Management of adverse effects

Clinical description

Second-line drugs have more adverse drug reaction than first-line anti-TB drugs.

Proper management of adverse effects begins with patient education. Before starting treatment, the patient should be instructed in detail about the potential side effects that could develop due to the prescribed drugs, and the need to notify a health-care provider.

Minor side effects can be managed with ancillary drugs if needed while continuing the treatment regimen. Some side effects may disappear or diminish with time, and patients may be able to continue receiving the drugs as recommended. The side effects of many second-line drugs are highly dose dependent. Reducing the dosage of the offending drug is another method of managing adverse effects but only in cases where the reduced dose will not compromise the regimen. With cycloserine and ethionamide, for example, a patient may be completely intolerant at one dose and completely tolerant at a slightly lower dose. Unfortunately, given the narrow therapeutic margins of these drugs, lowering the dose may also affect efficacy, so every effort should be made to maintain an adequate dose of the drug based on body weight. Lowering the dose by more than one weight band should be avoided.

Psychosocial support is an important component of the management of side effects. This is an important role played by health workers and guardians, who educate patients about drug side effects and encourage them to continue treatment. Patient support groups are another means of providing psychosocial support.

The following table below summarizes the common adverse effects to second line drugs, the likely responsible agents and the suggested management strategies.

National Tuberculosis Control Programme 103 Grading and management of adverse events Table 10.6-1 Severity grading scale of adverse events24 Grade Description Mild or transient discomfort without limitation of normal daily activities*. No medical GRADE 1: Mild intervention or corrective treatment required.

GRADE 2: Moderate limitation of normal daily activities*. Minimal medical intervention or Moderate corrective treatment required.

Marked limitation of normal daily activities*. Medical intervention, therapy, stop or GRADE 3: Severe reduction of the offending drug is required. Possible hospitalization.

GRADE 4: Life- threatening or Severe limitation of normal daily activities*. Medical intervention and corrective permanently treatment required almost always in a hospital setting.

disabling *The term ‘activity’ covers basic self-care functions such as bathing, dressing, toileting, transfer/ movement, continence and feeding, as well as usual social and functional activities or adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, or pursuing a hobby.

Table 10.6-2 Severity grading scale of main laboratory parameters [13,14] K+ Neutrophils AST ALT Creatinine Platelets(/ Hb (g/dL)

mm3)

(mEq/L) / (/mm3) (UI/L) (UI/L) (μmol/L)

(mmol/L)

Normal >12 >150,000 >1,500 * * * 3.5-5.0 values 100,000- Grade 1 10-11.9 1,000-1,500 1.5-2.5 x ULN 1.5-2.5 x ULN 1.1-1.5 x ULN 3.2-3.4 149,999 50,000- 2.6-5.0 x Grade 2 8- 9.9 750-999 2.6-5.0 x ULN 1.6-3 x ULN 2.8-3.1 99,999 ULN 20,000- Grade 3 6-8 500-749 5.1-10 x ULN 5.1-10 x ULN 3-6 x ULN 2.5-2.7 49,999 Grade 4 <6 <20,000 <500 >10 x ULN >10 x ULN > 6 x ULN <2.5 *Normal values vary from laboratory to laboratory and might be slightly different in men, women and children (check normal parameters for local laboratory).

ULN= upper limit of normal 24 endTB Clinical and Programmatic Guide for Patient Management with New TB Drugs v3.2 104 National Tuberculosis Control Programme Table 10.6-3 Management of adverse events associated with DR-TB treatment Prolonged QT interval Possible DR-TB drug causes: Bdq, Dlm, Mfx, Cfz Grade 4 Normal Values Grade 3 Grade 1 Mild Grade 2 Moderate Potentially Life- (msecs) Severe Threatening Borderline: Prolonged: Pathological: Life-threatening consequences:

Male: ≤430 Male: Male: > 500 QTcF ≥ 500 or and 430-450 > 450- <500 torsade de pointes or Female: ≤450 Female: Female: other associated serious ventricular dysrhythmia 450-470 > 470 -< 500 Monitor ECG Confirm with two Stop the suspected frequently Monitor more additional 12- causative drug. Hospitalize closely; at least lead ECG (15-30 and replete electrolytes as weekly ECG until min apart). Stop necessary. Check TSH.

QTcF has returned the suspected Action to grade 1 or less. causative drug.

Check electrolytes Hospitalize and and replete as replete electrolytes necessary as necessary. Check TSH.

Suggestions and precautions:

Close follow-up of patients at high risk who take several medicines that prolong the QT.

Follow-up of potassium in high risk patients.

Be careful in case of diarrhea, vomiting, use of diuretics, alcohol.

Stop the medicine if QTc persists over 500ms even if the patient is asymptomatic.

Think of arrhythmia when the patient suffers vertigo, syncope, palpitations.

If QTcF is prolonged ≥ 500 ms (confirmed with two additional 12 Lead ECG 15-30 minutes apart): Admit the patient Stop the QT prolonging drugs with shorter half-life: Mfx or Lfx followed by Cfz after 7-14 days. Check electrolyte and replace if necessary. If no improvement of QTc after this measure, stop Bdq /Dlm. ART is usually not stopped unless the patient is severely unstable.

Check electrolytes and manage accordingly. (If low potassium: urgent management with replacement and frequent monitoring). Give Magnesium sulphate supplements (orally or IV) and calcium.

Check a TSH and treat any hypothyroidism found.

Check albumin if on Delamanid.

Once stable (QTcF < 450 and normal electrolytes), critical prolonging QT drugs can be added back:

If the patient was on Mfx consider using Lfx instead.

If the patient was on Cfz consider suspending it permanently (if not critical to the regimen).

If the patient is on Bdq (or Dlm), and is critical to the regimen, add it back while suspending all other QT prolonging drugs (except for stopping ART, which should not normally be suspended in the management of QT prolongation).

National Tuberculosis Control Programme 105 Hypokalemia Possible DR-TB drug causes: Am, Km, Cm, S Normal value Grade 1 Mild Grade 2 Moderate Grade 3 Grade 4 Potentially Life- (mmol/L) Severe Threatening 3.5- 5.0 3.4-3.2 3.1-2.8 2.7-2.5 <2.5 Action Continue Continue injectable. Continue injectable. Stop injectable temporarily.

injectable. Start oral potassium Oral potassium: Slow Hospitalization. Start IV Start oral slow K* 600 mg = K* 600 mg = 8 mEq: potassium in addition to potassium 8 mEq: 2 tabs twice 2 tabs thrice daily oral. Replace magnesium slow K* 600 daily and other electrolytes mg = 8 mEq: Oral Magnesium:

1 tab twice Oral Magnesium: 1000 mg twice daily Monitor K 1 hour after daily. 1000 mg twice daily. replacement and repeat till Monitor K every K is >2.8 mmol/L Monitor K Monitor K every 2 1 week and adjust monthly weeks and adjust dose accordingly the slow K dose accordingly * The formulations of oral potassium chloride variates by manufacturer and countries. Slow-release versions are common in low resources settings. One slow K 600 mg tab contains 8 mEq of potassium. Adjust the number of pills according to the formulation available.

Oral potassium and magnesium should be administered either two hours before or four to six hours after fluoroquinolones as they can interfere with fluoroquinolone absorption.

Replacing serum electrolytes Replacement of 40 mEq of potassium increase 1 mEq/L the potassium.

Oral replacement: The replacement varies 40 mEq to 80 mEq day. Usually patients don’t tolerate more than 6 tabs of slow k (diarrhea, nausea). Doses should be divided to two or three times a day (no more than 20 mEq per dose)

Hypokalemia may be refractory if concurrent hypomagnesemia is not also corrected.

If unable to check serum magnesium, give empiric replacement therapy in all cases of hypokalemia with oral magnesium gluconate 1000mg twice daily.

In refractory cases can be given spironolactone 25 mg/ day or Amiloride 5-10 mg/day orally (decrease of potassium and magnesium wasting).

FOR HOSPITALIZED PATIENTS:

If severe hypokalemia (K ≤ 2.5 mmol/L or symptomatic hypokalemia): give Intravenous potassium concurrently with oral potassium replacement.

Dosing: 10 -15 mEq /h IV and 80 meq orally every six to eight hours. Recheck serum potassium 1 hour after infusion. Repeat IV replacement every 6 to 8 hours until serum potassium is ≥ 2.8 mmol/L.

The normal preparation of a potassium chloride infusion is 40mEq in200Ml of normal saline over 2-4 hrs.

Do not exceed an infusion rate of 20 mEq/hr.(100mL/hr.).

Magnesium replacement:

Dosing: 2000 mg/day. If Mg can be measured and is less than 1.0 increase the dose up to 3000 mg- 6000 mg if Mg IV (doses greater than 2000 mg are usually given IV). Magnesium IV: the normal preparation is magnesium sulfate 2g in 100mL or 4g in250mL of 5 % dextrose or normal saline. Do not exceed an infusion rate of 150mg/min (2g in100mL administered over one to two hours, 4g in 250mL administered over two to four hours). Repeat until serum K is > 2.8mmol/L.

Other considerations:

Check an ECG in patients with significant serum electrolyte disturbances.

Electrolyte abnormalities are reversible upon discontinuation of the injectable. Even after suspending the injectable, it may take weeks or months for this syndrome to disappear, so electrolyte replacement therapy should continue for several months after completion of the injectable phase of DR-TB treatment.

106 National Tuberculosis Control Programme Nephrotoxicity [15] Possible DR-TB drug causes: Am, Km, Cm, S Grade 1 Grade 2 Grade 3 Grade 4 Mild Moderate Severe Life-threatening Creatinine 1.1 - 1.5 x ULN 1.6 - 3.0 x ULN 3.1 - 6 x ULN > 6 x ULN or dialysis required Creatinine clearance* Normal value Cr Cl grading [13] 15-29ml/min >90ml/min 60-89ml/min 30-59ml/min Male: 97-137 ml/min Note: < 15 ml/min is grade 5 and requires dialysis Female: 88-128 ml/ min Stop injectable. ** Reduce injectable Reduce to 3 times a week injectable to 2 Monitor creatinine and Continue times a week Action electrolytes weekly till monitoring dosing at dosing at creatinine returns to normal.

12-15mg/kg** 12 mg/kg** Adjust other drug dosages **Suspend the injectable permanently if the nephrotoxicity recurs despite intermittent dosing, and replace by Bdq, Linezolid Consider other causes of renal insufficiency (pre-renal, renal and post-renal).

*Creatinine clearance formula:

Weight (Kg) x (140 – Age) x (constant)

Serum creatinine μmol/L Constant: 1.23 for men and 1.04 for woman If creatinine is reported in mg/dL multiply by 88.4 to convert to μmol/L National Tuberculosis Control Programme 107 Hearing loss (ANRS scale)

Possible DR-TB drug causes: Am, Km, Cm, S AUDIOMETRY TEST:

Exclude causes of conductive hearing loss: ear wax, otitis media, tympanic perforation *Attain a baseline record of the hearing status of a person prior to treatment initiation Perform a monthly audiogram that includes speech frequencies (500-4000 Hz) and higher up to 8000 Hz.

Calculate the average hearing loss (AHL) for each ear: sum the loss in dB at each frequencies of 500-1000-2000- 4000 Hz (if a frequency is not perceived consider a loss of 120 dB) and divide by 4. You have the average of the best ear and the bad ear. Then calculate the Weighted Average Hearing Loss (WAHL) for both ears: WAHL= (Average of the best ear multiplied by 7) + (Average of the worst ear multiplied by 3) and divide the total by 10.

Normal Grade 1 Grade 2 Grade 3 Grade 4 Values Mild Moderate Severe Profound <=25 dB 26-40 dB Moderate 41-55 dB 71-90 dB >90dB Speech perceived if voice Moderate /severe=56- Speech is perceived Speech is not is normal, difficulties 70dB if the voice is loud perceived at all. Only arise if voice is low- and close to the very loud noises are pitched or distant from Speech is perceived if ear. Loud noises are perceived.

the subject. Most of the voice is loud. The perceived.

the daily life noises are subject understands perceived. better what is being said if he can see his/ her interlocutor.

Stop the injectable if any abnormal hearing: >26dB or any ototoxic change between baseline and follow up audiometry A. Decrease in hearing threshold by >20dB at any one test frequency B. Decrease in hearing threshold by >10dB at any two adjacent frequencies C. Loss of response at three frequencies where response was previously obtained Also stop the injectable if the patient has vertigo.

Substitute the injectable by Lzd, Bdq or Dlm.

*Five percent of the world’s population has disabling hearing loss (>40dB in better ear in adults and > 30 dB in children). This includes one third of 65 years old. Hence, it is important to attain a baseline record of the hearing status of a person prior to treatment initiation. If there is a baseline hearing loss of >=25 dB don’t start injectable The toxicity to the eight-cranial nerve concerns the vestibule (dizziness) and the cochlea (hearing loss) and is irreversible.

The frequencies between 500 Hz and 4000 Hz are considered to be those of a normal conversation The higher frequencies (4000-8000 Hz) are the first to be affected; the frequencies of the human voice come next.

Hearing loss becomes perceptible for patients at a frequency <4000Hz when it reaches 25-30dB (Brummett 1989). When patients mention hearing loss there is already a severe degree of loss.

Children: above 4 years can perform pure tone audiometry. Below 4 years refer to audiologist.

Patient at higher risk of ototoxicity: previous use of aminoglycoside, elderly, renal insufficiency, preexisting hearing problems, receiving other ototoxic medications Consider hearing aid for patients with hearing loss grade >=2 108 National Tuberculosis Control Programme Hepatotoxicity Possible DR-TB drug causes: Z, H, Pto, Lzd, Cfz, Bdq, Mfx Grade 1 Grade 2 Grade 3 Grade 4 Mild Moderate Severe Life-threatening ALT (SGPT) 1,25 – 2,5 x ULN 2,6 – 5,0 x 5,1 – 10,0 x ULN > 10,0 x ULN ULN AST (SGOT) 1,25 – 2,5 x ULN 2,6 – 5,0 x 5,1 – 10,0 x ULN > 10,0 x ULN ULN Action Continue Continue Stop all drugs, Stop all drugs, including treatment treatment including anti-TB anti-TB drugs; measure LFTs Patients should Patients drugs; measure weekly. Treatment may be be follow until should be LFTs weekly. reintroduced after toxicity is resolution followed until Treatment may resolved.

(return to resolution be reintroduced baseline) or (return to after toxicity is stabilization baseline). resolved.

of AST/ALT elevation. If JAUNDICE:

Stop all anti-TB drugs until resolution Consider other potential causes of hepatitis: viral (hepatitis B and C), HIV, alcohol).

Avoid potentially hepatotoxic non-tuberculosis drugs.

Reintroduction of anti-TB drugs:

Check ALT/AST once a week. Reintroduce anti-TB drugs once liver enzymes return to at least Grade 2.

Anti-TB drugs should be reintroduced in serial fashion. The least hepatotoxic drugs should be added first: Km- E-Cfz-Mfx. Then introduce the more hepatotoxic one by one every three days: Pto-H-Z while monitoring liver function tests after each one to identify the responsible drug.

If reintroduction leads to signs of hepatotoxicity, stop the suspected drug and replace it by another if it is essential for the treatment. If the drug stopped is H or Z there is no need to replace by another agent. Follow transaminases monthly.

If patient is on ART and experienced Nevirapine (NVP) hepatotoxicity should not be re-challenged with NVP.

Peripheral neuropathy Possible DR-TB drug causes: Lzd, Cs, H, S, Km, Cm, H, FQ, Pto/Eto, E Possible other causes: Diabetes mellitus, alcohol, HIV infection, Vitamin B deficiency, hypothyroidism and other drugs Grade 1 Grade 2 Grade 3 Grade 4 Mild Moderate Severe Life-threatening National Tuberculosis Control Programme 109 Neurosensory Asymptomatic Sensory Sensory Disabling sensory alteration or alteration (including with sensory alteration or alteration or paresthesia causing inability paresthesia and alteration on paresthesia paresthesia to perform basic self-care painful neuropathy) exam or minimal causing causing inability functions paresthesia greater than to perform causing no minimal usual social or minimal interference and functional interference with usual activities with usual social social and and functional functional activities activities Action Stop offending Stop Lzd. Stop Lzd. Do not Stop Lzd. Do not reintroduce drugs (Lzd, Do not reintroduce Lzd. Lzd.

High dose INH). reintroduce If symptoms Lzd.

improve after 2 weeks consider restarting Lzd at a lower dose (300 mg)

Suggested management strategy All patients taking high dose INH and linezolid should receive 100 mg of pyridoxine (Vit B 6) day.

The neuropathy associated with Linezolid is common after prolonged use and often extremely painful and irreversible. For this reason, Linezolid should be immediately stopped and not reintroduced when symptomatic neuropathy develops (grade 2 and above).

Symptomatic relief:

Increase pyridoxine (Vit B 6) to a maximum of 150 mg.

Nonsteroidal anti-inflammatory drugs or acetaminophen may help alleviate symptoms.

Tricyclic antidepressants have also been used successfully. Start amitriptyline 25 mg at bedtime. The dose may be increased to a maximum of 150 mg daily for refractory symptoms.

Carbamazepine may also be effective in relieving pain and other symptoms of peripheral neuropathy.

Carbamazepine is a strong inducer of CYP3A4 and should not be used with Bedaquiline or Delamanid.

Myelosuppression (anemia, thrombocytopenia, or neutropenia)

Possible anti-TB drug causes: Lzd1 Possible other causes: AZT, cotrimoxazole, HIV Infection, chemotherapy Grade 1 Grade 2 Grade 3 Grade 4 Mild Moderate Severe2 Life-threatening2 Absolute neutrophil 1000 – 1300/ 750 – 999/ 500 – 749/mm3 < 500/ mm3 count mm3 mm3 Haemoglobin 8.5 – 10.0 g/dl 7.5 – 8.4 g/dl 6.5 – 7.4 g/dl < 6.5 g/dl Platelets, decreased 100,000 – 50,000 – 25,000 – 49,999 < 25,000 /mm3 124,999 /mm3 99,999 /mm3 /mm3 WBC, decreased 2000 – 2500 / 1500 – 1999 / 1000 – 1499 / < 1000 /mm3 mm3 mm3 mm3 110 National Tuberculosis Control Programme Action Monitor Monitor Stop Lzd Stop Lzd immediately. Give carefully, carefully and immediately. transfusion and erythropoietin and consider consider If Hb ≤ 7 g/ if available. Restart at reduced reduction of reduction of dl, transfuse. dose (300 mg) once toxicity dose of Lzd to dose of Lzd Restart at has decreased to Grade 1.

300mg daily to 300mg reduced dose daily; in case (300 mg) once of Grade 2 toxicity has neutropenia, decreased to stop Lzd Grade 1.

immediately.

Restart at reduced dose (300 mg) once toxicity has decreased to Grade 1.

Suggested management strategy All patients taking linezolid should also be receiving at least 100 mg of pyridoxine daily. This is largely to prevent myelosuppression but may also prevent peripheral neuropathy.

Stop the causative drug immediately.

Monitor full blood counts regularly.

Hospitalize the patient and consider transfusion if the myelosuppression is severe (e.g. Hb ≤ 7 g/dl).

Optic neuritis Possible anti-TB drug causes: Lzd, E Possible other causes: Multiple sclerosis, quinine, Herpes, Syphilis, Sarcoidosis, Cytomegalovirus (HIV)

The first sign of optic neuritis is usually the loss of red-green color distinction. This is best tested using the Ishihara test. Other symptoms include central scotoma (loss of central vision or blind spot)

Grade 1 Grade 2 Grade 3 Grade 4 Mild Moderate Severe Life-threatening Optic neuritis is Visual changes Visual Visual or changes Disabling visual loss.

inflammation of causing changes causing inability the optic nerve minimal or no causing to perform resulting in interference greater than usual social permanent vision with usual social minimal and functional loss. and functional interference activities.

activities. with usual social and functional activities.

Action Stop Lzd (or E Stop Lzd or E Stop Lzd or E Stop Lzd or E immediately if immediately if immediately immediately if there are any suspicions of there are any if there there are any optic neuritis. Do not restart suspicions of are any suspicions of it.

optic neuritis. suspicions optic neuritis. Do Do not restart it. of optic not restart it.

neuritis. Do not restart it.

National Tuberculosis Control Programme 111 Suggested management strategy Do not restart the suspected causative drug (linezolid or ethambutol)

Refer patient to an ophthalmologist for further evaluation and management.

Optic neuritis generally improves following cessation of offending drug, if it can be stopped early enough.

Patients with diabetes are at increased risk for optic neuritis. They should be managed with tight glucose control as a means of prevention. Patients with advanced kidney disease are also at increased risk for optic neuritis.

Lactic acidosis Possible anti-TB drug causes: Lzd Possible other causes: AZT, 3TC Grade 1 Grade 2 Grade 3 Grade 4 Mild Moderate Severe Life-threatening Lactate and pH < 2.0 x ULN ≥ 2.0 x ULN Increased Increased lactate with without lactate with pH without acidosis acidosis < 7.3 without pH < 7.3 with life threatening life threatening consequences consequences Action Continue Stop Lzd Stop Lzd Stop Lzd immediately. Do not treatment immediately. immediately. Do restart it.

regimen. Do not not restart it.

Patients should restart it.

be followed until resolution (return to baseline).

Early signs and symptoms include nausea, vomiting, abdominal pain, anxiety, and increased respiration rate and heart rate. Late symptoms include lethargy, hypotension and septic shock. Early detection of lactic acidosis is important because full-blown lactic acidosis is often fatal.

Diagnosis: analysis of an arterial blood sample showing a low pH and high lactate: anion gap, metabolic acidosis, lactate > 5 mmol/L, increased lactate/pyruvate.

If laboratory is not available, start treatment with clinical features Suggested management strategy Stop linezolid and NRTIs if lactic acidosis occurs. It may take months for the lactic acidemia to resolve completely even after the causative drug is stopped.

Hospitalize patient and monitor serum electrolytes, renal function, arterial blood gas, and lactate levels.

Check vital signs frequently and provide supportive care. Sodium bicarbonate therapy to correct a low pH has not been shown to be of benefit in lactic acidosis.

After lactic acidosis resolves, do not restart the suspected offending medication.

Pancreatitis Possible DR-TB drug causes: Bdq, Lzd Other causes: gallstones, heavy and long-term alcohol use, high triglycerides Grade 1 Mild Grade 2 Grade 3 Severe Grade 4 Life-threatening Moderate 112 National Tuberculosis Control Programme Pancreatitis Not Applicable Symptomatic Symptomatic and Life-threatening and Hospitalization consequences (e.g., Hospitalization indicated not circulatory failure, indicated hemorrhage, sepsis)

Lipase 1.1 – 1.5 x ULN 1.6 – 3.0 x 3.1 – 5.0 x ULN > 5.0 x ULN ULN Amylase 1.1 - 1.5 x ULN 1.6 - 2.0 x 2.1 - 5.0 x ULN > 5.1 x ULN ULN Action Continue Stop Lzd Stop Lzd Stop Lzd immediately. Do not treatment immediately. immediately. Do restart it.

regimen. Do not not restart it.

Patients should restart it.

be followed until resolution (return to baseline).

The most common symptoms and signs include severe epigastric pain (upper abdominal pain) radiating to the back in 50% cases, nausea and vomiting.

Suggested management strategy Monitor liver function tests, amylase, lipase, and full blood count.

Provide supportive care.

Permanently discontinue linezolid (or Bedaquilline if it is suspected to be the cause of the pancreatitis)

Gastrointestinal (Nausea and Vomiting)

Possible DR-TB drugs: Eto/Pto, PAS, Bdq (less common H, E, Z, Amx/Clv, Cfz, Dlm)

Grade 1 Grade 2 Grade 3 Grade 4 Mild Moderate Severe Life-threatening 1 episode in 24 hours 2-5 episodes in >6 episodes Physiologic consequences requiring 24 hours in 24 hours hospitalization or requiring parenteral nutrition or needing IV fluids National Tuberculosis Control Programme 113 Management and comments Nausea and vomiting are universal in early weeks of therapy and usually abate with time on treatment and adjunctive therapy. Some nausea and even vomiting may need to be tolerated at least in the initial period.

Assess for danger signs including dehydration, electrolyte disturbances and hepatitis.

Initiate rehydration therapy if indicated and correct any electrolyte disturbances.

Initiate a step-wise approach to manage nausea and vomiting.

Phase 1:

Give a light snack (biscuits, bread, rice, tea) before the medications. Give PAS with fruit juice.

Adjust medications and conditions without lowering the overall dose:

––Give Eto or PAS twice or thrice daily ––Give PAS two hours after other anti-TB drugs.

Another strategy is to stop the responsible medicine for two or three days and then add it back gradually increasing the dose (advise the patient that the medicine will be increased back to a therapeutic dose in a manner that will be better tolerated).

Phase 2: Start antiemetic(s):

––Metoclopramide 10 mg, 30 minutes before anti-TB medications.

––Ondansetron 8 mg, 30 minutes before the anti-TB drugs and again eight hours after. Ondansetron can either be used on its own or with metoclopramide. Odansetron prolongs the QT interval; avoid with bedaquiline or delamanid.

––If ondansetron is not available, promethazine can be used.) Promethazine25 mgPO,30 minutes before the anti-TB drugs (may be increased to 50 mg 3 times daily).

––Omeprazole or Ranitidine can also provide relief (omeprazole decreases the acid production, is also useful in the treatment of nausea).

Phase 3: Decrease dose of the suspected drug by one weight class if this can be done without compromising the regimen. It is rarely necessary to suspend the drug completely.

Note: For patients who are particularly anxious about the nausea, (and with “anticipatory nausea and vomiting”)

a small dose of an anti-anxiety medicine (5 mg of diazepam) can help when given 30 minutes prior to the intake of anti-TB drugs. Do not give diazepam longer than 2 weeks.

114 National Tuberculosis Control Programme Gastritis Possible DR-TB drug causes: Eto, Pto, PAS, Cfz, FQs, H, E, and Z If symptoms are associated consistent with gastritis (epigastric burning or discomfort, a sour taste in mouth associated with reflux) initiate medical therapy (prolonged duration):

Omeprazole 20 mg once daily (proton-pump inhibitors). Give 2 hours before or 3 hours after the TB medication Ranitidine 150 mg twice daily or 300 mg once daily (H2-blockers)

Avoid the use of antacids as they decrease absorption of fluoroquinolones.

Stop any nonsteroidal anti-inflammatory drugs the patient may be taking.

Diagnose and treat for Helicobacter pylori infections.

Abdominal pain Possible DR-TB drugs: Eto, Pto, Cfz, Lzd Abdominal pain is most commonly gastritis. However, can also be associated with serious adverse effects, such as pancreatitis, lactic acidosis (Lzd) and hepatitis. If any of these are suspected, obtain appropriate laboratory tests to confirm and suspend the suspected agent.

For severe abdominal pain stop suspected agent(s) for short periods of time (one to seven days).

Lower the dose of the suspected agent, if this can be done without compromising the regimen.

Discontinue the suspected agent if this can be done without compromising the regimen.

Severe abdominal distress has been reported with the use of clofazimine (deposition of Cfz crystal). Although these reports are rare, if this occurs, clofazimine should be suspended.

Diarrhea Possible DR-TB drugs: PAS, Eto/Pto Grade 1 Grade 2 Grade 3 Grade 4 Mild Moderate Severe Life-threatening Mild or transient; 3-4 Moderate or persistent; >7 loose stools/day or Hypotensive shock or loose stools/day or 5-7 loose stools/day bloody diarrhoea; or physiologic consequences mild diarrhoea last < 1 or diarrhoea lasting >1 orthostatic hypotension or requiring hospitalization week week electrolyte imbalance or >2L IV fluids required

Treatment

1. Encourage patients to tolerate some degree of loose stools and flatulence.

2. Encourage fluid intake.

3. Check other causes of Diarrhea. Fever and diarrhea and/or blood in the stools indicate that diarrhea may be secondary to bacterial enteritis or pseudomembranous colitis (C. difficile) related to FQ. If HIV positive assess CD4 and think other possible causes (CMV, isospora, microsporidium)

4. Check serum electrolytes (especially potassium) and dehydration status if diarrhea is severe.

5. Treat uncomplicated diarrhea (no blood in stool and no fever) with loperamide 4 mg by mouth initially followed by 2 mg after each loose stool to a maximum of 10 mg per day.

National Tuberculosis Control Programme 115 Rash, allergic reaction and anaphylaxis Possible DR-TB drugs: any drug Grade 1 Grade 2 Grade 3 Grade 4 Mild Moderate Severe Life-threatening Erythema; moderate Extended maculopapular eruption Extensive Exfoliative dermatitis, pruritus (with or without pruritus) papulovesicular mucous membrane eruption, palpable involvement or purpura cut., mist erythema multiforme desquamation or or suspected Stevens- ulcerations Johnson or cutaneus necrosis requiring surgery

Treatment

1. For serious allergic reactions (grade 3-4), stop all therapy pending resolution of reaction. In the case of anaphylaxis manage with standard emergency protocols (including adrenaline). If Steven Johnson Syndrome treat with IV corticosteroid, IV fluids and IV broad spectrum antibiotic.

Suspend permanently any drug identified to be the cause of a serious reaction. Any drug that resulted in anaphylaxis or Stevens–Johnson syndrome should never be reintroduced 2. Eliminate other potential causes of allergic skin reactions (like scabies or other environmental agents).

3. For minor dermatologic reactions, various agents may be helpful and allow continuation of the medication.

They include

• Antihistamines
• Hydrocortisone cream for localized rash
• Prednisone in a low dose of 10 to 20 mg per day for several weeks can be tried
• Dry skin may cause itching (especially in diabetics), liberal use of moisturizing lotion is recommended. Dry

skin is a common and significant problem with clofazimine.

4. Once the minor rash resolves, reintroduce remaining drugs, one at a time with the one most likely to cause the reaction last. Consider not reintroducing even as a challenge any drug that is highly likely to be the cause.

The order or reintroduction can be: H, Z, Eto/Pto, FQ, Cs, E, PAS, Km (or Am/Cm).

Arthralgia/ Arthritis Possible DR-TB drugs: Z (less frequent FQ, Bdq)

Grade 1 Grade 2 Grade 3 Grade 4 Mild Moderate Severe Life-threatening Arthralgia (joint Mild pain not Moderate pain, Severe pain; pain Disabling pain pain) interfering analgesics and/ and/or analgesics with function or pain interfering interfering with with function but ADL not with activities of daily life (ADL)

Arthritis Mild pain with Moderate pain Severe pain with Permanent and/ inflammation, with inflammation, inflammation, or disabling joint (inflammation erythema or erythema or joint erythema or joint destruction involving a joint) joint swelling, swelling; interfering swelling and but not with function, but interfering with interfering not with activities ADL with function of daily life (ADL)

116 National Tuberculosis Control Programme

Treatment

Give NSAIDs: ibuprofen 600 mg 3 times a day Rest the joint Initiate therapy with nonsteroidal anti-inflammatory drugs:

Ibuprofen 400 to 800 mg three times a day or Indomethacin 50 mg twice daily Lower the dose or discontinue the suspected agent (most commonly pyrazinamide) if this can be done without compromising the regimen.

Uric acid levels may be elevated in patients on pyrazinamide. There is little evidence to support the addition of allopurinol for arthralgia, although if gout is present it should be used.

If acute swelling, redness and warmth are present in a joint, consider aspiration for diagnosis of gout, infections, autoimmune diseases, etc.

National Tuberculosis Control Programme 117 Psychosis Possible DR-TB drugs: Cs, H, FQ, Eto/Pto Grade 1 Grade 2 Grade 3 Grade 4 Mild Moderate Severe Life-threatening Mild psychotic Moderate psychotic symptoms Severe psychotic Acute Psychosis (suicidal symptoms (e.g., disorganized speech; symptoms (e.g., ideation, maniac impaired reality testing) paranoid; extreme status, hallucinations).

disorganization); Life-threatening hospitalization not consequences, threats indicated of harm to self or others;

hospitalization indicated

Treatment

The most likely drug is cycloserine followed by high dose isoniazid.

1. Stop the suspected agent for a short period of time (1–4 weeks) while psychotic symptoms are brought under control.

2. Always check creatinine in patients with new onset psychosis. A decrease in renal function can result in high blood levels of cycloserine, which can cause psychosis.

3.. If moderate to severe symptoms persist, initiate antipsychotic therapy (haloperidol). Atypical antipsychotics should be used for DR-TB patients on multiple QT prolonging DR-TB drugs since haloperidol significantly prolongs the QTc interval and has been associated with torsades de pointes.

4.. Hospitalize in a ward with psychiatric expertise if patient is at risk to himself/herself or others.

5.. Increase pyridoxine to the maximum daily dose (200 mg per day).

6.. Lower the dose of the suspected agent (most commonly cycloserine to 500 mg a day)

7.. Discontinue the suspected agent if this can be done without compromising the regimen.

8.. Once all symptoms resolve and patient is off cycloserine, antipsychotic therapy can be tapered off. If cycloserine is continued at a lower dose, antipsychotic therapy may need to be continued and any attempts of tapering off should be done after referring to a psychiatrist.

Some patients will need to continue antipsychotic treatment throughout DR-TB treatment (and discontinued gradually upon completion of treatment)

Previous history of psychiatric disease is not a contraindication to cycloserine, but its use may increase the likelihood of psychotic symptoms developing during treatment. Avoid if there is an alternative.

Psychotic symptoms are generally reversible upon completion of DR-TB treatment or cessation of the offending agent.

Depression Possible DR-TB drugs: Cs, FQ, H, Eto/Pto Other causes: Psychological and socioeconomic circumstances, chronic disease Grade 1 Grade 2 Grade 3 Grade 4 Mild Moderate Severe Life-threatening 118 National Tuberculosis Control Programme Mild depressive Moderate Severe depressive Life-threatening consequences, threats of harm symptoms; and/or depressive symptoms; to self or others; PHQ9 depression score 20-27;

PHQ9 depression symptoms; limiting self- and/or hospitalization indicated.

score 1-9. limiting care ADL;

instrumental hospitalization Activities of not indicated;

Daily Life and/or PHQ9 (ADL); and/ depression score or PHQ9 15-19.

depression score 10-14.

Treatment

Anti-TB Therapy may contribute to depression. Depressive symptoms may fluctuate during the therapy.

Asses and address underlying emotional and socioeconomic issues.

Provide psychological support (for the patient and family)

If depression is significant, initiate antidepressant therapy (amitriptyline, fluoxetine)

Avoid serotonin reuptake inhibitors and tricyclic antidepressant with linezolid (risk of serotonin syndrome)

Lower the dose of the suspected agent if this can be done without compromising the regimen. (Reducing the dose of cycloserine and ethionamide to 500 mg daily).

Discontinue the suspected agent if this can be done without compromising the regimen.

National Tuberculosis Control Programme 119 Seizures Possible DR-TB drugs: Cs, H, FQ, Imp/Cln First address other causes of seizures: infection, epilepsy, meningitis, encephalitis, alcohol withdrawal, hypoglycemia, cerebrovascular accident, malignancy or toxoplasma in PLHIV).

Then:

1. Hold cycloserine, fluoroquinolones and isoniazid pending resolution of seizures.

2. Initiate anticonvulsant therapy (carbamazepine, phenytoin or valproic acid are most commonly used).

3. Increase pyridoxine to the maximum daily dose (200 mg per day).

4. Check serum electrolytes including potassium, sodium, bicarbonate, calcium, magnesium and chloride (replace accordingly).

5. Check creatinine level. A decrease in renal function can result in high blood levels of cycloserine, which can cause seizures. Adjusting the dose of cycloserine in the presence of low creatinine may be all that is needed to control the seizures 6. When seizures have resolved, restart medications one at a time. Cycloserine should not be restarted unless itis absolutely essential to the regimen. If cycloserine is reinitiated, start a dose one weight band lower.

Notes:

An anticonvulsant is generally continued until DR-TB treatment is completed or suspected agent is discontinued.

History of previous seizure disorder is not a contraindication to the use of agents listed here if a patient’s seizures are well controlled and/ or the patient is receiving anticonvulsant therapy. (Do not include cycloserine if an alternative drug is available.)

Carbamazepine is a strong inducer of CYP3A4 and should not be used with Bedaquiline or Delamanid.

Hypothyroidism Possible DR-TB drugs: Eto/Pto/PAS Grade 1 Grade 2 Grade 3 Grade 4 Mild Moderate Severe Life-threatening Sub-clinical Simple hypothyroidism Severe hypothyroidism Myxedematous coma.

hypothyroidism (TSH without complications. with clinical symptoms.

6-10mIU/L, T4 free Treatment required (TSH > Urgent treatment.

normal) 10 mU/L)

120 National Tuberculosis Control Programme

Treatment

Start treatment when TSH > 10 mIU/L Dose of levothyroxine:

Adults: 1.2- 1.4 ucg/kg/day (50-200 ucg dia)

Children: 4-5 ucg/kg/day (max 200 ucg/dia). Children need higher dose due to hormone metabolism.

1. Most adults will require 100–150 mcg of levothyroxine daily. Start levothyroxine in the following manner:

• Young healthy adults can be started on 75–100 mcg daily
• Older patients should begin treatment with 50 mcg daily
• Patients with significant cardiovascular disease should start at 25 mcg daily.

2. Monitor TSH every month and increase the dose by 12.5–25 mcg until TSH normalizes. Adjust the dose more slowly in the elderly and in patients with cardiac conditions.

Note: it could be considered to start treatment with TSH >6 mlU/L to 10 mUI/L with low dose of levothyroxine (25 to 50 mcg)

Thyroid dysfunction resolves upon discontinuation of the cause agent. Hormone replacement must continue at least 2 to 3 months after completed DR-TB treatment.

National Tuberculosis Control Programme 121