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Guidelines for the Management of Adverse Drug Effects of
Antimycobacterial Agents
Lawrence Flick Memorial Tuberculosis Clinic
Philadelphia Tuberculosis Control Program
November 1998
Table of Contents
Drugs Used in the Treatment of Tuberculosis
Section I: Most Common Adverse Drug Effects
Listed by Adverse Effect
Section II: Adverse Drug Effects and Drug Interactions
Listed by Drug
Tables
Table 1: Drug Rechallenge Protocol
Table 2: Aminoglycoside Monitoring Parameters Figures
Figure 1: Management of Nausea & Vomiting
Appendixes
Appendix 1: Selected Antihistamines for the Prevention/ Treatment of Cutaneous “Flushing” Reactions Appendix 2: Oral Desensitization Protocol for Isoniazid Appendix 3: Oral Desensitization Protocol for Rifampin Appendix 4: Guidelines for Medication Administration Appendix 5: Technique for Medication Administration to References
Drug Used in the Treatment of Tuberculosis
First Line Drugs
Second Line Drugs
Section I
Most Common Adverse Drug Effects Listed
by the Type of Adverse Effect
Dermatologic (Skin) Adverse Effects
Mild “flushing” reactions (two different types of reactions)
Clinical presentations
flushing and/or itching of the skin with or without a rash usually involves the face and scalp; may cause redness/watering of the eyes usually occurs 2-3 hours after drug ingestion  flushing and/or itching of the skin with or without a rash PLUS hot flashes, palpitations,
headache and/or increased blood pressure
occurs immediately after ingestion of certain foods (see below) Causative agents
Reaction 2: isoniazid + tyramine containing foods (cheese, red wine) or certain fish (tuna, Management
flushing is usually mild and resolves without therapy if flushing is bothersome to the patient, an antihistamine may be administered to treat or prevent the reaction (refer to Appendix 1, page 49) advise patient not to ingest foods listed above while receiving INH Refer also to individual drug monographs: isoniazid pages 32-34pyrazinamide pages 38-39rifampin pages 42-45 Dermatologic (Skin) Adverse Effects
Moderate/severe hypersensitivity (immune) reactions
Clinical Presentation
hives (raised, itchy rash) with or without fever Causative Agents1
INH < rifampin < PZA < ethionamide < cycloserine < ethambutol <para-aminosalicylic acid < streptomycin Note: in children, viral infections (e.g. Epstein-Barr and Herpes Simplex) commonly result
in hives that may be confused with a drug reaction.
Management
1. Discontinue all drugs2. Rule out a viral infection a. full physical examb. complete blood count (examine for lymphocytosis) 3. If a viral infection is present, restart all of the TB medications (no rechallenge is required)4. If a viral infection is ruled out, follow drug rechallenge guidelines outlined in the adult management guidelines (below); doses must be adjusted for age and weight.
1. Discontinue all drugs until the reaction resolves2. Identify the causative drug by rechallenging (restarting) each drug every 4 days according to Table 1 (example follows on next page).
Drug Rechallenge Protocol
Challenge Doses
a. begin the rechallenge with INH 50mg on day 1 1) if the original reaction was severe, begin the rechallenge with 1/10 the day 1 dose b. if a reaction does not occur after the day 1 dose, increase the INH to 300mg on day 2c. if a reaction does not occur after the day 2 dose, continue INH 300mg q dayd. continue to add drugs in the order and doses specified on Table 1 every 4 days 1) if the original reaction was severe, begin the rechallenge with 1/10 the day 1 dose 2) if the day 2 dose is less than the normal recommended dose based on the patient’s weight, increase to the appropriate dose on day 3(a) example for ethambutol dosing in a 70kg person: day 1=100mg, day 2=500mg, 3. If a reaction occurs during drug rechallenge and the causative drug can not be discontinued, drug desensitization will be necessary1,3 Drug desensitization should not be attempted with severe skin reactions or those
involving the mouth or mucous membranes (e.g. exfoliative dermatitis and Stevens-
Johnson Syndrome)1.
a. consideration should be given to desensitizing patients under monitored conditions for b. the patient should be receiving > 2 other TB medications before undergoing drug c. three desensitization protocols have been utilized (a) initiate the day 1 dose as indicated in Table 1(b) if a reaction occurred after day 1 of drug rechallenge, begin desensitization with (c) double each dose and administer twice daily until the recommended daily dose (d) administer the recommended daily dose for 3 days, then switch to once daily dosing (e.g. INH 150mg bid x 3 days, then 300mg q day) (e) if a reaction develops during desensitization, decrease the dose to the highest dose (the previous dose) that did not cause a reaction and begin increasing the doses insmaller increments (ii) rapid desensitization for isoniazid4 (refer to Appendix 2, page 50)(iii)rapid desensitization for rifampin and ethambutol5 (refer to Appendix 3, page 51) d. steroids may be utilized if drug desensitization is urgent1: (ii) severe drug reaction(iii) hypersensitivity to > 1 drug e. patients should receive daily dosing after drug desensitization is completed (no twice Gastrointestinal Adverse Effects
Nausea/vomiting
Causative Agents
clofazimine, ethionamide, para-aminosalicylic acid (PAS)
rifabutin, isoniazid (twice and thrice weekly dosing) ethambutol, pyrazinamide, ofloxacin, levofloxacin isoniazid (qD), rifapentine, cycloserine, aminoglycosides , capreomycin* Management
1. Examine how the medication is being administered a. Is the medication being administered as a liquid? 1) administration of large volumes may cause vomiting because of the limited stomach 2) if this is the cause, the child usually vomits immediately after medication b. Is the child gagging when medicine is administered? 1) children frequently “gag” to avoid taking medicine2) administration of medication through a syringe is the best method to avoid “gagging”3) refer to Appendixes 4-5, pages 52-53 c. Does the child take the medicine on an empty stomach? 1) if so, give medications after meals (e.g. ask school nurse to administer medications 2. Rule out other causes of nausea and vomiting a. How often does nausea and vomiting occur?b. When does it start in relation to taking the medications?c. Could the child have a viral infection? 3. If the TB medications are the likely cause of gagging, nausea or vomiting, follow the nausea and vomiting management algorithm on page 9.
∗Although nausea and vomiting are uncommon adverse effects of the aminoglycosides (streptomycin, amikacin,kanamycin) and capreomycin, it may be an indication of vestibular toxicity (inner-ear toxicity). If this occurs,contact a TB Control physician.
1. Rule out other causes of nausea and vomiting “Have you had stomach problems in the past?”“If so, did it feel like this?”“What made your stomach problems better in the past?”“Did you eat/drink or do anything differently than usual the day you had “How often do you have nausea and vomiting?”“When does it start in relation to taking your TB medications?”“How long does it last?”“Does it happen every time you take your medicine?”“Is it difficult for you to swallow your pills?”“How much water or juice do you drink when taking your pills?” b. Consider measuring liver function tests to rule out drug induced hepatic dysfunction (refer to “Hepatotoxicity” section, pages 12-13).
2. If the TB medications are the likely cause of the patient’s nausea/vomiting, follow the management algorithm on the following page.
Refer also to individual drug monographs, pages 19-48 [Insert Figure 1]
Gastrointestinal Adverse Effects
Diarrhea
Clinical Presentation
Causative Agents
clofazimine, ethionamide, para-aminosalicylic acid (PAS)
isoniazid, ethambutol, pyrazinamide, rifapentine, cycloserine,aminoglycosides, capreomycin Management
1) Are liquid preparations being administered? a) diarrhea can be caused by the lactose and sucrose contained in liquid preparations b) usually, the first episode of diarrhea occurs when therapy is initiated c) crush medications (refer to Appendix 4, page 52) instead of using liquid 2) Is the diarrhea caused by a viral infection? a) rotavirus season is between February to May and is a common cause of diarrhea b) send viral stool culturesc) an example of diarrhea that is more likely caused by a virus than the medications is if the child develops diarrhea after previously tolerating the medicine for aprolonged time period “Have you had problems with diarrhea in the past?”“Did you eat/drink anything unusual within 1-2 days of the onset of diarrhea?”“When does the diarrhea occur in relation to taking your TB medications?”“How long does it last?”“Does it happen every time you take your TB medications?” 2) If suspected, rule out C. difficle 2. Withhold drugs until diarrhea resolves 3. Restart drugs one at a time every 4 days a. begin with drugs that are least likely to cause diarrheab. consider crushing pills/capsules and administering as outlined in Appendix 4, page 52c. if the patient was receiving a twice or thrice weekly regimen when the diarrhea began, 4. If diarrhea recurs when one particular drug is added to the regimen, consider discontinuing the causative agent and adding other TB drugs and/or extending the duration of treatment 5. If diarrhea occurs with multiple drugs, consider separating medication administration times a. different drugs in the regimen should be administered several hours apartb. do not split doses for individual drugs (possible exceptions: ethionamide, ofloxacin)c. example: administer INH 300mg in the morning and rifampin 600mg in the evening 6. If diarrhea continues and an alternate regimen can not be utilized consider the addition of an antimotility agenta. loperamide (Imodium®) 1) adult dose: 4mg x 1, then 2mg after each loose stool (maximum dose=16mg/d)2) child dose: day 2 and subsequent days: 0.1mg/kg/dose after each loose stool (dose should notexceed the day 1 dose for each age/weight group) b. adsorbents (kaolin-pectin, polycarbophil) should not be prescribed because decreased Refer also to individual drug monographs, pages 19-48.
Gastrointestinal Adverse Effects
Hepatotoxicity (Hepatitis)
Clinical Presentation
symptoms: nausea, vomiting, abdominal tenderness, discomfort near the ribs on the right upper abdomen, jaundice (yellowing of skin and whites of the eyes) signs: hepatic enlargement, increased LFTs Causative Agents2,6
INH + rifampin > INH alone >> pyrazinamide alone > rifampin alone > ethionamide Hepatotoxicity in Children
Note: hepatotoxicity is very uncommon in children7. If suspected, the child should be
referred to the Flick Memorial Tuberculosis Clinic for evaluation.
Routine Monitoring for Hepatotoxicity in Adults
1. Obtain baseline liver function tests (LFTs) 8,9 1) aspartate aminotransferase (AST) [normal 0-40 u/l]2) alanine aminotransferase (ALT) [normal 0-40 u/l] b. alkaline phosphatase [normal 25-115 u/l]c. gamma glutamyl transpeptidase (GGTP) [normal 10-50 u/l]d. total bilirubin [normal 0.2-1.5 mg/dl] a. patients < 35 years old with normal baseline LFTs and without a history of hepatic disease: follow-up labs are not required unless the patient becomes symptomatic8,9 b. patient > 35 years old, daily alcohol consumption, abnormal baseline LFTs or a history of hepatic disease: obtain LFTs every 4-6 weeks2 Management in Adults
1. Asymptomatic patients with an increase in LFTs from baseline:
a. if the increase in LFTs is < 3-5x normal: continue the current regimen and monitor for symptoms of liver dysfunction3,9 (see “Clinical Presentation” section) b. for asymptomatic patients, if the serum transaminases increases > 3-5x normal: hold
∗ Early reports of pyrazinamide hepatotoxicity occurred in patients who received 40-50mg/kg/d for prolongedperiods. Hepatotoxicity has not been reported with extensive use of lower doses (15-30mg/kg/d) in short courseregimens.2 1) if the patient is receiving a two drug regimen, substitute at least one other drug (e.g.
2) if the transaminases increase with rechallenge of INH, discontinue INH, substitute another drug (e.g. ethambutol) and adjust the treatment duration as required3,8 c. if the serum total bilirubin increases: therapy usually does not require modification (rifampin competes with bilirubin for elimination resulting in increased serum bilirubininitially; bilirubin levels usually return to normal with continued therapy)2 2. Symptomatic patients (see “Clinical Presentation”)
a. Hold all drugs and obtain LFTsb. If LFTs are within the normal ranges, refer to the Management of Nausea/Vomiting c. If LFTs are elevated, hold drugs until symptoms resolve and the transaminases decreases to < 2x normal3,61) ethambutol and pyrazinamide should be started if drug therapy can not be held secondary to the patient’s clinical conditiona) use streptomycin if pyrazinamide is suspected to be the cause of hepatotoxicity 2) rechallenge the patient after resolution of signs and symptoms by adding drugs to the regimen every 4 days6:a) rifampin for 3 days, if patients remains asymptomatic then addb) INH for 3 days, if patients remains asymptomatic then addc) pyrazinamide (15-20mg/kg/d) for 3 days 3) if signs and symptoms recur with rechallenge, discontinue the responsible drug and modify the regimen and/or duration of therapy as required ethionamide pages 30-31isoniazid pages 32-34pyrazinamide pages 38-39rifampin pages 42-45 Miscellaneous Adverse Effects
Arthalgias (joint pain)
Arthalgias Type 1
Causative Agents1,2
pyrazinamide>>ethambutol>isoniazid Clinical Presentation
pain and tenderness of joints: fingers, shoulders, knees, etc. (usually mild) Management
TB medications do not require discontinuation low dose nonsteroidal antiinflammatory agents (NSAIDS) can be used for pain relief as if symptoms persist, consider referral for rheumatologic evaluation Arthalgias Type 2 (Gouty Arthritis)
Causative Agents1,2
Clinical Presentation
symptoms: pain, tenderness and swelling of joints: fingers, shoulders, knees, etc.
signs: elevated serum uric acid concentrations Management
1. TB medications usually do not require discontinuation2. If acute swelling is present, the affected joint should be aspirated and examined for urate crystals to confirm the diagnosis of acute gouty arthritis.
a. nonsteroidal antiinflammatory agents include: 50mg tid-qid until pain relief, then 25mg tid-qid b. colchicine is an alternative to NSAIDS 1) dose: 0.5-1.2 mg x1, then 0.5-0.6 mg q 1-2 hours until joint pain is relieved or 2) pain usually resolves after 4-8 mg cumulative dose3) maximum dose: 8mg d. a steroid taper may be required for severe attacks 4. Recurrent episodes may occur while the patient remains on pyrazinamide or ethambutol.
a. consider using prophylactic colchicine 1) 0.6mg one to two times daily2) continue until causative agent is discontinued 5. Consider referral for rheumatologic evaluation for acute gouty arthritis attacks ethambutol pages 28-29isoniazid pages 32-34pyrazinamide pages 38-39 Miscellaneous Adverse Effects
“Influenza Syndrome”
Causative Agents2
rifampin > rifabutin (intermittent regimens > daily regimens) Clinical Presentation2
usually occurs 1-2 hours after drug administration usually resolves within 12 hours of drug administration Management
•switch from intermittent therapy to daily dosing2 (7 days/week) •symptomatic therapy may be required when switching from intermittent to daily therapy to Refer also to the rifampin monograph pages 42-45 Miscellaneous Adverse Effects
Neurotoxicity (Nervous System)
Peripheral Neuropathy
Causative Agents1,2
Clinical Presentation
prickling, tingling or burning sensation of the fingers and/or toes usually occurs in a stocking glove distribution Management
peripheral neuropathy rarely occurs in children unless severe malnutrition is present8,9 peripheral neuropathy is uncommon if the patient is receiving pyridoxine (vitamin B6) if peripheral neuropathy occurs, it can be treated with pyridoxine 100-200mg po q day Nervous System Effects in Children
Causative Agents
Clinical Presentation
Management
a. make sure the dose does not exceed 10mg/kg/db. add pyridoxine 50mg to the regimenc. administer medications around afternoon naps or at bedtime (e.g. administer school DOT at the end of the day so the child can take a nap after school) a. make sure the dose does not exceed 10mg/kg/db. switch to twice weekly dosing as soon as possible 1) if the child becomes hyperactive only on the days of medication administration, then 2) add pyridoxine 50mg daily for 6 weeks, then twice weekly for the remainder of a. make sure the dose does not exceed 10mg/kg/d a. hospitalize the child and administer isoniazid to document the reactionb. if a seizure occurs, discontinue isoniazid and add an alternative agent to the regimen Refer also to drug monographs: ethambutol (pages 28-29), isoniazid 32-34 Miscellaneous Adverse Effects
Optic Neuritis (vision)
Causative Agents
Clinical Presentation
blurred vision (decrease in the “sharpness” of objects)  “spots” present in patient’s field of vision optic neuritis has not been documented in children7 Management
•children with complaints of vision changes should be referred to the Flick Memorial ethambutol pages 28-29isoniazid pages 32-34 Section II
Adverse Drug Effects (ADE) and Drug Interactions∗
Listed Alphabetically by Drug
∗ This list is not all inclusive. Common and/or clinically important adverse drug effects and drug interactions are Aminoglycosides (amikacin, kanamycin, streptomycin)
Adverse Drug Effects (ADEs)
Nephrotoxicity (kidneys)
•nonoliguric acute renal failure (patient continues to have 1-2 liters/day urine output)10 •serum creatinine increases 7-10 days after initiation of therapy •magnesium and potassium wasting may occur •the frequency of agents causing nephrotoxicity is kanamycin = amikacin > streptomycin •the mechanism of toxicity is acute tubular necrosis •high aminoglycoside serum concentrations •concurrent use of other nephrotoxic drugs Ototoxicity (ears)
•cochlear toxicity: loss of hearing (usually high frequency hearing loss occurs first)12 •vestibular toxicity: vertigo, incoordination, dizziness, nausea •cochlear: kanamycin ≥ amikacin > streptomycin •vestibular: streptomycin > kanamycin ≥ amikacin •high aminoglycoside serum concentrations •total dose (amikacin > 15gm2, kanamycin > 14gm2, streptomycin 120gm9) •concomitant ototoxins (e.g. loop diuretics) Hypersensitivity (immune mediated reaction)
•most common adverse effect of streptomycin (rash, hives, fever) •occurs rarely with amikacin and kanamycin refer to the Hypersensitivity Management Guidelines, pages 5-6 Monitoring for ADEs
Table 28,9
Monitoring Parameters
Audiometry
Vestibular
Renal Function
K+, Mg2+,
Serum Drug
Symptoms
(e.g. Scr, BUN)
Amikacin
Kanamycin
Streptomycin
*ATS=American Thoracic Society; CDC=Center for Disease Control Capreomycin
Adverse Drug Effects (ADEs)
Nephrotoxicity (kidneys)
•increased blood urea nitrogen and serum creatinine •alkalosis and potassium, magnesium and calcium wasting may occur •36% of 722 patients who received capreomycin had ↑ in BUN to > 20mg/dl •the mechanism of toxicity is usually acute tubular necrosis •limit the dose of capreomycin to 750mg/day in elderly patients9 •discontinue capreomycin if nephrotoxicity occurs2 Ototoxicity (ears)
•cochlear toxicity: loss of hearing (usually high frequency hearing loss occurs first)8 •vestibular toxicity: vertigo, incoordination, dizziness, nausea •clinically apparent hearing loss occurred in 3% of 722 patients who received capreomycin •hearing loss usually occurs before vestibular toxicity (dizziness, incoordination) Monitoring for Adverse Effects
•audiometry at baseline and then at least every other month •vestibular function should be assessed periodically •assess hearing and vestibular function Clofazimine
Adverse Drug Effects (ADEs)
Gastrointestinal (stomach)
•nausea, vomiting, abdominal pain, loss of appetite and/or diarrhea •severe cramping, abdominal pain and diarrhea may occur in patients receiving > 100mg/day for prolonged time periods (may progress to a partial or complete bowel obstruction if drugis not discontinued) •up to 60% of patients will experience gastrointestinal adverse effects • gastrointestinal effects are the major dose limiting effect of clofazimine •dose related (↑ dose = ↑ adverse gastrointestinal effect) •clofazimine should be administered with food •refer to Nausea/Vomiting and Diarrhea Management Guidelines, pages 7-11 •if severe abdominal pain and diarrhea occur, discontinue therapy Dermatologic (skin)
pigmentation (pink to brownish-black discoloration) of the skin, hair, urine and feces15 •develops within the first few weeks after initiation of therapy •resolution usually occurs 6-12 months after drug discontinuation but may take up to 4 years •counsel patients that discoloration of skin, urine, etc. is likely to occur • the benefits of clofazimine should be weighed against cosmetic changes that may occur Ocular (eyes)
•red-brown discoloration of conjunctiva, cornea and lacrimal fluid (tears) •38-57% of patients may develop conjunctival discoloration •dose related (↑ dose = ↑ discoloration) •resolution usually occurs when clofazimine is discontinued • counsel patients that discoloration may occur •the benefits of clofazimine should be weighed against cosmetic changes that may occur Monitoring for Adverse Effects
Cycloserine
Adverse Drug Effects (ADEs)
Neurotoxicity (nervous system)
•emotional/behavioral effects include excitement, anxiety, aggression, confusion, depression,suicidal ideation and psychosis •other effects include headache, drowsiness, peripheral neuropathy, convulsions andseizures •most frequently reported adverse effect of cycloserine •30% of patients receiving 500mg daily experience these effects within 2 weeks of therapy •8% of patients receiving 500mg twice daily will develop convulsions •dose related: occurs more frequently with peak serum concentrations > 30 mcg/ml • alcohol ingestion increases the risk of seizures •adverse nervous system effects resolve when the drug is discontinued •aviod cycloserine use in patients with a history of seizures or psychologic problems2,14 •counsel patients not to ingest alcohol during therapy •administer pyridoxine 150mg/day while the patient is receiving cycloserine9 •decrease the dose or discontinue the drug if adverse nervous system effects occur2,14 Hypersensitivity (immune mediated reaction)
refer to the Hypersensitivity Management Guidelines, pages 5-6 Drug Interactions14,16
nervous system adverse effects may increase with concomitant use Monitoring for Adverse Effects
Ethambutol
Adverse Drug Effects (ADEs)
Ocular toxicity (eyes): Optic Neuritis
•blurred vision (decrease in the “sharpness” of objects)• “spots” present in the patient’s field of vision•red/green color blindness •uncommon and mild with a dose of 25mg/kg/day for 60 days, then decreased to •optic neuritis has not been documented in children7 •dose related (↑ dose = ↑ ocular toxicity) •usually reversible if ethambutol is discontinued with the onset of initial symptoms •permanent vision impairment may result if ethambutol is continued after symptoms occur •children with complaints of vision changes should be referred to the Flick Memorial •refer to Optic Neuritis Management Guidelines, page 18 Neurotoxicity (nervous system)
peripheral neuropathy: prickling, tingling or burning sensation of the fingers and/or toes consider ethambutol as the causative agents in patients who continue to experience peripheral neuropathy even after discontinuing isoniazid refer to Peripheral Neuropathy Management Guidelines, page 17 Arthalgias (joint pain)
symptoms: pain, tenderness and/or swelling of joints (usually mild) signs: elevated serum uric acid concentrations secondary to inhibition of urate secretion a majority of patients develop mild hyperuricemia while receiving ethambutol refer to Arthralgia Management Guidelines, pages 14-15 Hypersensitivity (immune mediated reaction)
refer to the Hypersensitivity Management Guidelines, pages 5-6 Drug Interactions14,16
Antacids (aluminum and magaldrate containing) •results in decreased ethambutol absorption •separate administration times by > 2 hours Monitoring of ADEs
•measurement of baseline visual acuity and red-green color perception in adults •repeat testing based on results of symptom assessment CDC recommendations8baseline and monthly monitoring of visual acuity and color vision Ethionamide
Adverse Drug Effects (ADEs)
Gastrointestinal (stomach)
•nausea, vomiting, abdominal pain, diarrhea, metallic taste and loss of appetite •very common: occurs to some degree in the majority of patients receiving ethionamide •may be severe enough to require discontinuation of drug therapy •consider starting therapy at a low dose and increasing as tolerated8 •consider administering with an antiemetic at bedtime for severe symptoms9 •refer to the Nausea/Vomiting and Diarrhea Management Guidelines on pages 7-11 Hepatotoxicity (liver)
•symptoms: nausea, vomiting, abdominal tenderness, discomfort near the ribs on the right upper abdomen, jaundice (yellowing of skin and whites of the eyes) •signs: hepatic enlargement, increased LFTs (refer to the Hepatotoxicity Management •usually resolves after drug discontinuation •children who are suspected of developing hepatotoxicity should be referred to the Flick Memorial Tuberculosis Clinic for evaluation •refer to the Hepatotoxicity Management Guidelines, pages 12-13 Hypersensitivity (immune mediated reaction)
refer to the Hypersensitivity Management Guidelines, pages 5-6 Monitoring of ADEs
Isoniazid
Adverse Drug Effects (ADEs)
Neurotoxicity (nervous system)
•peripheral neuropathy: prickling, tingling or burning sensation of the fingers and/or toes that usually occurs in a stocking glove distribution2 •other: insomnia, restlessness, muscle twitching2 •children: drowsiness, hyperactivity, dizziness, tonic/clonic seizures •peripheral neuropathy is uncommon with the recommended doses of isoniazid2 •patients who are likely to be pyridoxine deficient are at greater risk of developing peripheral •other nervous system effects are common at the recommended doses but are usually mild9 •nervous system effects are uncommon in children unless: Spatient is malnourished (vitamin B6 deficient)7 •tonic/clonic seizures occur rarely in children7 •pyridoxine 10-50mg should be administered to adults receiving isoniazid to prevent •pyridoxine administration is not usually required in children unless their diet is deficient in •refer to Neurotoxicity Management Guidelines, page 17 Hepatotoxicity (liver)
•symptoms: nausea, vomiting, abdominal tenderness, discomfort near the ribs on the right upper abdomen, jaundice (yellowing of skin and whites of the eyes) •signs: hepatic enlargement, increased LFTs (refer to the Hepatotoxicity Management Soccurs in 1% of patients receiving isoniazid Soccurs in 4% of patients receiving rifampin and isoniazid Sthe risk of hepatitis increases with concomitant alcohol use and age > 35 years Susually develops within the first 1-2 months of therapy •asymptomatic increases in serum transaminases2,14 Susually occurs within the first 4-6 months of therapy Stransaminase levels usually return to pretreatment levels even if isoniazid is continued •children who are suspected of developing hepatotoxicity should be referred to the Flick Memorial Tuberculosis Clinic for evaluation •refer to Hepatotoxicity Management Guidelines, pages 12-13 Gastrointestinal (stomach)
the likelihood of developing gastrointestinal effects increases with increasing doses refer to the Nausea/Vomiting and Diarrhea Management Guidelines on pages 7-11 “Flushing Reaction”
•flushing and/or itching of the skin with or without a rash •hot flashes, palpitations, headache and/or increased blood pressure •some patients experience this reaction immediately after ingesting certain foods Styramine containing foods: cheese, red wineShistamine containing foods: skipjack tuna •reaction usually resolves within 2 hours •counsel patients not to ingest these foods while receiving isoniazid •refer to Mild Cutaneous (“Flushing”) Reactions Management Guidelines, page 4 Hypersensitivity (immune reaction)
•usually occurs 3-7 weeks after initiation of therapy refer to the Hypersensitivity Management Guidelines, pages 5-6 Ocular toxicity (eyes): Optic Neuritis
•blurred vision (decrease in the “sharpness” of objects) •children with complaints of vision changes should be referred to the Flick Memorial •refer to Optic Neuritis Management Guidelines, page 18 Arthalgias (joint pain)
pain, tenderness and/or swelling of joints refer to Arthralgia Management Guidelines, pages 14-15 Drug Interactions14,16
Isoniazid may increase the serum concentrations/toxic effect of: •anticonvulsants: carbamezepine, phenytoin, primidone, and valproic acid Monitoring for ADEs
ATS recommendations/ CDC recommendations8,9 •refer to “Routine Monitoring for Hepatotoxicity”, pages 12-13, for guidelines formonitoring LFT Kanamycin (see aminoglycosides)
Levofloxacin (see quinolones)
Ofloxacin (see quinolones)
Para-aminosalicylic acid (PAS)
Adverse Drug Effects (ADEs)
Gastrointestinal (stomach)
nausea, vomiting, abdominal cramps, loss of appetite, diarrhea •a majority of patients experience some degree of gastrointestinal side effects •drug discontinuance may be required in some patients •diarrhea may be severe enough to cause steatorrhea, malabsorption, secondary folic acid •consider administration of vitamin B12 in patients receiving PAS > 1 month14 •refer to the Nausea/Vomiting and Diarrhea Management Guidelines on pages 7-11 Hypersensitivity (immune mediated reaction)
•itchy rash, fever, conjunctivitis (most common) •immune induced hepatitis: above symptoms plus hepatomegally (enlarged liver), leukocytosis (increased white blood cell count), lymphadenopathy and/or eosinophilia.
•5-10% of patients experience hypersensitivity reactions •usually occurs within the first 5 weeks of therapy •immune related hepatitis usually occurs within the first 3 months of therapy and is commonly preceded by rash, fever, conjunctivitis and eosinophilia •discontinue and do not attempt to restart PAS if immune related hepatitis occurs •refer to the Hypersensitivity Management Guidelines, pages 5-6 Drug Interactions14,16
•PAS may decrease the absorption of digoxin •decreased serum digoxin concentrations/therapeutic effect may occur Monitoring for ADEs
Pyrazinamide
Adverse Drug Effects (ADEs)
Arthalgias (joint pain)
symptoms: pain, tenderness and/or swelling of joints Saffects fingers, shoulders, knees, etc.
Susually mild but can be severe (acute gouty arthritis) signs: serum uric acid concentrations may be elevated 40% of patients receiving pyrazinamide experience nongouty, polyarthalgias pyrazinamide decreases renal uric acid secretion refer to Arthralgia Management Guidelines, pages 14-15 Hepatotoxicity (liver)
•symptoms: nausea, vomiting, abdominal tenderness, discomfort near the ribs on the right upper abdomen, jaundice (yellowing of skin and whites of the eyes) •signs: hepatic enlargement increased LFTs (refer to the Hepatotoxicity Management • uncommon with doses of 20-30mg/kg/d or with high dose intermittent regimens •hepatotoxicity was reported frequently when doses of 40-50mg/kg/day were used for •asymptomatic increases in LFTs may occur early in therapy •children who are suspected of developing hepatotoxicity should be referred to the Flick Memorial Tuberculosis Clinic for evaluation •refer to Hepatotoxicity Management Guidelines, pages 12-13 Gastrointestinal (stomach)
mild nausea and loss of appetite are commonvomiting is uncommon refer to Nausea/Vomiting Management Guidelines, pages 7-9 “Flushing Reaction”
flushing and/or itching of the skin with or without a rash refer to Mild Cutaneous (“Flushing”) Reactions Management Guidelines, page 4 Hypersensitivity (immune mediated reaction)
refer to the Hypersensitivity Management Guidelines, pages 5-6 Drug Interactions14,16
pyrazinamide may increase serum cyclosporin concentrations Monitoring for ADEs
ATS recommendations/CDC recommendations8,9 •baseline uric acid and LFTs; repeat based on symptom assessment •refer to “Routine Monitoring for Hepatotoxicity”, pages 12-13, for guidelines formonitoring LFTs Quinolones (levofloxacin, ofloxacin)
Adverse Drug Effects (ADEs)
Neurotoxicity (nervous system)
•in Phase II/III clinical trials the following percentages of patients experienced these •headache: ofloxacin 9%, levofloxacin 5.4%•insomnia: ofloxacin 7%, levofloxacin 2.9%•dizziness: ofloxacin 5%, levofloxacin 2.5% •usually occurs in the first few days of therapy14 •commonly resolves even with continued therapy14 •theoretically, the once daily regimens utilized in TB regimens may produce more central nervous system effects (insomnia, dizziness) because of higher peak serum concentrations •seizures occurred in <1% of patients receiving ofloxacin and levofloxacin in Phase II/III •quinolones should be used cautiously in patients with seizure disorders or other CNS •symptomatic therapy (e.g. analgesics for headache) •administer in the morning to minimize the occurrence of insomnia •consider administering doses twice daily if nervous system effects do not resolve Gastrointestinal (stomach)
• in Phase II/III clinical trials the following percentages of patients experienced these •nausea: ofloxacin 10%, levofloxacin 6.6%•diarrhea: ofloxacin 4%, levofloxacin 5.4% •gastrointestinal effects are usually mild and transient14 Managementrefer to Nausea/Vomiting and Diarrhea Management Guidelines, pages 7-11 Arthropathy (joints)
•quinolones cause damage to cartilage in weight-bearing joints in immature animals •reviews of quinolone use in children have not found joint cartilage damage ofloxacin and levofloxacin should be used cautiously in children Drug Interactions14,16
Antacids, iron and calcium, products, sucralfate (Carafate ) and multivitamins •results in decreased absorption of levofloxacin and ofloxacin •levofloxacin and ofloxacin should be administered 2 hours before or after these products •no significant alteration in serum levels or therapeutic effect of these drugs occurred when combined with levofloxacin or ofloxacin, unlike other quinolones •monitor for symptoms of increased levels (theophylline, cyclosporin) or therapeutic effect Monitoring for ADEs
ATS recommendations/CDC recommendations8,9 Rifamycins (rifampin, rifabutin, rifapentine)
Rifampin
Adverse Drug Effects (ADEs)
Discoloration of Body Fluids
reddish/orange discoloration of body fluids including urine, tears, saliva •monitoring for discoloration of urine can be used to assess drug absorption and patient •counsel patients to expect discoloration •patients should be advised that contact lenses may be stained Gastrointestinal (stomach)
•nausea, vomiting, heartburn, abdominal cramps, loss of appetite •diarrhea is less common than nausea and vomiting •most common adverse effect of rifampin refer to Nausea/Vomiting and Diarrhea Management Guidelines, pages 7-11 “Flushing Reaction”
flushing and/or itching of the skin with or without a rash usually involves the face and scalp; may cause redness and watering of the eyes up to 5% of patients experience the “flushing reaction” 1 usually occurs 2-3 hours after drug ingestion1 refer to Mild Cutaneous (“Flushing”) Reactions Management Guidelines, page 4 Hepatotoxicity (liver)
•symptoms: nausea, vomiting, abdominal tenderness, discomfort near the ribs on the right upper abdomen, jaundice (yellowing of skin and whites of the eyes) •signs: hepatic enlargement, increased LFTs (refer to the Hepatotoxicity Management •up to 1% of patients develop rifampin-induced hepatitis •4% of patients receiving both rifampin and isoniazid develop hepatitis •hepatotoxicity is uncommon in children •asymptomatic increases in serum transaminases may occur in the first few weeks of therapy •bilirubin levels may increase with initial therapy due to competition for excretion with rifampin; levels normalize with continued rifampin therapy •children who are suspected of developing hepatotoxicity should be referred to the Flick Memorial Tuberculosis Clinic for evaluation •refer to Hepatotoxicity Management Guidelines, pages 12-13 Hypersensitivity-immune mediated reactions involving the skin
refer to the Hypersensitivity Management Guidelines, pages 5-6 Hypersensitivity-immune mediated “influenza syndrome”
•more common with high dose (>1200mg), intermittent therapy than with daily dosing •occurs in 10% of patients receiving 600mg twice weekly •may also occur with daily therapy when administered irregularly (e.g. in noncompliant •usually presents after 3-6 months of intermittent therapy •usually occurs 1-2 hours after rifampin administration •resolution of symptom usually occurs within 12 hours refer to “Influenza Syndrome” Management Guidelines, page 16 Hypersensitivity-immune mediated hematologic (blood) disorders
•thrombocytopenic purpura: decreased platelet count, excessive bruising, nose bleeds, •more common with high dose (>900mg), intermittent than daily dosing •may occur with daily therapy when administered irregularly (e.g. in noncompliant patients) Sthe platelet count decreases within 3 hours of rifampin administration Sthe platelet count usually return to normal levels 36 hours after rifampin is discontinued Shemolysis may become evident within 2 to 3 hours after rifampin administration Sresolution occurs when rifampin is discontinued •thrombocytopenic purpura and hemolytic anemia are contraindications for further rifampin Hypersensitivity-immune mediated acute renal failure (kidneys)
sudden onset of lower back pain, fever and decreased urine output •occurs with intermittent therapy or in patients administering rifampin irregularly (e.g. in •acute renal failure is a contraindication for further rifampin use Drug Interactions14,16
•Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system.
•Rifampin may increase the metabolism of many drugs resulting in decreased therapeutic effect.
•Rifabutin and rifapentine induce the cytochrome P450 hepatic enzyme system to a lesser extent than rifampin (rifampin > rifapentine > rifabutin).
•Practitioners should always check for drug interactions when initiating rifamycin therapy.
Rifampin and the other rifamycins may decrease serum levels/therapeutic effects of (list is not allinclusive): •antiarrhythmic agents: disopyramide, mexilitine, propaferone, tocainide •antifungals: fluconazole, itraconazole, ketoconazole •benzodiazepines: alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flurazepam, midazolam, quazepem, triazolam •β-blockers: bisoprolol, metoprolol, propranolol •calcium channel blockers: diltiazem, nifedipine, verapamil non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine)
•protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir)*
•sulfonylureas: acetohexamide, chlorpropamide, glimepiride, glipizide, glyburide, Drugs that decrease rifamycin serum concentrations/therapeutic effect Drugs that increase rifamycin serum concentrations Monitoring for ADEs
refer to “Routine Monitoring for Hepatotoxicity”, pages 12-13, for guidelines for ∗ Concomitant rifampin and protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI) use is contraindicated. Rifabutin is the rifamycin of choice in patients receiving PI or NNRTI. Preferred PI for thiscombination are indinavir and nelfinavir. Preferred NNRTI are neviripine and efavirenz. Delavirdine and ritonavirshould not be used in combination with any of the rifamycins.22 Rifabutin
Adverse Drug Effects (ADEs) 2,9,23
Generally, adverse effects of rifabutin are similar to those of rifampin (refer to Rifampin Section, pages 42-45). The frequency and severity of adverse effects are < to rifampin.
In clinical trials with HIV infected patients, the most common reasons for discontinuing rifabutin were rash (4%) and gastrointestinal intolerance (3%).
Uveitis appears to be a unique adverse effect of rifabutin that does not occur with rifampin.
Uveitis (inflammation of the eyes: iris, ciliary body, choroid)
in clinical trials with HIV infected patients, uveitis occurred with increased rifabutin serum levels (doses > 300mg/d with concomitant use of clarithromycin or fluconazole) uveitis usually resolves with use of topical steroids and cycloplegics and mydriatics discontinuance of rifabutin is not required unless the uveitis recurs or is refractory to Drug Interactions15,23
Rifabutin decreases the serum levels/therapeutic effect of: many of the same drugs as rifampin (refer to page 45) rifabutin will have less of an effect on these drugs than rifampin because it is a less potent inducer of the cytochrome P450 hepatic enzyme system than rifampin monitor serum levels and/or therapeutic effect when these drugs are used concomitantly Drugs that increase rifabutin serum concentrations: Monitoring for ADEs
Rifapentine
Rifapentine (Priftin ) received FDA approval for the treatment of pulmonary tuberculosis inJune 1998.
Adverse Drug Effects (ADEs)
In comparative clinical trials, the frequency of ADEs was similar for rifapentine and SADEs were similar to those previously reported with rifampin (refer to Rifampin Section, Sdifferences between rifapentine and rifampin were seen with the occurrence of: rash (rifapentine 3.6%, rifampin 6.1%)itching (rifapentine 2.5%, rifampin 4.4%) Sdrug was discontinued secondary to ADEs more frequently in the rifampin group (5%) than Drug Interactions25
Rifapentine decreases the serum levels/therapeutic effect of:
many of the same drugs as rifampin (refer to page 45) rifapentine’s cytochrome P450 hepatic enzyme system induction potential is < rifampin but monitor serum levels and/or therapeutic effect when these drugs are used concomitantly Streptomycin (see aminoglycosides)
Appendix 1
Selected Antihistamines for the Prevention/Treatment of Cutaneous (“flushing”) Reactions
Antihistamine*
Dosage Form
Adult Dose
Pediatric Dose
>20 lbs:12.5-25mg 1 hour before medsthen 4-6hr prn max dose=12mg/24h2-6yo:1mg 1 hour before meds, then q4-6 hours prn *Incidence of drowsiness: diphenhydramine > chlorpheniramine > loratidine
Appendix 2
Oral Desensitization Protocol for Isoniazid4
Drug desensitization should not be attempted with severe skin reactions or those involving
the mouth or mucous membranes (e.g. exfoliative dermatitis and Stevens-Johnson
Syndrome).
consideration should be given to desensitizing patients under monitored conditions for severe reactions 2. administer isoniazid as outlined in the table below (doses require adjustment in children)3. isoniazid syrup (50mg/ml) should be used for initial doses tubercillin syringes may be used to administer small volume doses 4. isoniazid tablets may be administered beginning with the 50mg or 100mg dose5. if a reaction develops during desensitization, decrease the dose to the highest dose (the previous dose) that did not cause a reaction and begin increasing the doses in smaller increments Protocol for Oral Desensitization of Isoniazid in Adults
Dose (mg)
Appendix 3
Oral Desensitization Protocol for Rifampin and Ethambutol5
Drug desensitization should not be attempted with severe skin reactions or those involving
the mouth or mucous membranes (e.g. exfoliative dermatitis and Stevens-Johnson
Syndrome).
consideration should be given to desensitizing patients under monitored conditions for severe reactions 2. administer rifampin or ethambutol as outlined in the table below (doses require adjustment in children)3. if a reaction develops during desensitization, decrease the dose to the highest dose (the previous dose) that did not cause a reaction and begin increasing the doses in smaller increments after completing the protocol, continue dosing BID (rifampin) or TID (ethambutol) for 3 days, then administerthe total daily dose once daily thereafter Protocol for Oral Desensitization of Rifampin and Ethambutol in Adults
Time from start
Rifampin (mg)
Ethambutol (mg)
Dosage Preparation for the Desensitization Protocol
1. empty and mix 4 rifampin 300mg capsules with 120ml of cherry syrup (10mg/ml suspension)2. administer the specified amount of drug for each time period via an oral syringe a. shake well before drawing suspension into syringeb. e.g. 0.1mg rifampin = 0.01ml of the rifampin suspensionc. tubercillin syringes can be used to administer small volume doses 3. begin using rifampin capsules with the 150mg dose 1. crush 1 ethambutol 400mg tablet and mix with 400ml of 70% sorbital/water (1 mg/ml suspension) and/or crush 10 ethambutol 400mg tablets and mix with 400ml of 70% sorbital/water (10mg/ml suspension) 2. administer the specified amount of drug for each time period via an oral syringe a. shake well before drawing suspension into syringeb. e.g for 1mg/ml suspension: 0.1mg of ethambutol = 0.1ml suspensionfor 10mg/ml suspension: 0.1mg of ethambutol = 0.01ml suspension c. tubercillin syringes can be used to administer small volume doses begin using ethambutol tablets with the 50mg or 100mg dose Appendix 4
Guidelines for Medication Administration
Tablets and capsules should be administered all together once a day except in very unusual situations (e.g.
extreme side effects to the drugs). TB Control personnel should be consulted before dividing doses throughoutthe day.
If medication administration times are divided, the entire dose of each drug should be given at one time (e.g.
isoniazid 300mg in the morning, rifampin 600mg in the evening).
Isoniazid and rifampin should be administered 1 hour before or 2 hours after food ingestion for maximumdrug absorption.
If nausea and/or vomiting occurs, administer isoniazid and rifampin with food (better to give the drug withfood and have some decreased absorption than to not have the patient ingest the drug at all because of theside effect).
All other TB medications can be administered without regard to food.
4. Options for patients who can not swallow tablets and capsules (some adults and infants/children) a) isoniazid is the only commercially available liquid productb) rifampin and pyrazinamide suspensions can be prepared from the tablets/capsules ethambutol suspensions can not be prepared because of drug stability problems the volume of the liquid required for each dose may be too large for the patient to tolerate(especially in infants and children) diarrhea may occur due to the lactose and sucrose content in liquid preparations prepared suspensions have limited stability26 some suspension are not palatable (bitter tasting) Crushing capsules and tablets1) preferred to administration of liquid formulations26,27 a) drug stability is not an issueb) administration of a large volume of liquid in children is avoided a) open and empty capsule contents into mortar, place tablets in the mortar and crush to a fine powder with a pestle (or other suitable container and “crusher” if mortar and pestle are notavailable) b) mix the powder with a pleasant tasting substance to mask the taste of the pills i) juiceii) flavored syrup (e.g. cherry)iii) applesauceiv) puddingv) ice creamvi) chocolate syrup (seems to mask bitter tastes well)vii) whatever else works! c) administer immediately after mixing with a spoon, medication cup or syringed) if the mixture does not taste good and is rejected by the patient, continue to mix medications with different substances until an acceptable mixture is found (especially with children) Administer medication through a nasogastric tube1) alternative for children who are unable or unwilling to ingest medications Appendix 5
Technique for Medication Administration through an Oral (needleless) Syringe
The following administration technique helps to minimize the amount of liquid medication spilled because of infant“squirming” or the amount spit out once it had been administered.
The infant should be held in the arm or lap of the person administering medication. The infant’s arms closest tothe caregiver should be extended behind the caregiver’s back. The infant’s other arm is held down by thecaregiver’s arm as the medication is being administered.
The medication in the oral or needleless syringe should be injected into the infant’s cheek at the gums towardthe back of the mouth. The volume of medication injected at one time should be determined based on thechild’s size (the entire dose may not be able to be injected at one time).
Appendix 6
Tuberculosis: Drug Therapy in Pregnancy
Pregnancy Risk Categories28
Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (andthere is not evidence of a risk in later trimesters), and the possibility of fetal harm appearsremote.
Either animal-reproduction studies have not demonstrated a fetal risk but there are nocontrolled studies in pregnant women or animal-reproduction studies have shown an adverseeffect (other than a decrease in fertility) that was not confirmed in controlled studies inwomen in the first trimester (and there is no evidence of a risk in later trimesters).
Either studies in animals have revealed adverse effects on the fetus (teratogenic orembryocidal, or other) and there are no controlled studies in women or studies in women andanimals are not available. Drugs should be given only if the potential benefit justifies thepotential risk to the fetus.
There is positive evidence of human fetal risk, but the benefits from use in pregnant womenmay be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation orfor a serious disease for which safer drugs cannot be used or are ineffective).
Studies in animals or human beings have demonstrated fetal abnormalities, or there isevidence of fetal risk based on human experience, or both, and the risk of the use of the drugin pregnant women clearly outweighs any possible benefit. The drug is contraindicated inwomen who are or may become pregnant.
Tuberculosis: Drug Therapy During Pregnancy
Pregnancy
∗Breast Feeding28,29,30
Comments
Recommendations
Category28
for Use8,9
•considered “compatible” with breast feeding •pregnant women may be at an  risk of developing •INH, acetylisoniazid are excreted into breast milk hepatitis when INH is administered as preventive •the INH peak milk concentration ranges from 6-16 •pyridoxine should be administered to pregnant women •monitor baby for hepatitis and peripheral neuritis29 •considered “compatible” with breast feeding •the peak milk concentration ranges from 1-3mcg/mlafter a 600mg dose •considered “compatible” with breast feeding •ethambutol is excreted into breast milk •the milk concentration is 1.4 mcg/ml after a 15 mg/kgdose •general PZA use is not recommended by U.S.
•the peak milk concentration is 1.5 mcg/ml after a 1 organizations because of lack of teratogenicity data •PZA is recommended for use by international TBorganizations •the risks vs. benefits of using PZA in pregnancy shouldbe considered carefully if MDR-TB is suspected30,31 •a few reports of PZA use in pregnancy have beenpublished:33,34,35•total of 15 patients when reports combined•primarily during 3rd trimester (2-1st trimester, 3-notspecified)•9 patients received PZA for 2 months, 6 patients-duration not specified•no adverse effects to babies noted (5 patients-nomention of babies made at all)•a review article written in 1992 by members of the LosAngeles TB control program recommends using PZA forthe first two months of treatment in pregnancy 36 ∗ If baby receiving treatment for TB, breast feeding should be avoided. Additional drug received by the baby through breast milk increases the risk of adverse drugeffects.
Pregnancy
Breast Feeding28,29,30
Comments
Recommendations
Category28
for Use8,9
•the peak milk concentration was •ofloxacin has produced lesions of the articular cartilage in immature animals at •a small observational study compared pregnancy outcomes in 38 women who received quinolones (28-norfloxacin, 10-ciprofloxacin) to 38 women who receiveda nonteratogenic antibiotic:38•doses=norfloxacin 800mg/d, ciprofloxacin 1 gm/d•mean treatment duration was 7.7 ± 5.4 days•35/38 received the quinolone during the first trimester•31/38 in the quinolone group and 30/38 in the control group had live births•fetal distress and use of cesarean delivery was more common in the quinolonegroup than the control group•no fetal malformations were found in the quinolone group •ofloxacin was administered at a dose of 200mg po bid to a woman during the 2ndtrimester for 6 days; no teratogenetic effects were seen 39 •a postmarketing surveillance of ofloxacin use included a report on 39 womenwho received ofloxacin during pregnancy:40•dose/duration of therapy was not included•33 women delivered healthy babies (15 received ofloxacin <17 days afterbecoming PG, 9>17 days after PG, 9 unknown)•1-miscarriage, 1-hydatidiform mole, 4-congenital malformations (3 of thesejudged not related to ofloxacin, there was insufficient information to evaluate the4th) •another postmarketing study of ofloxacin, norfloxacin and ciprofloxacin wasconducted in the UK using “prescription event monitoring”: 41•dose/duration was not indicated (use for UTI, respiratory tract infections)•outcome for patients receiving drug during 1st trimester reported (an additional208 PG but data not reported)•total PG=32, normal birth=21, PG termination=5, spontaneous abortion=5,ectopic PG=1•total PG for ofloxacin=10, normal birth=8, PG termination=1, spontaneousabortion=1•no congenital abnormalities were reported •no reports of using ofloxacin or levofloxacin (or other quinolones) in TB regimenin PG patients or for prolonged use in pregnancy were found by a MEDLINEsearch Pregnancy
∗Breast Feeding28,29,30
Comments
Recommendations
Category29
for Use8,9
•considered “compatible” with breast feeding •streptomycin can cause eighth cranial nerve damage and result •streptomycin is excreted into breast milk •this effect can occur anytime throughout a pregnancy 42,43 •ototoxicity is not expected since oral absorption •kanamycin and capreomycin are expected to have similar of streptomycin is poor but it may cause
effects (data is not available on use in PG) •considered “compatible” with breast feeding •ATS recommends avoiding use when possible because of lack •cycloserine is excreted into breast milk •milk concentration after 250mg qid dosing ranges •Briggs notes that 50,282 mother-child pairs were monitoredfrom 6-19mcg/ml (72% of serum levels) during the Collaborative Perinatal Project. No adverse fetaleffects were noted. Only 3 of these pairs had 1st trimesterexposure to cycloserine28 •One study compared cycloserine, sulphadimidine or no AB forthe management of asysmptomatic bacteruria in PG:44•patients received cycloserine 250mg bid x 2 weeks then 250mgevery other day until delivery (total duration not noted)•31 patients received cycloserine: 3 stillbirths, untreated group:1 stillbirth, 1 neonatal death•31 patients did not receive AB: 1 stillbirth, 1 neonatal death •An editorial review of an author’s 10 year experience withcycloserine(from 1970) stated that it he had used it in pregnantwomen to treat UTIs without adverse effect to the fetus (exceptfor 1 spontaneous abortion not believed to be related). Thenumber of PG women treated was not noted.45 •information is not available about ethionamide •a MEDLINE search of ethionamide and PG showed 5 citations (references are not available for review) •ATS recommends avoiding use when possible because of lackof information about teratogenicity •peak milk concentration after 1 gm was 1.1 mcg/ml (plasma concentration was 70 mcg/ml) •Briggs review of clofazimine included  90 pregnant women reported from several different sources. No congenitalanomalies were reported (however, in the largest report of 76women, PG outcome was not noted by the author)28 •pigmentation may occur in the newborn (reports noted thatpigmentation resolved over a 1 year period in some infants) ∗ If baby receiving treatment for TB, breast feeding should be avoided. Additional drug received by the baby through breast milk increases the risk of adverse drugeffects.
References
Girling DJ. Adverse effects of antituberculous drugs. Drugs 1982;23:56-74.
Kucers A, Crowe S, Grayson ML, Hox J, editors. The use of antibiotics. Fifth edition.
Oxford: Butterworth Heinemann, 1997.
Patel AN, McKeon J. Avoidance and management of adverse reactions to antituberculosisdrugs. Drug Safety 1995;12:1-25.
Holland CL, Malasky C, Ogunkoya A, et. al. Rapid oral desensitization to isoniazid andrifampin. Chest 1990;98:1518-19.
Matz J, Borish LC, Routes JM, et. al. Oral desensitization to rifampin and ethambutol inmycobacterial disease. Am J Respir Crit Care Med 1994;149:815-7.
Obrien RJ. Hepatoxic reaction to antituberculous drugs: adjustments to therapeuticregimen. JAMA 1991;265:3323.
Starke JR. Current chemotherapy for tuberculosis in children. ID Clinics of N. America1992;6:215-238.
CDC Core Curriculum on Tuberculosis. Third edition, 1994.
American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adultsand children. Am J Respir Crit Care Med 1994;149:1359-1374.
10. Humes, HD. Aminoglycoside nephrotoxicity. Kidney Int 1988;33:900-911.
11. Bennett WM. Aminoglycoside nephrotoxicity. Nephron 1983;35:73-77.
12. Begg EJ, Barclay ML. Aminoglycosides-50 years on. Br J Clin Pharmac 1995;39:597- 13. Product information: capreomycin. Eli Lilly and Company, October 1996.
14. McEvoy GK, ed. American Hospital Formulary Service Drug Information 1998.
Bethesda: American Society of Health-System Pharmacists, 1998.
15. Garrelts JC. Clofazimine: a review of its use in leprosy and Mycobacterium avium complex infections. DICP 1991;25:525-31.
16. Tatro DS, ed. Drug Interaction Facts. St. Louis: Facts and Comparisons, 1997.
17. Product information: isoniazid. Barr Laboratories, October 1997.
18. Product information: levofloxacin. Ortho/McNeil Pharmaceuticals, December 1996.
19. Product information: ofloxacin. Ortho/McNeil Pharmaceuticals, February 1997.
20. Hampel B, Hullmann R, Schmidt H. Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use-safety report. Pediatr Infect Dis J 1997;16:127-9.
21. Jick S. Ciprofloxacin safety in a pediatric population. Pediatr Infect Dis J 1997;16:130-4.
22. CDC. Prevention and Treatment of Tuberculosis among patients infected with human immunodeficiency virus: principles of treatment and revised recommendations. MMWR1998;47(RR-20):1-74.
23. Product information: rifabutin. Pharmacia, Inc., April 1995.
24. Nichols, CW. Mycobacterium avium complex infection, rifabutin, and uveitis—is there a connection? CID 1996;22(Suppl 1):S43-47.
25. Product information: rifapentine. Hoechst Marion Roussel, Inc., June 1998.
26. AHSP. Handbook on Extemporaneous Formulations. Bethesda: American Society of Pagliaro AN. Administering medications to infants, children, and adolescents. In:Pagliaro LA, Pagliaro AM, eds. Problems in Pediatric Drug Therapy. Hamilton, IL: DrugIntelligence Publications, 1987:1-14.
28. Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in Pregnancy and Lactation. 4th ed.
Baltimore: Williams and Wilkins, 1994.
29. Snider DE, Powell KE. Should women taking antituberculosis drugs breast-feed? Arch 30. American Academy of Pediatrics. The transfer of drugs and other chemicals into human 31. Franks AL, Binkin NJ, Snider DE, et. al. Isoniazid hepatitis among pregnant postpartum hispanic patients. Public Health Reports 1989; 104:151-155.
32. Moulding TS, Redeker AG, Kanal GC. Twenty isoniazid-associated deaths in one state.
Am Rev Respir Dis 1989; 140:700-705.
33. Margono F, Garely A, Mroueh J, et. al. Tuberculosis among pregnant women-New York City, 1985-1992. MMWR 1993; 42:605, 611-612.
34. Warner TT, Khoo SH, Wilkins EGL. Reactivation of tuberculosis lymphadenitis during pregnancy. J Infect 1992; 22:181-184.
35. Jana N, Vasishta K, Jindal SK, et. al. Perinatal outcome in pregnancy complicated by pulmonary tuberculosis. Int J Gynecol Obstet 1994; 44:119-124.
36. Davidson PT, Quoc Le H. Drug treatment of tuberculosis. Drugs 1992:651-673.
37. Giamarellou H, Kolokythas E, Petrikkos G. Pharmacokinetics of three newer quinolones in pregnant and lactating women. Am J Med 1989; 87(suppl5a):49s-51s.
38. Berkovitch M, Pastuszak A, Gazarian M, et. al. Safety of the new quinolones in pregnancy. Obstet Gynecol 1994; 84:535-8.
39. Peled Y, Friedman S, Hod M, et. al. Ofloxacin during the second trimester of pregnancy.
DICP Ann Pharmacother 1991; 25:1181-1182.
40. Jungst G, Mohr R. Overview of postmarketing experience with ofloxacin in Germany.
J Antimicob Chemother 1988; 22(suppl c):167-175.
41. Wilton L, Pearce GL, Mann RD. A comparison of ciprofloxacin, norfloxacin, ofloxacin, clarithromycin and cefixime examined by observational cohort studies. Br J ClinPharmacol 1996; 41:277-284.
42. Hamadeh MA, Glassroth J. Tuberculosis and pregnancy. Chest 1992; 101:1114-20.
43. Jacobs RF, Abernathy RS. Management of tuberculosis in pregnancy and the newborn.
44. Robertson JG, Livingstone JRB, Isdale MH. The management and complications of asymptomatic bacteriuria in pregnancy. J Obstet Gynecol Br 1968; 75:59-65.
45. Sanguingno, N. Considerations of ten years’ use of cycloserine. Scand J Resp Dis-Suppl

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