9.5 Management of adverse effects in patients on first-line regimens

9.5.1 Symptom-based approach to managing adverse effects

The drugs used to treat TB may cause adverse reactions. Managing drug reactions rapidly and aggressively is an important means to increase tolerance. Generally with minor adverse effects, drugs need not be stopped and encouragement to the patient and use of ancillary medicines is all that is necessary. With major adverse effects, the drugs often have to be stopped and modified regimen continued.

Table 9.1 - Main adverse effects and probably responsible drugs

Adverse effects

Drug(s) probably responsible

Management

Minor

Nausea, vomiting

R, H, Z

See Appendix 10

Arthralgia

Z

See Appendix 10

Peripheral neuropathy

H

See Section 9.5.4

Orange/red urine, tears, etc.

R

Patients should be told when starting treatment that this is normal.

Major

Skin rash

S, E, Z, R, H

See Section 9.5.2

Auditory toxicity

S

See Appendix 10

Vestibular toxicity

S

See Appendix 10

Nephrotoxicity

S

See Appendix 10

Hepatitis

Z, H, R

See Section 9.5.3

Optic neuritis

E

See Appendix 10

Thrombocytopenic purpura

R

See Appendix 10

Generally it is not necessary to monitor renal or liver function, or blood counts unless there are clinical reasons to do so (e.g. a history of liver disease).

For more information, see individual drug sheets in Appendix 9.

9.5.2 Cutaneous or generalized hypersensitivity

Hypersensitivity reactions usually appear early during treatment, often in the first month, but rarely during the first week. The drug the most likely to provoke these reactions is streptomycin however, other drugs can be involved. Consider also other causes of skin rash (e.g. scabies).

Hypersensitivity reactions show up in the form of itching and skin rashes. General signs, such as fever, dizziness, vomiting and headache, may occur.

Severe —even lethal— exfoliative dermatitis may occur very occasionally (Stevens-Johnson's syndrome), particularly if administration of the drug continues after signs of hypersensitivity appear.

In the event of simple itching: symptomatic treatment (e.g. antihistaminics), without interrupting or modifying treatment.

In the event of skin rash with or without itching:
1 - Stop anti-TB drugs; give symptomatic treatment (no corticosteroids except in emergencies) and wait for disappearance of symptoms.
2 - Identify the drug that caused the reaction in order to re-start treatment as rapidly as possible. Use trial doses as in the table below. Test first the drugs least likely to have caused the reaction: start with isoniazid over 3 days then add rifampicin over 3 days, etc.
For patients on re-treatment regimen including streptomycin: if isoniazid, rifampicin, pyrazinamide and ethambutol have been all re-introduced without recurrence of rash, streptomycin should be discontinued without testing.

Table 9.2 - Re-challenge of first-line anti-TB oral drugs and streptomycin (adapted fromthe WHO7)

Drug Likelihood Trial doses From Day 3
Day 1 Day 2

H

least likely

50 mg

Full dose

Full dose

R


75 mg

300 mg

Full dose

Z


250 mg

1000 mg

Full dose

E


100 mg

500 mg

Full dose

S

most likely

125 mg

500 mg

Full dose

Note: if the initial reaction to treatment was severe, a weaker trial dose should be used (approximately 1/10th of the dose indicated for Day 1).

9.5.3 Hepatotoxicity

All anti-TB drugs may cause hepatotoxicity. Pyrazinamide is the most hepatotoxic and isoniazid the second but to a much lesser extent. Some combinations, such as rifampicinpyrazimanide potentiate the hepatotoxic effect of each drug.

Clinical aspects resemble that of viral hepatitis: anorexia, nausea, vomiting, jaundice, etc.

If available, laboratory examination of liver injury is useful in diagnosing and following liver toxicity. Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are elevated in liver toxicity.

AST or ALT or serum bilirubin > 3 times upper limit of normal with symptoms or > 5 times normal limit in the absence of symptoms are considered elevated. An AST or ALT or serum bilirubin < 5 times normal limit defines mild toxicity; 5 to 10 times normal limit defines moderate toxicity and > than 10 times normal limit defines severe toxicity.

When such symptoms occur or if liver enzymes are moderately or severely elevated, all anti- TB drugs should be stopped while waiting for resolution of signs. Treatment with the same drugs may, most of the time, be resumed without incident. The objective is to resume treatment either with the initial regimen or with another, and as rapidly as possible.

When the clinical status of the patient does not allow interruption of TB treatment, the least toxic drugs, streptomycin and ethambutol, can be used while waiting for clinical resolution of the hepatitis.

If symptoms reappear, it might be wise to reintroduce the drugs one by one and stopping the last drug re-introduced if symptoms recur or liver tests become abnormal. Some authors recommend starting with rifampicin (and ethambutol) and reintroduce isoniazid 3 to 7 days later. If rifampicin, ethambutol and isoniazid have been introduced and the biochemical abnormalities have not recurred, do not introduce pyrazinamide as it is most likely the causative agent.

The alternative regimen depends of the drug causing the toxic hepatitis, these regimen are similar to those recommended in case of resistance to the given drug.

– Pyrazinamide is involved: 2 S(HR)/7 (HR) or 2 (HR)E/7 (HR)
– Isoniazid is involved: 9 RZE
– Rifampicin is involved: 3 S-Lfx-HZE/12 Lfx-HZE or 3 Km-Lfx-HZE/12 Lfx-HZE
– Pyrazinamide and rifampicin are involved: 3 S-Lfx-HE/12 Lfx-HE or 3 Km-Lfx-HE/12 Lfx-HE

In the rare event of rifampicin and isoniazid are involved the treatment regimen is as an MDR regimen.

9.5.4 Isoniazid-associated neuropathy

Peripheral neuropathy refers to damage to the nerves located outside of the central nervous system. This usually occurs more commonly in pregnant and breastfeeding women and patients with HIV infection, alcohol dependency, malnutrition, diabetes, chronic liver disease, and renal impairment. These patients should receive preventive treatment with pyridoxine PO (5 to 10 mg/day in children; 10 mg/day in adults) along with their anti-TB drugs. Other guidelines recommend 25 mg/day but there is some evidence that this dose may overcome the antibiotic action of isoniazid. If only 25 mg tablets are available give 3 times weekly or cut in half and give daily.

If peripheral neuropathy develops, administer pyridoxine PO:
– Children less than 12 years: 20 to 40 mg/day in 2 divided doses
– Children over 12 years: 60 to 100 mg/day in 2 divided doses
– Adults: 100 to 200 mg daily