Pharmacology of Anti‐TB Medications · Pharmacology of Anti‐TB Medications Vanessa Meyer, PharmD March 18, 2015 ... – Do not use with drugs that increase concentrations of serotonin

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EXCELLENCE EXPERTISE INNOVATION

PharmacologyofAnti‐TBMedications

VanessaMeyer,PharmDMarch18,2015

TB Nurse Case ManagementMarch 17‐19, 2015San Antonio, Texas

• No conflict of interests

• No relevant financial relationships with any commercial companies pertaining to this educational activity

VanessaMeyer,PharmD hasthefollowingdisclosurestomake:

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Anti-Tuberculosis Medications

Vanessa Meyer, PharmD

Objectives

• First-line anti-tuberculosis medications

• Second-line anti-tuberculosis medications

• New and investigational drugs

• Food-drug interactions

• Drug-drug interactions

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FIRST-LINEANTI-TUBERCULOSIS MEDICATIONS

RifampinRifabutin*IsoniazidPyrazinamideEthambutol

* Not FDA approved for TB

Rifampin

• Dose– Adults: 10 mg/kg/dose up to 600 mg (PO or IV)– Children: 10-20 mg/kg/dose up to 600 mg (PO or

IV)

• Administration– Take 1 hour before or 2 hours after meals– Take 1 hour before antacids– Avoid alcohol– May mix the contents of capsule with applesauce

or jelly

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Rifampin

• Common side effects– Reddish-orange body fluids

• Will stain contact lenses

– Nausea/vomiting/diarrhea– Rash & pruritis– Increase in LFTs– Flu-like syndrome

• Serious adverse reactions– Hepatitis– Hematological (thrombocytopenia, hemolytic anemia)– Renal failure

Images Courtesy: http://dermnetnz.org/common/image.php?path=/treatments/img/rifampicin‐urine.jpg; http://www.ptclworkers.com/news/health‐scientists‐to‐pave‐way‐for‐hepatitis‐c‐vaccine/

Rifampin

• How supplied– Oral capsule: 150 mg, 300 mg

– Injection, powder for reconstitution: 600 mg

– Suspension available through compounding pharmacy

Images courtesy: www.epocrates.com

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RifampinRifampin 25 mg/ml Oral Suspension

Ingredients:

10120 ml

300 mg rifampin capsules1:4 cherry syrup concentrate/simple syrup

Directions:1. Empty contents of 10 300 mg rifampin capsules in a mortar and triturate

to a fine powder.2. Wet powder with approximately 20ml of vehicle and mix until it is a

uniform paste.3. Continue adding vehicle geometrically until almost 120 ml.4. Transfer to a graduated cylinder and rinse mortar with remaining vehicle. 5. Fill graduated cylinder to a total volume of 120 ml. Mix well.6. Label with “shake well” and “refrigerate.”

Total volume: 120 ml Shelf life: 28 days refrigerated (preferred) or at room temperature

Rifabutin

• Dose– Adults: 5 mg/kg

– Children: pediatric dose not established• 5-10 mg/kg/day have been used

• Administration– May be taken with or without food

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Rifabutin

• Common side effects– Reddish-orange body fluids – Rashes and skin discoloration

• Bronzing or pseudojaundice

– Arthralgias

• Serious adverse reactions– Hepatotoxicity– Leukopenia/neutropenia– Anterior uveitis and other eye toxicities

Rifabutin

• How supplied– Capsule, oral: 150 mg



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Rifabutin

Rifabutin 20 mg/ml Oral Suspension

Ingredients:

860 ml

Rifabutin 150 mg capsules1:1 Ora-Plus/Ora-Sweet

Directions:

1. Empty contents of 8 capsules into a glass mortar and triturate to a fine powder.2. Wet powder with approximately 20 ml of vehicle and mix to a uniform paste.3. Continue to mix and add vehicle geometrically to almost 60 ml.4. Transfer to a graduated cylinder.5. Rinse mortar with vehicle, and add to graduated cylinder.6. Add vehicle to cylinder to make 60 ml. Stir well.7. Add “shake well” label.

Total volume: 60 ml Shelf life: 84 days at room temperature

Isoniazid

• Dose– Adults

• 5 mg/kg/day

• 20-30 mg/kg two to three times weekly

– Children• 10-15 mg/kg/day

• 20-30 mg/kg/dose two to three times weekly

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Isoniazid

• Administration– Take 1 hour before or 2 hours after meals

– May take with small snack if needed

– Take 1 hour before or 2 hours after antacids

– Supplement with pyridoxine if needed

– Avoid alcohol

– Avoid tyramine-containing foods• Aged cheese, tap/draft beers, sauerkraut, soy

sauce

Isoniazid

• Common side effects– Peripheral neuropathy

• Pyridoxine deficiency

– Epigastric discomfort– Cramping with INH solution

• Serious adverse reactions– Hepatotoxicity– Hypersensitivity reactions

Images Courtesy: http://avicennalaser.com/LaserTherapyFacts/Peripheral‐Neuropathy.htm; http://www.healthline.com/health/abdominal‐bloating‐and‐abdominal‐pain; http://hepatitiscmx.com/hepatitis‐c‐treatments/

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Isoniazid

• How supplied– Injection, solution: 100 mg/mL

– Solution, oral: 50 mg/5 mL in sorbitol

– Tablet, oral: 100 mg, 300 mg

Causes diarrhea

Images courtesy: www.epocrates.com and dailymed.nlm.nih.gov/dailymed

Pyrazinamide

• Dose– Adult:

– Children: • 15-30 mg/kg/daily• 50 mg/kg twice weekly


Weight (kg) Daily Therapy Twice Weekly DOT Three/Week DOT

40-55 1000 mg 2000 mg 1500 mg

56-75 1500 mg 3000 mg 2500 mg

76-90 2000 mg (maximum) 4000 mg (maximum) 3000 mg (maximum)

*based on lean body weight

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Pyrazinamide

• Common side effects– Gout and arthralgias

**Contraindicated in patients with severe gout**

– Rash– Photosensitivity– Gastrointestinal upset

• Serious adverse reactions– Hepatitis

Images Courtesy: http://www.healthline.com/health‐slideshow/foods‐to‐avoid‐with‐gout; https://www.onlinedermclinic.com/archive/drug‐induced‐photosensitivity

Pyrazinamide

• How supplied– Tablet, oral: 500 mg



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Pyrazinamide

Pyrazinamide 100 mg/ml Oral Suspension

Ingredients:

340850 ml850 ml

Pyrazinamide 500 mg tabletsMethylcellulose 1%Simple Syrup

Directions:

1. Crush 200 Pyrazinamide 500 mg tablets.2. Mix with a suspension containing 500 ml methylcellulose 1% and 500 ml

simple syrup.3. Crush 140 Pyrzinamide 500 mg tablets and mix with a suspension

containing 350 ml methylcellulose 1% and 350 ml simple syrup.4. Combine both suspensions to make 1.7 liter suspension.5. Label “shake well” and “refrigerate.”

Total volume: 1.7 L Shelf life: 60 days refrigerated or 45 days at room temperature

Ethambutol

• Dose– Adult

• 15 mg/kg/day• 50 mg/kg twice weekly

– Children• 15-20 mg/kg/day• 50 mg/kg twice weekly


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Ethambutol

• Common side effects– Nausea/vomiting– Abdominal pain– Blurred vision– Rash– Peripheral neuropathy

• Serious adverse reactions– Optic neuritis– Blindness, irreversible

Images Courtesy: http://pixshark.com/optic‐neuritis‐vs‐normal.htm; http://swfhealthandwellness.com/treatment‐paradigm‐patients‐suffer‐peripheral‐neuropathy‐10/

Ethambutol

• How supplied– Tablet, oral, as hydrochloride: 100 mg, 400

mg



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SECOND-LINEANTI-TUBERCULOSIS MEDICATIONS

Cycloserine

Ethionamide

Levofloxacin

Moxifloxacin

Paser

Streptomycin

Amikacin

Capreomycin

Linezolid

Cycloserine

• Dose– Adults: 10-15 mg/kg/day divided every 12 hours

– Children: 10-15 mg/kg/day divided every 12 hours

– Titrate dose as tolerated

• Administration– Take on an empty stomach

– Supplement with pyridoxine

– Avoid alcohol

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Cycloserine

250 mg daily

250 mg BID

250 mg qam & 500 mg qhs

Dose titration should be completed within 2 weeks

Cycloserine

• Common side effects– Behavioral changes– Headache– Skin changes– Dizziness

• Serious adverse reactions– Seizure– Depression– Psychosis– Suicidal ideation

Images Courtesy: http://maddieruud.hubpages.com/hub/Psychosis_Vs_Neurosis; http://blogs.psychcentral.com/nlp/2013/11/top‐five‐natural‐supplements‐for‐depression/

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Cycloserine

• How supplied– Capsule, oral: 250 mg


Ethionamide

• Dose– Adults:15-20 mg/kg/day

• 500-750 mg/day in single or divided dose

– Children: 15-20 mg/kg/day divided in 2-3 doses– Titrate dose as tolerated

• Administration– Take with or after meals– Supplement with pyridoxine– Avoid alcohol

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Ethionamide

250 mg daily

250 mg BID

250 mg qam& 500 mg qhs


Ethionamide

• Common side effects– GI upset/anorexia– Metallic taste– Hypothyroidism– Acne– Hair loss– Gynecomastia– Menstrual irregularity

• Serious adverse reactions– Hepatotoxicity

Images Courtesy: http://www.abc.net.au/health/library/stories/2005/06/16/1831822.htm; http://www.livescience.com/36330‐ovarian‐cancer‐facts‐symptoms‐tests‐statisitcs.html; http://www.medicinenet.com/thyroid_disorders/article.htm

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Ethionamide

• How supplied– Oral, tablet: 250 mg

Levofloxacin

• Dose– Adult: 500-1000 mg/day– Children: 10 mg/kg/day for older children and 15-

20 mg/kg/day divided bid for younger children

• Administration– Take 2 hours before or after aluminum,

magnesium, or calcium-containing antacids, iron, vitamins, sucralfate, and/or milk-containing products

– Promote adequate hydration

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Levofloxacin

• Common side effects– Nausea and bloating– Headache– Dizziness– Insomnia– Arthralgias

• Serious adverse reactions– Tendon rupture (rare)– QT prolongation

Images Courtesy: https://olearystudio.wordpress.com/randoms/medical‐matters/achilles‐tendon‐rupture/; http://paininjuryrelief.com/take‐control‐of‐your‐knee‐pain/

Levofloxacin

• How supplied– Tablets, oral: 250 mg, 500 mg, 750 mg

– Injection, solution: 25 mg/ml

– Solution, oral: 25 mg/ml

– Infusion, premixed with D5W: 250 mg, 500 mg, 750mg


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Moxifloxacin

• Dose– Adults: 400 mg daily– Children: No established dose

• Administration– Do not take milk-based products, antacid

(especially aluminum-coating), vitamin supplements, or sucralfate within 2 hours of this medication

Moxifloxacin

• Common side effects– Nausea/diarrhea– Headache/dizziness– Arthralgias (< levofloxacin)

• Serious adverse reactions– Hepatotoxicity (rare)– Tendon rupture (rare)– QTc prolongation

Images Courtesy: http://www.stratfordacupuncture.com/acupuncture‐and‐migraines‐pain‐management‐acupuncture‐for‐addictions‐ct/

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Moxifloxacin

• How supplied– Tablets: 400 mg

– Solution for IV: 400 mg/250 ml


Paser

• Dose– Adults: 8-12 grams per day divided 2-3 times daily– Children: 200-300 mg/kg/day divided 2-4 times daily

• Administration– Keep in the refrigerator– Take with or immediately following meals– Do not chew granules– Sprinkle on applesauce or yogurt; swirl in acidic juices

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Paser

2 gm BID

2 gm qam & 4 gm qhs

4 gm BID


Paser

• Common side effects– GI upset

– Hypothyroidism

• Serious adverse effects– Hepatotoxicity

Images Courtesy: http://blog.partnersforyourhealth.com/Blog/bid/53288/Abdominal‐Aortic‐Aneurysm‐Can‐Be‐a‐Silent‐Killer; http://www.emedicinehealth.com/thyroid_problems/article_em.htm

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Paser

• How supplied– Oral, granules: 4 gram packet

AmikacinCapreomycinStreptomycin

• Dose– Adults

• 15mg/kg/day, 5-7 days per week • 15-20 mg/kg/dose 2-3 days per week after initial dosing

*after culture conversion*

– Children• 15-30 mg/kg/day, 5-7 days per week• 15-30 mg/kg/day, 2-3 days per week after initial dosing

• Administration– Z-track method

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Capreomycin

• Reconstitute 1 gram vial – 2 ml 0.9% Sodium Chloride Injection, or – 2 ml Sterile Water for Injection

• May be stored up to 24 hours under refrigeration

• 2-3 minutes should be allowed for complete dissolution

• IV: – Reconstituted vial should be diluted in 100 ml of

0.9% Sodium Chloride Injection– Administer over 60 minutes

Capreomycin

• For administration of 1 gram dose, entire contents of vial should be given

• Smaller doses, follow chart below:

Dilution Table

Diluent Added to 1-g, 10 ml Vial

Volume of Capastat® Sulfate solution

Concentration(Approximate)

2.15 ml 2.85 ml 370 mg/ml

2.63 ml 3.33 ml 315 mg/ml

3.3 ml 4 ml 260 mg/ml

4.3 ml 5 ml 210 mg/ml

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Capreomycin

• Example– RJ comes into the clinic requiring 750 mg

capreomycin IM. How many ml will you give IM if you reconstituted the vial with 2.15 ml?

750 mg

? ml

370 mg

1 ml

What we know

What we want to know

370 mg x ? 750 mg x 1ml

370 mg 370 mg


• Common side effects– Local pain with IM injections– Electrolyte abnormalities

• Hypocalcemia• Hypokalemia• Hypomagnesemia

• Serious adverse reactions– Nephrotoxicity– Vestibular toxicity/ototoxicity

Images Courtesy: http://www.webmd.com/urinary‐incontinence‐oab/picture‐of‐the‐kidneys; http://forwardthinkingpt.com/2012/07/09/vestibular‐rehabilitation‐how‐learning‐about‐inner‐ear‐strengthening‐breathed‐life‐into‐a‐dead‐therapist‐part‐1/

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• How supplied– Amikacin:

• Injection, solution: 250 mg/ml (2ml, 4ml)

– Capreomycin:• Injection, powder for reconstitution: 1 g

– Streptomycin:• Injection, powder for reconstitution: 1 g

Image courtesy http://dailymed.nlm.nih.gov/dailymed

Linezolid

• Dose– Adults: 600 mg daily– Children: 10 mg/kg/dose every 8 hours

• Administration– May be taken with or without food– Supplement with pyridoxine– Avoid tyramine containing food/drinks

• Aged cheeses, dried meats, sauerkraut, soy sauce, tap beers, red wines

– Do not use with drugs that increase concentrations of serotonin in the body

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Linezolid

• Common side effects– Diarrhea

– Nausea

– Optic and peripheral neuropathy

• Serious adverse reactions– Myelosuppression

Linezolid

• How supplied– Infusion, premixed: 200mg; 600mg

– Powder for suspension, oral: 100mg/5ml

– Oral, tablet: 600 mg


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NEW AND INVESTIGATIONAL DRUGS

Bedaquiline (Sirturo®)

Clofazimine

Bedaquiline

• FDA indicated for multi-drug resistant pulmonary TB in adults ≥ 18 years old– Only used when effective treatment regimen

cannot otherwise be provided– Not used for:

• Latent TB• Drug-sensitive TB• Extra-pulmonary TB

• Should be used with at least 3 other susceptible drugs

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Bedaquiline

• Dose– Adults

• Weeks 1-2: 400 mg once daily, then• Weeks 3-24: 200 mg three times per week

(with at least 48 hours between doses)

• Administration– Give with food– Swallow tablets whole with water– Avoid alcohol

Bedaquiline

• Common side effects– Nausea– Arthralgia– Headache– Elevated AST/ALT

• Serious adverse reactions– QT prolongation– Hepatotoxicity– Increase in mortality

Images Courtesy: http://arthritishealth.cnconfucius.asia/health/15141‐arthritis‐weight‐lifting‐exercises‐glenohumeral‐joint‐arthritis‐pain/

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Bedaquiline

• Restricted use in the United States

• How supplied– Oral, tablet: 100 mg

Image courtesy http://dailymed.nlm.nih.gov/dailymed

Clofazimine

• Dose– Adults: 100 to 200 mg daily

– Children: limited data, but doses of 1 mg/kg/day have been given

• Administration– Take with food

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Clofazimine

• Common side effects– Pink or red discoloration

• Skin, conjunctiva, cornea and body fluids

– GI upset– Rash/pruritis– Dry skin

• Serious adverse reactions– Gastrointestinal bleeding– Bowel obstruction

Clofazimine

• Not commercially available in the United States

• How supplied:– Oral, capsule: 50 mg

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Drug-Drug Interactions

Drug Interactions

• CYP450 are the major enzymes involved in drug metabolism

• Most drugs undergo deactivation by CYPs (some activation)

• Many drugs may increase or decrease the activity of various CYP450 enzymes – Increase activity (inducers)

• Rifampin• Rifabutin (< than rifampin)

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Drug Interactions

CYP450 3A4

Rifampin

Rifabutin

CYP inducer

CYP substrate

Terbinafine

Inactivated terbinafine

Substrates (CYP3A) Inhibitors Inducers

Alprazolam/clonazepam Amiodarone Carbamazepine

Atorvastatin Cimetidine Gluccocorticoids

Buspirone Clarithromycin Phenobarbital

Calcium channel blockers Erythromycin Phenytoin

Carbamazepine Fluconazole Primidone

Cilostazol Fluoxetine Rifampin

Citalopram Fluvoxamine

Clindamycin Grapefruit juice

Clindamycin Indinavir

Dapsone Itraconazole

Estrogens Ketoconazole

Protease inhibitors Metronidazole

Losartan Miconazole

Ondansetron Nefazodone

Prednisone Nelfinavir

Sertraline Ritonavir

Simvastatin Saquinavir

Warfarin Sertraline

Increase levels of rifabutin in blood

Decrease levels of rifabutin in bloodRifampin will

decrease levels of these meds in blood

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Food-Drug Interactions

!

Food-Drug Interactions

Best on empty stomach

• Rifampin

• Isoniazid

• Cycloserine

• Moxifloxacin

• Levofloxacin

Best with food

• Paser

• Clofazimine

• Ethionamide

• Bedaquiline

Avoid antacids

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References1. Francis J. Curry National Tuberculosis Center and California Department of Public Health, 2008: Drug-Resistant

Tuberculosis: A Survival Guide for Clinicians, Second Edition.

2. Dana WJ, Fuller MA, Goldman MP, et al. Drug Information Handbook, 20th ed. Hudson, Ohio, Lexi-Comp, Inc.; 2011: 1143-7.

3. Micromedex® 2.0, Drugdex® Evaluations, Greenwood Village, CO: Truven Health Analytics, Inc. (Accessibility verified on September 15, 2014)

4. Dailymed. Bethesda, MD: U.S. National Library of Medicine, National Institutes of Health, Health & Human Services, 2005. http://dailymed.nlm.nih.gov/dailymed/index.cfm (Accessibility verified on September 20, 2014)

5. Epocrates Rx Online [database on the Internet]. San Francisco, CA: Epocrates, Inc. 2014. Retrieved at www.epocrates.com. Web-based; continuous content updates. (Accessibility verified on September 15, 2014)

6. Bedaquiline [package insert]. Titusville, NJ: Janssen Therapeutics; 2013.

7. Centers for Disease Control and Prevention (CDC). Treatment of Tuberculosis: American Thoracic Society, CDC, and Infectious Diseases Society of America, 2003. MMWR Morb Mortal Wkly Rep. 2003;52(RR-11):1-79.

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Pharmacology of Anti‐TB Medications · Pharmacology of Anti‐TB Medications Vanessa Meyer, PharmD March 18, 2015 ... – Do not use with drugs that increase concentrations of serotonin