Appendix 19. Drug interactions and overlapping toxicities

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    Update: October 2022

     

    19.1 Interactions between cytochrome P450 inducers/inhibitors and bedaquiline

    Drugs interfering with the cytochrome P450 (CYP450) enzyme system should be avoided with bedaquiline.

     

    Strong CYP450 inducers

    Moderate CYP450 inducers

    Effect

    Rifampicin

    Phenytoin

    Carbamazepine

    Phenobarbital

    Efavirenz

    Rifapentine

    Rifabutin

    Decrease bedaquiline plasma concentrations

    Strong CYP450 inhibitors

    Moderate CYP450 inhibitors

    Effect

    Atazanavir

    Itraconazole

    Clarithromycin

    Lopinavir

    Nelfinavir

    Ritonavir

    Erythromycin

    Fluconazole

    Verapamil

    Increase bedaquiline plasma concentrations

    Drugs metabolized by CYP

    Effect

    Emtricitabine

    Can increase bedaquiline plasma concentrations

     

    This list is not exhaustive. Clinicians should be informed of any cytochrome P450 inducers and inhibitors their patients may be taking.

    19.2 Overlapping toxicity of QT-prolonging drugs

    TB drugs (mean QT interval prolongation)

    • Mild QT prolongation: delamanid (8.6 ms) [1] Citation 1. Dooley KE, Rosencrantz SL, Conradie F, et al. QT effects of bedaquiline, delamanid or both in patients with rifampicin-resistant-tuberculosis: a phase 2, open-label, randomised, controlled trial. Lancet Infect Dis. 2021. , levofloxacin (4.6 ms) [2] Citation 2. Ethan Rubinstein, John Camm. Cardiotoxicity of fluoroquinolones. Journal of Antimicrobial Chemotherapy, Volume 49, Issue 4, April 2002, Pages 593–596.
      https://doi.org/10.1093/jac/49.4.593             .
    • Moderate QT prolongation: bedaquiline (12.3 ms) [2] Citation 2. Ethan Rubinstein, John Camm. Cardiotoxicity of fluoroquinolones. Journal of Antimicrobial Chemotherapy, Volume 49, Issue 4, April 2002, Pages 593–596.
      https://doi.org/10.1093/jac/49.4.593             , moxifloxacin (12.3 ms) [3] Citation 3. Moon SJ, Lee J, An H, et al. The effects of moxifloxacin on QTc interval in healthy Korean male subjects. Drugs R D. 2014;14(2):63-71.
      https://doi.org/10.1007/s40268-014-0040-1             .
    • Strong QT prolongation: clofazimine (28.5 ms) [4] Citation 4. Abdelwahab MT, Court R, Everitt D, Diacon AH, Dawson R, Svensson EM, Maartens G, Denti P. 2021. Effect of clofazimine concentration on QT prolongation in patients treated for tuberculosis. Antimicrob Agents Chemother 65:e02687-20. 
      https://doi.org/10.1128/AAC.02687-20             , moxifloxacin high dose (23.14 ms) [3] Citation 3. Moon SJ, Lee J, An H, et al. The effects of moxifloxacin on QTc interval in healthy Korean male subjects. Drugs R D. 2014;14(2):63-71.
      https://doi.org/10.1007/s40268-014-0040-1             .

     

    Non-TB drugs [5] Citation 5. Khatib R, Sabir FRN, Omari C, et al. Managing drug-induced QT prolongation in clinical practice. Postgraduate Medical Journal 2021;97:452-458.
    https://doi.org/10.1136/postgradmedj-2020-138661

    • Antimalarials: artemisinine derivatives (high risk), quinine
    • Antipsychotics: haloperidol (high risk), chlorpromazine, fluphenazine, olanzapine, risperidone
    • Cardiac drugs: amiodarone (high risk), beta-blockers, digoxin
    • Oral azole antifungals: fluconazole, itraconazole
    • Macrolides: azithromycin, clarithromycin, erythromycin
    • Anti-nausea drugs: ondansetron
    • Antiretrovirals: boosted protease inhibitors, efavirenz

     

    This list is not exhaustive. Clinicians should be informed of any QT-prolonging drugs their patients may be taking.

    19.3 Interactions between TB and antiretroviral drugs

    AZT: zidovudine; ATV: atazanavir; 3TC: lamivudine; RAL: raltegravir; ABC: abacavir; DTG: dolutegravir; FTC: emtricitabine; TDF: tenofovir disoproxil fumarate; LPV/r: lopinavir/ritonavir; EFV: efavirenz; RTV or r: ritonavir.

    R: rifampicin; Rfb: rifabutin; P: rifapentine; Bdq: bedaquiline.

     

    TB drugs

    NRTI

    (ABC, 3TC, TDF, AZT)

    INI

    (DTG, RAL)

    NNRTI

    (NVP, EFV)

    Boosted PI

    (LPV/r, ATV/r, DRV/r)

    R [6] Citation 6. World Health Organization. WHO Consolidated guidelines on tuberculosis. Module 1: Prevention. Geneva: World Health Organization; 2020.
    https://www.who.int/publications/i/item/9789240001503           [7] Citation 7. University of Liverpool HIV Drug Interaction Checker.
    https://www.hiv-druginteractions.org/checker

    All NRTI

    • Can be combined.
    • No dose adjustment.  

    DTG

    • Can be combined.
    • Double the dose of DTG (a) Citation a. DTG: administer 50 mg 2 times daily, rather than the usual dose of 50 mg once daily. .

    RAL

    • Can be combined.
    • Double the dose of RAL (b) Citation b. RAL: e.g. administer 12 mg/kg 2 times daily, rather than the usual dose of 6 mg/kg 2 times daily. .

    NVP

    • Do not combine.
    • Replace NVP with DTG or EFV.
    • If not possible, replace R with Rfb.

    EFV

    • Can be combined.
    • No dose adjustment.  

    ATV/r or DRV/r

    • Do not combine.
    • Replace R with Rfb.

    LPV/r

    • Replace R with Rfb.
    • If not possible and a PI is essential, dose adjustment is required (c) Citation c. LPV/r:
      • Child: increase the dose of RTV to obtain a one-to-one (1:1) LPV/r ratio.
      • Adult: double the dose (e.g. 800/200 mg 2 times daily, rather than the usual dose of 400/100 mg 2 times daily).             .

    Rfb [7] Citation 7. University of Liverpool HIV Drug Interaction Checker.
    https://www.hiv-druginteractions.org/checker

     

    All NRTI

    • Can be combined.
    • No dose adjustment.  

    All INI

    • Can be combined.
    • No dose adjustment.  

    NVP

    • Can be combined.
    • No dose adjustment.  
    • Monitor Rfb toxicity. 

    EFV

    • Do not combine.

    All boosted PI

    • Can be combined.
    • Reduce the dose of Rfb by half
    • Monitor Rfb toxicity. 

    P [6] Citation 6. World Health Organization. WHO Consolidated guidelines on tuberculosis. Module 1: Prevention. Geneva: World Health Organization; 2020.
    https://www.who.int/publications/i/item/9789240001503           [7] Citation 7. University of Liverpool HIV Drug Interaction Checker.
    https://www.hiv-druginteractions.org/checker

    All NRTI

    • Can be combined.
    • No dose adjustment.  

    All INI

    • Can be combined.
    • No dose adjustment.  

    NVP

    • Do not combine.
    • Replace NVP with DTG or EFV.

    EFV

    • Can be combined.
    • No dose adjustment.

    All boosted PI

    Do not combine.

    Bdq [7] Citation 7. University of Liverpool HIV Drug Interaction Checker.
    https://www.hiv-druginteractions.org/checker         [8] Citation 8. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment. Geneva: World Health Organization; 2020.
    https://www.who.int/publications/i/item/9789240007048

    • Can be combined.
    • No dose adjustment.  

    All INI

    • Can be combined.
    • No dose adjustment.  

    NVP

    • Can be combined.
    • No dose adjustment.

    EFV

    • Do not combine.
    • Replace EFV with DTG or NVP.

    All boosted PI

    • Do not combine.
    • Replace boosted PI with DTG.
    • If no alternative, closely monitor ECG. 

    For more information, see University of Liverpool HIV Drug Interaction Checker: https://www.hiv-druginteractions.org/checker.

    19.4 Overlapping toxicities of antiretrovirals and TB drugs

    Drugs strongly associated with the listed toxicities appear in bold lettering.

     

    Toxicity

    ARVs

    TB drugs

    Comments

    Abdominal pain

    All ARVs

    Eto or Pto, PAS, Cfz, Lzd, FQs, H, Z

    Common. Often benign, but can be an early symptom of severe adverse effects (Appendix 17).

    Depression

    EFV, DTG

    Cs or Trd, FQs, Eto or Pto, H
    • EFV: consider replacing EFV in the event of severe depression.
    • DTG: can cause depression, but less frequently [9] Citation 9. Fettiplace A, Stainsby C, Winston A, et al. Psychiatric symptoms in patients receiving dolutegravir. J Acquir Immune Defic Syndr, 2017 Apr 1, 74 (4): 423.
      https://doi.org/10.1097/QAI.0000000000001269             .

    Diarrhoea

    All PI, DTG

    Eto or Pto, PAS, FQs, Amx/Clv, Ipm/Cln

    Common. Also consider opportunistic infections as a cause of diarrhoea or Clostridium difficile infection (pseudomembranous colitis).

    Electrolyte disorders

    TDF (rare)

    Am, S

    See Nephrotoxicity.

    Haematological disorders

    AZT

    Lzd
    • Monitor full blood count.
    • Replace AZT in the event of bone marrow suppression.
    • For Lzd, see Appendix 17.
    • If the patient takes cotrimoxazole (CMX), also consider CMX as a cause of haematological disorders.

    Headache

    AZT, EFV, DTG

    Cs or Trd, Bdq, Dlm

    Rule out bacterial or cryptococcal meningitis, toxoplasmosis, etc. Headache secondary to AZT, EFV, DTG and Cs or Trd are usually transient.

    Hepatotoxicity

    NVP, EFV, boosted PIs, DTG

    Z, H, R, E, PAS,

    Eto or Pto, Bdq, Amx/Clav
    • If severe, stop ART and TB drugs. When treatment is resumed, start the TB drugs first (Appendix 17).
    • If the patient takes CMX, also consider CMX as a cause of hepatotoxicity.

    Nausea and vomiting

    RTV, NVP,

    and most other ARVs

    Eto or Pto, PAS, Z, Amx/Clv, Cfz, Lzd, Ipm/Cln, Bdq

    Persistent vomiting can be a result of more severe conditions, such as lactic acidosis and/or drug-induced hepatitis.

    Nephrotoxicity

    TDF

    Am, S
    • Avoid TDF in patients on aminoglycosides.
    • If an aminoglycoside is essential:
      • For patients already on ART, replace TDF with ABC.
      • For new patients, start with AZT or ABC.
    • If TDF and aminoglycoside cannot be avoided, monitor serum creatinine, creatinine clearance and electrolytes at least every 2 weeks.

    Neurotoxicity

    EFV, DTG

    Cs or Trd, H, Eto or Pto, FQs
    • EFV: numerous transient effects on the central nervous system during first 2-3 weeks of treatment. If they do not resolve, consider replacing EFV. There are limited data on the use of EFV with Cs or Trd; concomitant use is accepted practice provided the patient is closely monitored for neurotoxicity.
    • DTG: can cause insomnia and dizziness. Administer in the morning or consider replacing with EFV, a boosted PI or RAL.

    QT prolongation

    Boosted PIs, EFV

    Cfz, Mfxh, Bdq, Mfx, Dlm, Lfx

    For monitoring, see Appendix 15.

    Skin reactions

    ABC, NVP, EFV,

    and all other ARVs

    All TB drugs
    • Do not re-introduce ABC (risk of anaphylaxis).
    • Do not re-introduce any agent that may have caused Stevens-Johnson syndrome.
    • If the patient takes CMX, also consider CMX as a cause of skin reactions.

     

     

    • (a)DTG: administer 50 mg 2 times daily, rather than the usual dose of 50 mg once daily.
    • (b)RAL: e.g. administer 12 mg/kg 2 times daily, rather than the usual dose of 6 mg/kg 2 times daily.
    • (c)LPV/r:
      • Child: increase the dose of RTV to obtain a one-to-one (1:1) LPV/r ratio.
      • Adult: double the dose (e.g. 800/200 mg 2 times daily, rather than the usual dose of 400/100 mg 2 times daily).
    References
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