Management of Adverse Effects of Anti-TB drugs (part I) Dr. Ashraf Abdulhaseeb Chest Diseases Consultant Chief of DR-TB center, Abbassia Chest Hospital

Presentation outline: Monitoring adverse effects Main adverse effects and suspected drugs. General considerations of adverse effects management. Commonly used ancillary drugs.

Monitoring of adverse effects: Aims at: Early detect and treat adverse effects Prevent /minimize toxic effects or organ damage

Monitoring should consider the following factors: Patient factors: Age, initial clinical condition, HIV testing, Socioeconomic condition Providers: trained and alert to early detect adverse effects Specialists and consultants in referral centers are available.

Monitoring schedule I) Initial pretreatment screening and evaluation: Initial evaluation serves to: Establish a baseline clinical view of the patient identify patients who are at increased risk for adverse effects or poor outcomes.

Initial pretreatment monitoring includes: Thorough medical history and physical examination. History of concomitant conditions which can contribute occurrence of drug intolerance History of adverse drug reactions. History of allergic reactions Complete blood count Liver functions: Total serum Bilirubin SGPT & SGOT Total serum albumin, total serum protein and A/G ratio.

Serum Creatinine, blood urea, complete urine analysis with estimation of total urine protein content Serum uric acid. Fasting and PP blood sugar. Pregnancy test. Initial chest x-ray Visual acuity, color vision Audiometry Direct smear examination DST for first and second line anti-TB drugs.

II) Lab investigation schedule during treatment to monitor adverse effects Weight monthly to adjust doses. Urea & Serum creatinine monthly while receiving injectable drugs then quarterly. Risk group patients may need more frequent testing e.g. elder, patients with renal troubles. Serum electrolytes Monthly while receiving injectable drugs then quarterly, may be more frequent in risk group patients e.g. elder, vomiting & diarrhea TSH Every 6 months if receiving ethionamide / prothionamide or PAS and monitor monthly for signs and symptoms of hypothyroidism. Liver enzymes Periodic monitoring (every 1month) in patients receiving Pyrazinamide for extended periods or for patients at risk for or with symptoms of hepatitis. Audiometry Monthly while receiving the injectable drug Visual acuity & color discrimination Monthly CBC

II) Lab investigation schedule during treatment to monitor adverse effects, cont. Hemoglobin and WBC If on linezolid, monitor weekly at first, then monthly Lipase Indicated for work up of abdominal pain to rule out pancreatitis in patients on linezolid 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

Monitoring of adverse effects should also include: In high risk patients (over 50 years, renal insufficiency, DM, HIV, underweight), creatinine should be evaluated every week or every other week for at least the first month of treatment. Creatinine clearance may be needed for high risk group patients. If Serum potassium is low, check the Magnesium and Calcium levels.

Special attention should be paid for: Liver toxicity. Vestibular and hearing toxicity with injectable drugs. Psychiatric disorders with Cycloserine. Allergic reactions. Hematological changes.

Recording the adverse effects in patient file: Patient name__________________________________ Patient ID____________________ TB registrations number ___________________________________________________ Description of the adverse reaction Date Severity* Change Of treatment if made treatment change Other actions Outcome **   Severity code: *1=asymptomatic 2=does not affect daily activities 3=limits daily activities 4=life threatening hospitalization  Outcome code: **1= complete resolution 2= partial resolution 3 = no change 4 = worse  comments:_______________________________________________________________

Adverse effects in cohort 127 patients, Egypt 2009

Common adverse effects and suspected drugs Seizures Cycloserine & less frequently Isoniazid, Fluoroquinolone Peripheral neuritis Cycloserine, Isoniazid & less frequently, Streptomycin, Amikacin, Kanamycin, Capromycin, Viomycin, Fluoroquinlones, Prothionamide/Ethionamide, Linedazole Hearing loss and vestibular disturbance All Aminoglycosides, Capreomycin & less frequently clarithromycin Psychotic symptoms Cycloserine, Fluoroquinolones, Isoniazid, Prothionamide/Ethionamide Depression Maybe due the disease condition of the patient or drugs Cycloserine & less frequently Fluoroquinolones, Isoniazid, Prothionamide/Ethionamide Hypothyrodism Prothionamide/Ethionamide, PAS Nausea and vomiting PAS, Prothionamide/Ethionamide, Pyrazinamid & less frequently Ethambutol, Isoniazid,

Common adverse effects and suspected drugs, cont. Gastritis PAS, Prothionamide/Ethionamide, Pyrazinamid Hepatitis Pyrazinamid, Isoniazid, Rifampicin & less frequently Fluoroquinolones, Prothionamide/Ethionamide Renal toxicity All Aminoglycosides, Capreomycin Electrolyte disturbance Capreomycin and Viomycin & less frequently Streptomycin, Kanamycin and Amikacin Optic neuritis Mainly Ethambutol & less frequently Prothionamid/Ethionamid Arthralgia Mainly Pyrazinamid & less frequently Fluoroquinolones

Classification of Adverse Effects Allergic and dermatological: Mild Moderate to severe Skin pigmentations Photo-sensitivity Dry skin Hypersensitivity Fever Rash Purpura Allergic dermatitis Exfoliative dermatitis Anaphylaxis /Angiodema

Classification of Adverse Effects Gastrointestinal: Mild Moderate to severe Nausea/Vomiting Anorexia Metallic taste/salivation Stomatitis /Glossitis Diarrhea Bloating Abdominal cramps Gastritis Gastric ulcer Hepatitis

Classification of Adverse Effects Neurological and Psychiatric: Mild Moderate to severe Dizziness Headache Fatigue Somnolence Insomnia Irritability Anxiety Seizure Peripheral neuropathy VIII nerve damage: hearing loss, vestibular impairment Psychosis Suicidal tendency Depression Confusion Behavior changes

Classification of Adverse Effects Fluid and electrolyte disturbance &others: Mild Moderate to severe Myalgia Cramps Arthralgia Candidiasis, stomatitis Electrolyte disturbances Dehydration Renal failure Optic neuritis Anemia

Classification of Adverse Effects Endocrine adverse effects: Mild Moderate to severe Changes in menstrual cycle Gynecomastia Impotence Uncontrolled diabetes Hypothyroidism

Management of adverse effects General considerations: majority of adverse effects are easy to recognize. have a systematic method of patient interviewing to early detect. Proper management of adverse effects begins with patient education. Inform the patient to report adverse effects. Monthly evaluation by a physician during ambulatory treatment

General considerations, cont. DOT workers should be trained to screen patients for adverse effects. Scheduled laboratory screening to detect occult adverse effects e.g. nephrotoxicity. Electrolyte disturbance is generally a late effect occurring after months of starting treatment. Complete discontinuation of therapy because of adverse effects is rare.

General considerations, cont. Mild adverse effect is or not dangerous, continue the treatment regimen, with the help of ancillary drugs if needed. Some adverse effects may disappear or diminish with time, and patients may be able to continue receiving the drug if sufficiently motivated. adverse effects of a number of second-line drugs are highly dose dependent, reducing the dosage of the offending drug is another method of managing adverse effects

General considerations, cont. Pyridoxine (vitamin B6) should be given to all patients receiving cycloserine or terizidone to help prevent neurological adverse effects. Recommended dose is dose is 50 mg for every 250 mg of cycloserine Psychosocial support is an important component of the management of adverse effects.

General considerations, cont. Psychosocial support is an important component of the management of adverse effects. A stock of these drugs should be always available. Timely and intensive monitoring for, and management of, adverse effects caused by second-line drugs are essential components of DR-TB control program.

Commonly used ancillary medications Nausea, vomiting, upset stomach Metoclopramide, prochlorperazine, promethazine Heartburn, acid indigestion, sour stomach, ulcer H2-blockers (ranitidine, famotidine, etc.), proton pump inhibitors (omeprazole etc.) Avoid antacids because they can decrease absorption of Flouroquinolones Oral candidiasis (non-AIDS patient) Fluconazole, clotrimazole lozenges ..etc Diarrhoea Loperamide or other anti-diarrheal Depression Selective serotonin reuptake inhibitors (fluoxetine, sertraline), tricyclic antidepressants (amitriptyline)

Commonly used ancillary medications Prophylaxis of neurological complications of cycloserine Pyridoxine (vitamin B6) Peripheral neuropathy Amitriptyline vestibular symptoms Meclizine, dimenhydrinate, prochlorperazine, promethazine Musculoskeletal pain, arthralgia, headaches Ibuprofen, paracetamol Cutaneous reactions, itching Hydrocortisone cream, calamine, caladryl lotions Systemic hypersensitivity reactions Antihistamines (diphenhydramine, chlorpheniramine, dimenhydrinate), corticosteroids (prednisone, dexamethasone)

Commonly used ancillary medications 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

Commonly used ancillary medications Severe anxiety Lorazepam, diazepam, clonazepam Insomnia Dimenhydrinate Psychosis Haloperidol, thorazine, risperidone (consider benzotropine or biperiden to prevent extrapyramidal effects) Seizures Phenytoin, carbamazepine, phenobarbital

Thank you