Tuberculosis Medication Review Jacob J. Olson, Pharm D Dane County’s TB Summit 2014 Epic Campus, Verona, WI April 24, 2014

Disclosure  President/CEO of Skywalk Pharmacy located in Children’s Hospital of Wisconsin  Pediatric compounding pharmacy located in Milwaukee, WI  Also provide many specialty medications

Objectives  Identify references for locating information about medications used in TB  Describe how the different medications attack M. Tuberculosis  Identify a resource for information about drug shortages  Identify the differences between the rifamycin class drugs  Discuss the adverse reactions of TB medications  Discuss the challenges of medication administration in pediatrics  Discuss new methods for administering medications in liquid form Upon completion of this presentation, participants will be able to:

References  Curry International Tuberculosis Center and California Department of Public Health, 2012: Tuberculosis Drug Information Guide, 2nd edition.    Heartland National TB Center – U of Texas Health Science Center at Tyler   poster.pdf poster.pdf  interactions.pdf interactions.pdf 

Doc Holladay – The Face of TB

History of TB medications  November 20 th, 1944 Streptomycin first administered to a critically ill TB patient  Immediately impressive results  Side effects  Resistance within a few months!!!  P-aminosalicyclic acid (1949)  Isoniazid (1952)  Pyrazinadmide (1952)  Cycloserine (1955)  Ethambutol (1961)  Rifampin (1966)

Antituberculosis Drugs  First-line drugs  Isoniazid  Rifampin/Rifapentine/Rifabutin*  Ethambutol  Pyrazinamide  * Not FDA approved for TB  Second-Line drugs  Cycloserine  Ethionamide  Levofloxacin*  Moxifloxacin*  PAS  Streptomycin  Amikacin/Kanamycin  Capreomycin  Linezolid  Bedaquiline

Populations of Mycobacteria Semi-Dormant Persisters Rifampin  Actively Dividing  INH/Rifampin/Ethambutol  Slowly Dividing  Rifampin/Pyrazinamide Dormant

Importance of the Intensive Phase  Actively dividing bacterial subpopulation  Isoniazid is the most potent drug for killing actively dividing bacteria  Associated with decrease in infectiousness  Persisters  Revert back and forth to other subpopulations  Source of relapses  Rifampin is the only first line drug with activity against persisters  Optimizing bactericidal and sterilizing activity early will minimize overall bacterial load present during continuation phase

Photo Credit: The photo of Mycobacterium tuberculosis was obtained from the Centers for Disease Control and Prevention, CDC/ Dr. Ray Butler; Janice Carr. Illustration Credit: This illustration is in the public domain. Please credit the National Institute of Allergy and Infectious Diseases (NIAID).Centers for Disease Control and Prevention First-Line Treatment of Drug Sensitive TB

Photo Credit: The photo of Mycobacterium tuberculosis was obtained from the Centers for Disease Control and Prevention, CDC/ Dr. Ray Butler; Janice Carr. Illustration Credit: This illustration is in the public domain. Please credit the National Institute of Allergy and Infectious Diseases (NIAID).Centers for Disease Control and Prevention MDR TB

Photo Credit: The photo of Mycobacterium tuberculosis was obtained from the Centers for Disease Control and Prevention, CDC/ Dr. Ray Butler; Janice Carr. Illustration Credit: This illustration is in the public domain. Please credit the National Institute of Allergy and Infectious Diseases (NIAID)Centers for Disease Control and Prevention XDR TB Diminishing Options for Treatment

Drug Shortages  American Society of Health-System Pharmacists (ASHP) website   Amikacin injection  Reason for the shortage  Ben Venue has stopped production of its plant in Bedford Ohio of multiple sterile injectable products  Hospira discontinued amikacin in May 2010 due to a raw material shortage  Teva’s product was unavailable due to manufacturing delays  Sandoz discontinued Amikin injection in 2006  Heritage launched amikacin injection March 2014

Drug Shortages  Isoniazid tablets  Reason for shortage  Were only 4 manufactures of isoniazid tablets = Versapharm, West-Ward, Sandoz, Teva  West-Ward discontinued isoniazid tablets in late-November 2013  Versapharm could not provide a reason for their shortage  I can tell you I can no longer order it from my wholesalers  Sandoz and Teva had to ramp up production to meet demand of 2 other manufactures issues

New TB drugs Under Development Photo Credit: The photo of Mycobacterium tuberculosis was obtained from the Centers for Disease Control and Prevention, CDC/ Dr. Ray Butler; Janice Carr. Illustration Credit: This illustration is in the public domain. Please credit the National Institute of Allergy and Infectious Diseases (NIAID).Centers for Disease Control and Prevention

Rifampin, Rifapentine, Rifabutin What are the differences in the rifamycin class of drugs?

Rifampin/Rifampicin  Rifampin is bacteriocidal, well absorbed, good tissue levels  Dosed daily, twice weekly or three times per week  Activity against rapidly dividing and semi-dormant bacterial populations  Toxicity includes rashes, orange discoloration of body fluids, GI symptoms, flu-like symptoms, hepatoxicity, immunologic reactions  Drug interactions due to induction of liver enzymes cytochrome P-450 that accelerates metabolism of multiple drugs  Major concern is reduction in serum concentrations of common drugs (OCP, warfarin, seizure medications, etc.) to ineffective levels  Complete drug history is a must!!

Rifapentine  Rifapentine is a long acting rifampin that can be used once weekly  Long half-life + high plasma binding + long post-antibiotic effect = weekly dosing  Should not be used in patients with  HIV seropositive patients  Cavitary disease  Positive sputum smears after the initiation phase of therapy  Adverse reactions identical to rifampin  Drug interactions identical to rifampin  No activity against MDR TB

Rifabutin  Substitute for rifampin for patients who are receiving drugs, especially antiretroviral drugs, that have unacceptable interactions with rifampin  Drug interactions are reduced due to less severe induction of CP-450 enzymes, therefore, less effect on the metabolism of other drugs  Adverse reactions are somewhat less, but similar to the other drugs

Adverse Reactions  Rash – any agent  If only minor itching = antihistamines may be prescribed  Petechial rash = thrombocytopenia?  Check platelets and assume rifamycin hypersensitivity  Generalized rash = stop all agents  When rash has improved, begin rechallenge one drug at a time at 2-3 day intervals  Start with Isoniazid, then Rifamycin, then ethambutol then pyrazinamide.  If rash recurs, last drug added is the likely cause and should be D/C  See reference Curry International Survival Guide for Clinicians Chapter 7 for suggested rechallenge doses for individual drugs

Adverse Reactions  GI intolerance – any agent  Nausea, vomiting, poor appetite, abdominal pain  Common, may be transient, and are caused by many anti-TB drugs, particularly in the first few weeks  Rule out hepatitis (ALT/AST)  Change the hour of drug administration. Give drugs at bedtime (if not on DOT)  Give medications with food/light snacks (Rifapentine, PAS and clofazimine)  Increase fluid intake  Rifampin and Cycloserine should be taken on an empty stomach  Fluoroquinolones – avoid minerals (Ca, Al, Mg)

Adverse Reactions  Peripheral Neuropathy – Isoniazid, ethionamide, cycloserine, linezolid  Diabetics, alcoholism, HIV infection, pregnancy, breast feeding infants, poor nutrition, seizure disorders, uremia  Pyridoxine 50mg daily  TB department now covers pyridoxine and multivitamins if requested on Wisconsin TB medication form  Ototoxicity - Aminoglycosides  Ophthalmic toxicity– Ethambutol  Depression – avoid cycloserine, Isoniazid?  Seizures – Pyridoxine deficiency  Musculoskelatal (Myalgias, arthralgias, tendonitis/rupture) - quinolones

Renal dosing of TB meds  Creatinine Clearance < 30ml / min or on hemodialysis  Receiving hemodialysis increases risk of developing TB times  General strategy is to increase the interval between dosing rather than to decrease dose  Medications that do NOT require change  Isoniazid, Rifampin, Moxifloxacin, Ethionamide, PAS  Medications that DO require change  Pyrazinamide, Ethambutol, Levofloxacin, Cycloserine, Aminoglycosides  Monitoring of serum drug concentrations to avoid toxicity  Peritoneal dialysis – Begin with hemodialysis dosing and verify with serum drug concentrations

TB Medications in Liver Disease  Isoniazid  Most likely med to cause hepatitis  Usually reversible if drug stopped as soon as symptoms present  Increased hepatotoxicity when used with rifampin  Rifampin  More common for cholestatic jaundice than hepatitis  Potentiate damage from Isoniazid  Pyrazinamide  Less likely than Isoniazid….but events are more severe and prolonged and worsen even after stopping therapy  Ethionamide and PAS have also been implicated, but less likely

TB Medications in Liver Disease  Isoniazid and Pyrazinamide are most often associated  Second-line TB meds are less commonly associated  End –Stage Liver disease patient  Consider avoiding all hepatotoxic drugs  Use levofloxacin, Ethambutol, an aminoglycoside and cycloserine (if appropriate)  Non-life threatening  Use a rifamycin if the isolate is susceptible

Therapeutic Drug Monitoring  First-line drugs have predictable pharmacokinetics and are highly efficacious when given as DOT in standard doses  Many experts feel strongly about routine use of TDM  2 nd and 3 rd line agents have narrow therapeutic window  MIC is very close to concentration that causes toxicity  Increase dose if you see level is well below toxicity level  See high level before patient complains of toxicity symptoms  Routinely used for aminoglycosides  Disadvantages  Time necessary from both patients and providers to obtain and ship blood samples  High cost of measuring serum drug concentrations

Therapeutic Drug Monitoring  Helpful in the following situations:  Treatment failure not explained by non-adherence or resistance  Patients with medical conditions that may result in abnormal pharmacokinetics of the first-line drugs (renal, liver, g-tubes, HIV with evidence of malabsorption, etc.)  MDR TB with second line agents  Cycloserine serum concentrations can help predict and minimize CNS adverse reactions and prevent seizures  Ethambutol concentrations in patients with reduced renal function  Caution  Lack of data to formulate clinically validated therapeutic ranges  Using healthy volunteers in studies for rifamycin distribution of concentrations achieved  HIV-infected patients have serum concentrations lower than healthy volunteers, but still respond well to standard treatment regimens See reference Curry International Survival Guide for Clinicians “Medication Fact Sheets” and Appendix 12 “Therapeutic Drug Monitoring” for details about timing of blood draws, levels, etc. for individual drugs

Therapeutic Drug Monitoring - Tools

Therapeutic Drug Monitoring – Tools

Pediatrics  Approximate doses of medications are adequate  “Exact doses of pill fragments and portions of capsules are impossible to attain. If the child’s dose is 100 mg and the drug comes as a 250 mg tablet, 2 tablets will supply 5 doses. Any small discrepancy in dosing will even out over time”  Cut tablets into approximate fragments  Jiggle capsules open and approximate fractions for serial doses  Give lots of praise and incentives  Be flexible, but firm – “The child should get a few choices, but not whether or not to take the medicine.”  The method of delivery may need to be changed throughout the course of treatment

Pediatric Weight Based Dosing  See reference Curry International Survival Guide for Clinicians Chapter 5 – Tables 1 to 8 for Pediatric doses for individual drugs “Tables 1 to 8. Pediatric Drug Dosing The following tables are designed to help clinicians select pediatric doses based on fractions of tablets and capsules. These are approximate doses. If a fraction of the tablet is given for one dose, and the remainder is given over subsequent doses, the exact dose will be given over a series of doses. It does not matter if each individual dose is exact; in fact, it will not be.”

Pediatric Weight Based Dosing

Pediatric Weight Based Dosing

Oral liquids commercially available  Isoniazid 50mg/5ml in sorbitol  Levofloxacin 25mg/ml  Linezolild 100mg/5ml  Dry powder for reconstitution  Only stable for 21 days after mixing  Prior authorization required, $$$$  P-aminosalicylate (Paser) 4gm packets  Refrigerated enteric coated granules  DIY solution, but must be mixed in acidic juice due to enteric coated granules

Compounded medication FAQ  Frequently asked to reduce pill burden or volume of liquid  Can’t mix more than 1 medication in same dosage form (capsule or liquid)  Solubility issues with chemicals  Stability issues in acidic environment (PAS)  Patient information leaflets for compounded products  Assurance of compounded medication preparation

Compounded Isoniazid

Compounded medications - *off label*  Isoniazid 50mg/ml oral suspension – 90 days room temp  Ethambutol 100mg/ml oral suspension – 60 days room temp  Pyrazinamide 100mg/ml oral suspension – 60 days room temp  Rifabutin 20mg/ml oral suspension – 90 days room temp  Rifampin 50mg/ml oral suspension – 60 days room temp  Compound capsules with exact dose required –  cycloserine 375mg caps  Isoniazid 250mg caps

Pediatric Weight Based Dosing Challenges  Lot’s of weight changes and growth in early stages of life  Treatment over 9-12 months  Weight at month 0 and weight at month 9 can be very different  How would the patient continue to receive the most accurate dosing over the entire course of therapy?  Weight is being tracked by the Local Health Department  Prescription can be written in mg/kg

Approaches to Address Challenges  Collaborative practice to allow pharmacist to change doses and prescription orders based on current weight  Requires each health department to sign an agreement with the pharmacy  Workaround without a collaborative practice  Prescription written as mg/kg  Health department calls pharmacy with patient’s current weight every month  Pharmacy able to adjust volume to dispense each month, but can’t put exact dose on the label unless receive a new prescription every month  Challenges  Prescriber is not available for new prescription each month  Causes delays in refills and potential gaps in therapy  Medication is not stable for entire 9 months of therapy in a liquid form

Wisconsin TB Standard of Care Statement

Wisconsin DHS Initial Request for Medication Form

Pharmacy Label

How to Dissolve Tablets in an Oral Syringe

How to Flavor Liquid Medications

Conclusion  Know where to find resources  Complete and accurate drug history is a must  Monitoring of the patient for side effects and drug interactions  Kids are fun! Obligatory Thank You and Questions?