TB lecture - Mayo Clinic Center for Tuberculosis
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Transcript TB lecture - Mayo Clinic Center for Tuberculosis
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
Upon completion of this presentation,
participants will be able to:
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
References
Curry International Tuberculosis Center and California Department of Public
Health, 2012: Tuberculosis Drug Information Guide, 2nd edition.
http://www.nationaltbcenter.ucsf.edu/drtb/
http://www.currytbcenter.ucsf.edu/products/index.cfm
Heartland National TB Center – U of Texas Health Science Center at Tyler
http://www.heartlandntbc.org/products.asp
http://www.heartlandntbc.org/products/tuberculosis_treatment_guidelines_2003_
poster.pdf
http://www.heartlandntbc.org/products/tuberculosis_medication_drug_and_food_
interactions.pdf
http://www.heartlandntbc.org/products/card1_side_effects_drug_interactions.pdf
Doc Holladay – The Face of TB
History of TB medications
November 20th, 1944 Streptomycin
first administered to a critically ill
TB patient
P-aminosalicyclic acid (1949)
Isoniazid (1952)
Pyrazinadmide (1952)
Immediately impressive results
Side effects
Cycloserine (1955)
Resistance within a few months!!!
Ethambutol (1961)
Rifampin (1966)
Antituberculosis Drugs
First-line drugs
Second-Line drugs
Isoniazid
Cycloserine
Rifampin/Rifapentine/Rifabutin*
Ethionamide
Ethambutol
Levofloxacin*
Pyrazinamide
Moxifloxacin*
PAS
Streptomycin
Amikacin/Kanamycin
Capreomycin
Linezolid
Bedaquiline
* Not FDA approved for TB
Populations of Mycobacteria
Actively Dividing
INH/Rifampin/Ethambutol
Semi-Dormant
Persisters
Rifampin
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
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).
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).
XDR TB Diminishing Options for Treatment
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)
Drug Shortages
American Society of Health-System Pharmacists (ASHP) website
http://www.ashp.org/menu/DrugShortages
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).
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
http://www.nationaltbcenter.ucsf.edu/drtb/docs/07AdvReact.pdf#table1
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 10-25 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
http://www.nationaltbcenter.ucsf.edu/drtb/docs/05SpecialSit.pdf
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
http://www.nationaltbcenter.ucsf.edu/drtb/docs/05SpecialSit.pdf
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
http://www.nationaltbcenter.ucsf.edu/drtb/docs/05SpecialSit.pdf
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
2nd and 3rd 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
http://www.nationaltbcenter.ucsf.edu/drtb/docs/T1DrugOGram.pdf
Therapeutic Drug Monitoring – Tools
http://www.nationaltbcenter.ucsf.edu/drtb/docs/T2CarePlan.pdf
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
http://www.nationaltbcenter.ucsf.edu/drtb/docs/05SpecialSit.pdf
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
http://www.nationaltbcenter.ucsf.edu/drtb/docs/05SpecialSit.pdf
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?