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2. 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 BorstelUniversity of Lübeck; Germany

3. Definitions - I

4. Definitions - II

5. 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 Major Clinical Categories in Events Dictionary

6. Individual medicines for TB therapy (alphabetical)

7. Antituberculosis drugs (by group)

8. ADRs commonly associated with anti-TB drugs

9. Potentially overlapping toxicities of antiretrovirals and anti-tuberculosis agents

11. Grade of toxicity

13. Major adverse reactions

14. Minor adverse reactions

19. Cessation of a single drug

20. 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.

21. Drug-induced hepatitis Diagnosis • AST/ALT > 3-5x upper limit of normal • Rise in bilirubin above normal Action • Stop RHZ • If treatment required  SEFq

22. 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)

23. 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

24. 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)

25. 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”.

26. 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. Clinical review of symptoms andsigns, medication use, side-effects, complications

27. Monitoring during treatment of DR-TB

29. 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) Prevention of adverse effects of drugs

30. Commonly used ancillary medications