Moving Past the Basics of Tuberculosis Phoenix, Arizona May 8-10, 2012 Managing Anti-TB Therapy Side Effects and Complications Lisa Armitige, MD, PhD May 9, 2012 Lisa Armitige, MD, PhD has the following disclosures to make: No conflict of interests No relevant financial relationships with any commercial companies pertaining to this educational activity 1
TB Medications and Adverse Effects Lisa Armitige, MD, PhD Medical Consultant Heartland National TB Center Associate Professor of Internal Medicine and Peditarics Division of Infectious Diseases UT-Tyler HSC Objectives Describe the monitoring process for adverse drug events associated with anti-tb drugs Side effects and drug toxicities Recognizing the most common adverse effects of TB therapy Discuss the nursing interventions and medical management of the most common adverse drug events seen in patients on first-line antituberculosis therapy Case studies 2
Monitoring Process Ongoing process Begins with initial assessment Requires a food provider patient relationship Case management plan Patient Education Toxicity assessment Daily/BIW when administering DOT Monthly Drug Monitoring Goals Recognize adverse drug events Assess appropriately Intervene rapidly Prevent further morbidity/mortality Minimize treatment interruptions Reduce opportunities for medical mismanagement Avoid development of psychological intolerance Support adherence and the therapeutic relationship 3
Side Effects Unpleasant, but mild reactions No long lasting health effects Do not usually require changes in therapy -Gas Bloating Mild nausea Discoloration of body fluids Irritability Difficulty sleeping Photosensitivity Adverse Drug Reactions More serious May be life threatening Require modifying the dose/discontinuation of drug May require additional therapy and/or hospitalization Significant GI disturbances Hepatotoxicity Dermatologic and hypersensitivity reactions Ophthalmic toxicity CNS toxicity Neurotoxicity Ototoxicity Musculoskeletal adverse effects Renal toxicity 4
First-line Drugs Isoniazid (INH) Rifampin (RIF) Rifabutin Rifapentine Ethambutol (EMB) Pyrazinamide (PZA) Isoniazid GI upset Nausea Vomiting Loss of appetite Rash Mild CNS toxicity Peripheral neuropathy Tingling to fingers & toes Hepatotoxicity 5
Gastrointestinal Upset Common in the first few weeks of therapy Evaluate for other causes Give a light snack before meds Administer antiemetics Phenergan Zofran Isoniazid GI upset Nausea Vomiting Loss of appetite Rash Mild CNS toxicity Peripheral neuropathy Tingling to fingers & toes Hepatotoxicity 6
Hepatotoxicity Early Signs Fatigue Poor appetite Taste alteration Nausea Abdominal discomfort Bloating Minimal rash Later Signs Vomiting Abdominal pain Jaundice Change in color of urine and stool Changes in behavior, memory loss Most at Risk for Hepatotoxicity Underlying liver disease Hepatitis B and C Alcoholics Immediate (4 months) post-partum period Those on other hepatotoxic medications 7
Hepatotoxic Drugs Tylenol Tetracycline, erythromycin, others Dilantin Valproate Cholesterol lowering medications Antifungal drugs Glucose lowering drugs Valium Monitoring Establish rapport Take a good medical history Clarify preexisting conditions that may increase risk of hepatotoxicity: History of Hepatitis B or C History of other liver disease Take a good social history ETOH use (be specific) Educate patient of signs and symptoms of hepatotoxicity 8
Managing Hepatotoxicity Hold medications and repeat LFT s immediately Continue therapy ALT <5 x upper limit of normal and asymptomatic 20% of patients on standard therapy have asymptomatic elevation in LFT s Stop therapy ALT > 3 times upper limit of normal and symptomatic ALT > 5 times upper limit of normal and asymptomatic Hepatotoxicity Restarting therapy LFT s must be < 2 times upper limit of normal Rechanllege Medications Introduce one drug at a time Monitor enzymes carefully Stop therapy if symptomatic or increased enzymes and eliminate last drug added from regimen 9
Case Study # 1 - Hepatotoxicity 38 year old male diagnosed with Pulmonary TB while incarcerated. On Mar. 13, he started standard RIPE regimen. Baseline laboratory values were ALT 42, AST 63. On April 15, 1 month later, he was changed to BIW dosing. EMB was discontinued when susceptibility results showed isolate to be susceptible to INH/RIF. Patient was released from jail and continued medication on DOT by local health department. On June 4, 2½ months after starting anti TB therapy, follow-up lab results were ALT 304, AST 97. He was asymptomatic for hepatitis. Case Study # 1 - Hepatotoxicity What would be the next step for this patient with elevated LFT s? Take the following into consideration: Baseline LFT s : ALT 42, AST 63, Follow up LFT s : ALT 304, AST 97 (normal values: AST 10-42 u/l, ALT 10-40 u/l) 10
Normal values: AST: 10-42 u/l ALT: ALT 10-40 u/l Calculation Divide lab result by higher number of normal value AST 97/42 = 2.3 X ULN ALT 304/40 = 7.6 XULN Case Study #1- Hepatotoxicity What is the next step for this patient with elevated LFT s? Hold TB medications! ALT > 5 times upper limit of normal and asymptomatic ALT > 3 times upper limit of normal and symptomatic 11
Case Study #1 Hepatotoxicity When assessing this patient, what significant information is important for identifying if this patient is at risk for developing hepatotoxicity? Identify any underlying liver disease (hepatitis A, B, C) Identify if patient drinks any alcoholic beverages? Identify if patient is taking any other Hepatotoxic MEDICATIONS Case Study #1 Hepatotoxicity Anti-TB therapy was re-started by re-introducing one medication at a time when liver enzymes < 2 times upper limit of normal. Liver enzymes were monitored carefully. At a follow up appointment patient admitted to drinking 6-12 oz. beers almost every day with his neighbor What risk factors can you identify that place this patient at risk for developing hepatoxicity? He drinks 6-12 oz. beers almost every day with his neighbor. 12
Case Study #1- Hepatotoxicity How do we monitor him for the remainder of his treatment? Monitor closely/ monitor LFT s Re-educate patient to abstain from alcohol while on anti-tb medication Review adverse effects Encourage compliance Instruct patient to self monitor for side effects while on meds Consider a liver friendly regimen (Amikacin, levofloxacin, EMB) Most importantly: Instruct patient to stop taking TB medications immediately and seek medical attention if symptoms of hepatitis occur again. 13
Rifampin GI upset Nausea, vomiting loss of appetite Hepatotoxicity Thrombocytopenia, hemolytic anemia Bleeding Renal Toxicity Flu-like syndrome Fatigue, fever Orange Staining of body fluids Urine, tears, sweat Itching Rash Evaluate the Rash Where is it? What does it look like? Does it itch? When did it start? Has it spread? What makes it better or worse? Have you had an insect bite? 14
Other Possible Causes Insect bites Scabies Contact dermatitis Question patient about new soaps, lotions, perfumes, laundry detergents, etc Sunburn Dry skin Other drugs, especially new agents Viral or fungal infections Mild Rash Common Often resolve after first several weeks of treatment Usually do not require stopping medication Treated symptomatically with Benadryl, other antihistamines, low-dose prednisone 15
Drug Rash Usually begins on chest and later spreads to upper arms and thighs Itches Maculopapular Urticaria/hives Occurs and worsens after medications May be associated with more severe symptoms of airway compromise, angioedema, etc. Hold medications until reaction resolves May have to modify the drug regimen Managing & Monitoring Rifampin Monitor CBC monthly Advise women using hormonal contraceptive to use another form of control Reduction of methadone almost to an ineffective level Cannot use with some Antiretroviral drugs 16
Rifabutin Decreased WBC Decreased Platelet count Renal Impairment Hyperpigmentation Flushing G.I. upset Uveitis Eye pain/ irritation Arthralgias Joint pain Uveitis When given in higher doses with drugs that decrease renal clearance Hold Rifabutin until symptoms resolve Consider referral to ophthalmologist to rule-out other cause If infection is ruled-out, steroid eye drops may be used If recurring uveitis, stop rifabutin 17
Ethambutol Nausea Vomiting Loss of appetite Fever Headaches Dizziness Rash Changes in visual acuity Changes in red/green color discrimination Managing & Monitoring EMB Baseline & monthly visual acuity test (Snellen chart) Baseline & monthly color discrimination test (Ishihara tests) Question pt regarding possible visual disturbances including blurred vision. Observe children for eye rubbing, excessive blinking, sitting close TV, difficulty with accurate grasping Hold Rx Refer for Ophthalmologic evaluation Permanent vision impairment if Rx continued 18
Ophthalmic Toxicity 21 year old male arrested and incarcerated in county jail in February. After being incarcerated for 3 months he began to complain of fever, chills, productive cough, chest pain, night sweats, and weight loss. On October 7, five months after onset of symptoms, he continued to complain of previous symptoms. He was finally evaluated, CXR showed left upper lobe cavitary infiltrate, AFB smear (+) 1-10 per high power field. He was diagnosed with pulmonary TB. On October 12, he was started on the standard 4 drug therapy. The isolate was reported as isoniazid and streptomycin resistant. Pt. was improving, he was afebrile, had 6 lb wt. gain, night sweats had resolved, cough was improving. INH discontinued once susceptibilities were known, and he continued on RIF, PZA, EMB to complete 9 months of adequate therapy. Case Study #2- Opthalmic Toxicity After reviewing this case study, identify what should have been done differently in diagnosing this patient? Could have been diagnosed earlier, 5 months ago Should have been screened for TB TST Symptom review Baseline CXR If prior exposure, identify if patient had preventative treatment 19
Case Study # 2 Opthalmic Toxicity What Toxicities is a patient on EMB at risk for? Optic Neuritis Decreased visual acuity Decreased red-green color discrimination Case Study #2: Ophthalmic Toxicity What baseline testing should you do for your patient who is starting EMB? Visual Acuity (Snellen) Color Discrimination (Ishihara) 20
Case Study #2 - Ophthalmic Toxicity In March, 5 months after start of treatment, patient started c/o difficulty driving and reading road signs. As a provider managing this patient s anti-tb therapy, what would you do? Stop the EMB Refer to the Opthalmologist Case Study #2 - Ophthalmic Toxicity Called his nurse by phone, she instructed him to see his eye doctor. On March 21 he was seen by optometrist and given RX for corrective lenses. EMB continued 21
Case Study # 2 - Ophthalmic Toxicity On May 3 (7 months on anti-tb therapy) he again complains of worsening vision. Nurse finally assesses his vison. Baseline visual acuity in October was 20/20 both eyes, follow up visual acuity was now 20/200 in both eyes even with corrective lenses. On May 5 the EMB discontinued; continued on RIF, PZA and Levo added to regimen to complete 9 mo of treatment and referred to a retinal specialist. Ophthalmic Toxicity Follow-up Seen by retinal specialist in May and June DX: EMB optic neuropathy Central scotoma on right and parascotoma on left Vision uncorrected: 20/200 Nurse admitted to not performing visual acuity screening (Snellen chart), she only did color discrimination testing (Ishihara plates) 22
Pyrazinamide GI Upset Nausea Vomiting, Loss of appetite Rash Hepatotoxicity Arthralgias Joint pain Muscle Aches Gout (rare) Myalgias/Arthralgias If acute swelling, erythema, warmth present, evaluate for infection, gout PZA causes asymptomatic increase in uric acid, but rarely causes gout except in patients with pre-existing gout or decreased renal function NSAIDS often helpful in relieving discomfort Usually not necessary to discontinue medications 23
Second-line Drugs Cycloserine Ethionamide Levofloxacin Moxifloxacin PAS Streptomycin Amikacin Kanamycin Capreomycin Second-Line Drugs Amikacin Local Pain at injection site Rash Renal Toxicity Ototoxicity Vestibular Toxicity Electrolyte abnormalities (hypokalemia, hypomagnesemia) Capreomycin Local Pain at injection site Rash Renal Toxicity Ototoxicity Vestibular Toxicity Electrolyte abnormalities (hypokalemia, hypocalcemia, hypomagnesemia) 24
Auditory Toxicity Perform audiometry & vestibular screening Baseline Repeat monthly Identify pre-existing hearing loss Refer for evaluation if any decrease from baseline Vestibular Toxicity Vestibular toxicity monitoring Baseline and monthly vestibular screen Assess Hearing: fullness, stuffiness, unusual noises, hearing loss Dizziness, unsteadiness, giddiness, lightheadedness, floating sensation 25
Second-Line Drugs Levofloxacin, Moxifloxacin, Gatifloxacin Rash GI upset Mild CNS toxicity Photosensitivity EKG abnormalities Arthralgias Tendon rupture (rare) Ethionamide Rash GI upset Hepatotoxicity Endocrine effects Peripheral neuropathy Second-Line TB Drugs Cycloserine -Rash - CNS toxicity, may include seizure, depression, suicidal ideation, psychosis - Peripheral neuropathy - Skin changes (lichenoid eruptions, Stevens- Johnson Syndrome) Para-Aminosalicylate (PAS) -Rash - GI upset, may be significant - Hepatotoxicity - Reversible hypothyroidism Clofazimine -Rash -GI upset - Discoloration and dryness of skin - Photosensitivity - Retinopathy Linezolid -Rash - Myelosuppression - Nausea and diarrhea - Optic neuropathy - Peripheral neuropathy 26
Essential Monitoring Components Establish and Maintain a good a Provider Patient relationship Have a Case management plan Ongoing patient education Ongoing toxicity monitoring THEY ALWAYS COME BACK Do It Right The First Time! Barbara Seaworth, MD Medical Director, Heartland 27
Thank You! Questions? 28