytopenia • Often associated with:

• Intermittent regimen • Daily regimen that is taken irregularly • Restarted treatment after an interval of cessation

• Often need dialysis temporarily • Majority were recover

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 78: Antituberculosis Adverse Drug Reactions

•Other presentations: • RPGN with anti-RIF Ab • Acute interstitial nephritis • Light chain proteinuria • Minimal change nephrotic syndrome

• RFP-associated acute renal failure occurred in 0.05% of patients treated for TB

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• CYP450 enzymes inducer • -> increases metabolism of many other compounds • -> reduces their serum concentration and efficacy

• In HIV patients: • RFP should not be used with

• PIs (except: LPV/r, SQV/r) • NNRTIs (except: ddI, TDF, ABC, EFV)

• If these agents must be used, change rifampin to rifabutin

• May enhance hepatotoxicity of acetaminophen

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Myopathy • Organic brain syndrome • Oligomenorrhea and amenorrhea • Interstitial pneumonitis and ARDS • Exudative conjunctivitis • Shock-like syndrome • Fatigue • Myalgia • Headache

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Hyperglycaemia • Hypothyroidism

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• First synthesised in 1952 • Major PZA metabolite, pyrazinoic acid, inhibits renal excretion of uric acid • Major side effects:

• Hepatotoxicity • Rash • Arthralgias

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 83: Antituberculosis Adverse Drug Reactions

• Dose-related • Liver failure and death can occur • Incidence of PZA-induced hepatitis leading to drug discontinuation: 1.3 – 2.5% • Some of cases of hepatitis presented with a hypersensitivity reaction manifested as:

• Fever and eosinophilia • Granulomatous hepatitis

•Pre-existing liver disease increases the risk

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 84: Antituberculosis Adverse Drug Reactions

• Sensation of burning • Red-brown discoloration on sun-exposed areas • Darkening of the skin • Pellagra • Hypersensitivity dermatitis • Photoallergy • Flushing with nausea, dyspnea and abdominal discomfort followed by an itchy rash • Incidence of rash: 0.1 – 5%

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Arthralgias: Common • Affect both small and large joints • Occur during the first 1-2 months of treatment • Concomitant RFP administration does not influence this effect • Arthralgia symptoms is unrelated to uric acid level • 8% of patients can develop joint symptoms • 2% of patients discontinued PZA • Less frequent with intermittent regimens • Rx: NSAIDS (while PZA is continued)

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Effects on serum uric acid level • Average of 2.5-fold elevation • Occur in up to 86% of patients • May precipitate gout episodes, particularly with pre-existing gout • In children:

• > 90% develop elevation in uric acid • But only 10% exceeded normal range

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Nausea in 1 – 5% • Fever in 0.6% • Sideroblastic anaemia • Lupus erythematosus • Convulsions • Photodermatitis • Myoglobinuric renal failure • Aseptic meningitis • Gastrointestinal disturbances • Leukopenia • Acute porphyria

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Discovered in 1961 • Main adverse effect: Ocular toxicity • Probably a result of Cu or Zn binding

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 89: Antituberculosis Adverse Drug Reactions

• Dose-dependent • Incidence rate of 0.3% • Usually present after the 2nd month of treatment • May occur up to 1 year after Eth initiation • Non-inflammatory process that affects central axial fibers of the optic nerve:

• Most common form • Reduced visual acuity • Central scotoma • Loss of green vision (reported as white or grey) • Occasionally loss of red vision (reported as pink)

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

Page 90: Antituberculosis Adverse Drug Reactions

• Other form: • Periaxial toxicity • Peripheral constriction of visual field, especially bitemporal defects • Little or no decrease in visual acuity • Normal red-green discrimination

• Both are forms of retrobulbar neuritis • -> optic disks and fundi are normal in all cases

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Usually reversible • Occasionally, visual impairment, even blindness can be permanent • Subclinical disturbances in color vision found • Risk factors:

• Higher with daily treatment than intermittent regimen • Sex and clinical factors such as type of disease or renal function were not predictive

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Special concerns: In children, especially young children

• Difficulty in assessment of visual acuity • Uncertainty in reporting of symptoms • A reviewed studies found a very low incidence of ocular toxicity even in children < 5 years of age

Trebucq A., Int. J. Tuberc. Lung Dis. (1997) 1:12-15. EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Relatively uncommon • Rash occurred in 0.15% in one large study • Reactions include:

• Hair loss • Urticaria • Erythema multiforme • Angioedema • Hyperhydrosis • Skin striae

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Reactions include: • Bullous eruption • Exfoliative dermatitis • PruritisLichenoid eruption • Erythema multiforme with eosinophilia and elevated liver enzymes

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Macular toxicity • Cholestasis with jaundice • Aplastic anaemia • Neutropenia • Thrombocytopenia • Pulmonary infiltrates with eosinophilia • Exacerbation of lupus • Hyperuricemia

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Headache dependant on intracranial pressure • Relieved by CSF removal

• Tubulointerstitial nephritis with anuric renal failure

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Isolated from Streptomyces griseus in 1944 • Most common adverse effects are

• Ototoxicity, • Rash • Nephrotoxicity

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Dose-dependant • Vestibulocochlear toxicity, with vestibular damage

• Vertigo • Cochlear toxicity

• Present as hearing loss • Might not be clinically significant

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Morbiliform rash • Maculopapular rash • Erythematous rash • Urticarial lesions • Pruritis • Scaling • Lichenoid eosinophilia • Mouth ulcers • Purpura • Exfoliative dermatitis • Stevens-Johnson • DRESS EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Occur in 1 –5% of cases

• Occurred, both in patients and in personnel administering drug

• A case of anaphylaxis by contact with streptomycin through compromised skin barrier was reported

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Nephrotoxicity: • Renal damage in 0.1 – 1% • Transient Cr elevation

• Hematological reactions: • Neutropenia • Hemolytic anemia • Eosinophilia • Thrombocytopenia • Granulocytopenia • Pancytopenia • Aplastic anaemia

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Neurotoxicity: • Transient giddiness • Perioral numbness • Neuromuscular blockade (rare)

• Lupoid reactions

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

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• Streptomycin • Already presented!

• Kanamycin • Synthesized in 1957

• Amikacin • Semi-synthetic compound derived from kanamycin • Has been used since 1972

• Common ADRs: As of Streptomycin

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

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• Used as salvage drugs in the treatment of tuberculosis since 1985

•Essential structure Ciprofloxacin Levofloxacin

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

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• GI effects: • Most common side effects of fluoroquinolones • N/V, aerophagy, anorexia, abdominal discomfort, and diarrhea: 3-17% of the patients • Increased transaminase levels: 1-3% of the patients • Pseudomembranous colitis: rare

• CNS effects: • Dizziness, headache, insomnia, tremors, mood disorder: 0.9-11% of patients • Hallucinations, delusions, and convulsions: rare

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

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• Cutaneous effects: • Erythema, pruritus, and rash: 0.4-2.2% • Phototoxicity in UV exposure • Urticaria, angioedema, anaphylactic reactions, and vasculitis are uncommon

• Musculoskeletal effects: • Arthralgia: 2% (always reversible) • Achilles tendinopathy and Achilles tendon rupture:

• Rare and often associated with previous steroid use, rheumatoid arthritis, kidney failure, and hemodialysis

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

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• Cardiovascular effects: • QT prolongation: Rare

• Leading to VT, including polymorphic ventricular tachycardia (torsades de pointes) • Dose-dependent • Risky group:

• Kidney failure • Liver failure • Cardiomyopathy • HypoMg, hypoK • Using class IA antiarrhythmic drugs or class III antiarrhythmic drugs • Using terfenadine, erythromycin, cisapride, or tricyclic antidepressants

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

Presenter
Presentation Notes
class IA antiarrhythmic drugs (procainamide and quinidine) class III antiarrhythmic drugs (amiodarone and sotalol)
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• Nephrologic effects: • Interstitial nephritis: rare

• Endocrine effects: • Changes in glycemia levels in patient using oral hypoglycemic agents or insulin

• Hematologic effects: • Leukopenia and eosinophilia: <1% of the cases

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

Presenter
Presentation Notes
Interstitial nephritis, characterized by the presence of eosinophils and crystals in urine
Page 110: Antituberculosis Adverse Drug Reactions

• Cutaneous reactions and allergies: • Erythema, pruritus, and rash occur in 0.4-2.2% • Phototoxicity can occur by UV exposure • Urticaria, angioedema, anaphylactic reactions, and vasculitis are uncommon

• Musculoskeletal effects: • Arthralgia: About 2% (always reversible) • Achilles tendinopathy and Achilles tendon rupture

• Rare • Often associated with predisposing factors: previous steroid use, rheumatoid arthritis, kidney failure and hemodialysis

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

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• Synthesized in 1952, • Cycloserine

• Structural analogue of D-alanine amino acid

• Terizidone • Combination of 2 cycloserine molecules

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

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• CNS effects: • Headache, vertigo, dysarthria somnolence, convulsion, mental confusion, and memory deficit • Changes in pressure and quantity of proteins in CSF

• PNS effects: • Peripheral neuropathy

• Psychiatric adverse effects: • Psychotic states with catatonic, paranoid, and depressive reactions, with a risk of suicide

• Pyridoxine can aid in neuroprotective effects Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

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• Used as a 2nd line drug in the treatment of TB since 1956 • Its structure is analogous to INH

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

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• GI effects: • Metallic taste in the mouth, excessive salivation, severe N/V, loss of appetite, and abdominal pain • Hepatotoxicity : About 4.3%,

• Especially in patient with liver disease or alcoholism • Neurotoxicity:

• Peripheral neuritis, optic neuritis, diplopia, irritability, anxiety, depression, hallucinations, convulsions, and psychosis: 1-2% • Pyridoxine can reduce neurotoxicity

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

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• Cardiovascular effects: • Postural hypotension

• Endocrine effects: • Gynecomastia, alopecia, hypothyroidism, impotence, or menorrhagia • Disturb patient’s glycemic control

• Cutaneous reactions: • Acne, photosensitivity, and exanthema

• Hematologic reactions: • Thrombocytopenia and purpura

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

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• A polypeptide antibiotic • Obtained from Streptomyces capreolus • Used as an antituberculosis drug since 1959

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

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• Nephrotoxicity: 20-25% of the patients • Renal tubular damage, proteinuria, electrolyte disturbances (decreased serum Ca, Mg and K)

• Cutaneous effects: • Urticaria, maculopapular rash, pain, edema, and abscess at the site of application

• Ototoxicity • Especially vestibular

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

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• Used as an anti-TB drug since 1946 • Used to be 1st line drug in a combination regimen with INH and streptomycin

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

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• GI effects: • Anorexia, diarrhea, N/V • Hepatitis: 0.3-0.5% • Malabsorption syndrome

• Endocrine effects: • Hypothyroidism

• Especially when administered with ethionamide • Allergic reactions

• Fever, rash, and pruritus

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

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• Hematologic effects: • Hemolytic anemia, agranulocytosis, leukopenia, thrombocytopenia,

• Cardiovascular effects: Pericarditis • Neurological effects: Encephalopathy • Respiratory effects: Eosinophilic pneumonia • Ocular effects: Optic neuritis • Caution!:

• Patients with G6PD deficiency • Patients who are allergic to aspirin

Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

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•Prevention •INH-induced peripheral neuropathy

•Risky population: •Pregnant women •HIV infection •Alcohol dependency •Malnutrition •Diabetes •Chronic liver disease •Renal failure

•Preventive treatment: Pyridoxine 10-25 mg/day along with anti-TB drugs

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• Management of cutaneous reactions

• Itching without a rash • Symptomatic treatment with antihistamines and skin moisturizing • Continue TB treatment • Observing the patient closely

• If a skin rash develops

• All anti-TB drugs must be stopped

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• Management of cutaneous reactions • Once the reaction has resolved

• Rechallenge Anti-TB drugs 1 by 1 • Start with the least likely causative drug at small dose • Gradually increase the dosage over 3 days • Repeat the procedure by adding in 1 drug at a time for the causative drug identification

Page 126: Antituberculosis Adverse Drug Reactions

Anil M. et al., Drug Safety 12 (1): 1-25,1995

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• Management of hepatitis • Ruling out other possible causes is necessary • If TB drugs are the cause of hepatitis

• All drugs should be stopped • If it is considered unsafe to stop TB treatment, a non-hepatotoxic regimen should be used

• Streptomycin + ethambutol + fluoroquinolone • Wait for LFT to revert to normal and clinical symptoms (nausea, abdominal pain) to resolve before reintroducing the anti-TB drugs

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• Management of hepatitis • If TB drugs are the cause of hepatitis

• If LFT is not available, wait an extra 2 weeks after resolution of jaundice and upper abdominal tenderness before restarting TB treatment • If the signs and symptoms do not resolve and the liver disease is severe, use the mentioned non-hepatotoxic regimen for 18–24 months

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• Management of hepatitis • Once hepatitis has resolved

• Drugs are reintroduced one at a time • If symptoms recur or LFT become abnormal, the last drug added should be stopped

• Maybe: RFP -> 3–7 days -> INH • In patients with jaundice but tolerate the reintroduction of RFP and INH, it is advisable to avoid PZA

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• Management of hepatitis • Alternative regimens: Depends on drug implication

• If RFP is implicated: 2HES/10HE • If INH is implicated: Consider 6–9 months of RZE • If PZA is discontinued before complete intensive phase, HR therapy may be extended to 9 months • If neither INH nor RFP can be used, the mentioned non-hepatotoxic regimen should be used for 18–24 months

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สานกัโรคเอดส์ วณัโรค และโรคติดตอ่ทางเพศสมัพนัธ์ กรมควบคมุโรค กระทรวงสาธารณสขุ, แนวทางเวชปฏิบตัิการรักษาวณัโรคในผู้ ใหญ่ พ.ศ.2554

Page 134: Antituberculosis Adverse Drug Reactions

สานกัโรคเอดส์ วณัโรค และโรคติดตอ่ทางเพศสมัพนัธ์ กรมควบคมุโรค กระทรวงสาธารณสขุ, แนวทางเวชปฏิบตัิการรักษาวณัโรคในผู้ ใหญ่ พ.ศ.2554

Page 135: Antituberculosis Adverse Drug Reactions

สานกัโรคเอดส์ วณัโรค และโรคติดตอ่ทางเพศสมัพนัธ์ กรมควบคมุโรค กระทรวงสาธารณสขุ, แนวทางเวชปฏิบตัิการรักษาวณัโรคในผู้ ใหญ่ พ.ศ.2554

Page 136: Antituberculosis Adverse Drug Reactions

สานกัโรคเอดส์ วณัโรค และโรคติดตอ่ทางเพศสมัพนัธ์ กรมควบคมุโรค กระทรวงสาธารณสขุ, แนวทางเวชปฏิบตัิการรักษาวณัโรคในผู้ ใหญ่ พ.ศ.2554

Page 137: Antituberculosis Adverse Drug Reactions

สานกัโรคเอดส์ วณัโรค และโรคติดตอ่ทางเพศสมัพนัธ์ กรมควบคมุโรค กระทรวงสาธารณสขุ, แนวทางเวชปฏิบตัิการรักษาวณัโรคในผู้ ใหญ่ พ.ศ.2554

Page 138: Antituberculosis Adverse Drug Reactions

สานกัโรคเอดส์ วณัโรค และโรคติดตอ่ทางเพศสมัพนัธ์ กรมควบคมุโรค กระทรวงสาธารณสขุ, แนวทางเวชปฏิบตัิการรักษาวณัโรคในผู้ ใหญ่ พ.ศ.2554

Page 139: Antituberculosis Adverse Drug Reactions

สานกัโรคเอดส์ วณัโรค และโรคติดตอ่ทางเพศสมัพนัธ์ กรมควบคมุโรค กระทรวงสาธารณสขุ, แนวทางเวชปฏิบตัิการรักษาวณัโรคในผู้ ใหญ่ พ.ศ.2554

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• 1st Rapid oral INH desensitization protocol

CL Holland, et al., Chest 1990; 98:1518-19)

Presenter
Presentation Notes
A 45-year-old black woman, sputum AFB+, had hypersensitivity to both INH and RFP. She was admitted to the hospital and desensitized to both medications using modified penicillin protocols. Skin testing was negative to both drugs. Desensitization to INH was complicated by a drug fever that was controlled by prednisone. The patient was able to maintain once-a-day dosing without incident even with steroid taper.
Page 142: Antituberculosis Adverse Drug Reactions

• 1st Rapid oral RFP desensitization protocol

CL Holland, et al., Chest 1990; 98:1518-19)

Presenter
Presentation Notes
A 45-year-old black woman, sputum AFB+, had hypersensitivity to both INH and RFP. She was admitted to the hospital and desensitized to both medications using modified penicillin protocols. Skin testing was negative to both drugs. Desensitization to INH was complicated by a drug fever that was controlled by prednisone. The patient was able to maintain once-a-day dosing without incident even with steroid taper.
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•Single day protocol

J Matz, et al. Am J Respir Crit Care Med Vol 149. pp 815-817, 1994

Presenter
Presentation Notes
Rapid oral desensitization to 10 patients with mycobacterial disease who had experienced cutaneous hypersensitivity reactions to RFP and Eth. An adaptation of the rapid oral desensitization protocol for penicillin was used, with the dosing intervals increased to account for the different kinetics of these drugs. Adverse reactions were few and easily treated without necessitating cessation of therapy
Page 144: Antituberculosis Adverse Drug Reactions

•Single day protocol: Patient characteristics

J Matz, et al. Am J Respir Crit Care Med Vol 149. pp 815-817, 1994

Presenter
Presentation Notes
Rapid oral desensitization to 10 patients with mycobacterial disease who had experienced cutaneous hypersensitivity reactions to RFP and Eth. An adaptation of the rapid oral desensitization protocol for penicillin was used, with the dosing intervals increased to account for the different kinetics of these drugs. Adverse reactions were few and easily treated without necessitating cessation of therapy
Page 145: Antituberculosis Adverse Drug Reactions

•Single day protocol: Outcome

J Matz, et al. Am J Respir Crit Care Med Vol 149. pp 815-817, 1994

Presenter
Presentation Notes
Rapid oral desensitization to 10 patients with mycobacterial disease who had experienced cutaneous hypersensitivity reactions to RFP and Eth. An adaptation of the rapid oral desensitization protocol for penicillin was used, with the dosing intervals increased to account for the different kinetics of these drugs. Adverse reactions were few and easily treated without necessitating cessation of therapy
Page 146: Antituberculosis Adverse Drug Reactions

• A successful oral 7-days desensitization protocol in immediate-type reaction to RFP

S Buergin, et al., Int Arch Allergy Immunol 2006;140:20–26

Presenter
Presentation Notes
Methods: 3 patients with immediate urticarial reactions to rifampicin. Diagnostic procedures included skin and in vitro tests (specifi c IgE, lymphocyte transformation test, LTT, and CAST ® ). The non-irritant cutoff concentration was evaluated in 24 volunteers. A 7-day desensitization procedure was used. -Conclusions: Rifampicin rarely elicits immediate hypersensitivity symptoms which may be diagnosed by intradermal skin tests. In vitro tests did not contribute to the diagnosis.
Page 147: Antituberculosis Adverse Drug Reactions

S Buergin, et al., Int Arch Allergy Immunol 2006;140:20–26

Presenter
Presentation Notes
Methods: 3 patients with immediate urticarial reactions to rifampicin. Diagnostic procedures included skin and in vitro tests (specifi c IgE, lymphocyte transformation test, LTT, and CAST ® ). The non-irritant cutoff concentration was evaluated in 24 volunteers. A 7-day desensitization procedure was used. -Conclusions: Rifampicin rarely elicits immediate hypersensitivity symptoms which may be diagnosed by intradermal skin tests. In vitro tests did not contribute to the diagnosis.
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• A rapid oral desnsitization protocol

S Bavbek, et al., Int Arch Allergy Immunol 2012;157:209–212

Presenter
Presentation Notes
A 44-year-old woman with a recent history of hypersensitivity reaction to antituberculous drugs was admitted. She reported that she had developed diffuse ertyhema and itching, localized particularly on the palmar and plantar regions, as well as shortness of breath, fainting and loss of consciousness within 5 min of the first doses of INH, RIF, PZA and EMB, which had been taken simultaneously. Her systolic blood pressure had been measured as 50 mm Hg. Her symptoms had relieved within 2 h. Skin prick tests were performed with PZA tablet, RIF capsule, INH tablet and EMB tablet by the prick to prick method. A positive reaction was only seen with PZA, producing a wheal of 3x3 mm surrounded by erythema of 5 mm after 15 min
Page 149: Antituberculosis Adverse Drug Reactions

Latest accessible desensitization protocol specific to streptomycin …..1963!!!

S Lal, et, al., Tubercle, Lond., (1963), 44, 360-362

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• A protocol for 8 patients with SJS while on 4-drug anti-TB therapy

MM Kura, et al., Int J Derm, 2001, 40, 482-484

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• TB: Still a major health problem • Currently available drugs are effective treatment but may cause serious ADRs:

• Hepatitis • Cutaneous reactions • GI intolerance • Hematological reactions • Nephrological effects • Neurological effects

• ADRs must be recognised early, treated promptly and TB treatment must be adjusted properly (but might need application based on other drug’s available data)

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