Appendix 19. Drug interactions and overlapping toxicities | الأدلة الطبية لمنظمة أطباء بلا حدود

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المحتويات

19.1 Interactions between cytochrome P450 inducers/inhibitors and bedaquiline
19.2 Overlapping toxicity of QT-prolonging drugs
19.3 Interactions between TB and antiretroviral drugs
19.4 Overlapping toxicities of antiretrovirals and TB drugs

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)[3]Citation 3.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)[4]Citation 4.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)[5]Citation 5.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)[6]Citation 6.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[7]Citation 7.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[8]Citation 8.World Health Organization. WHO Consolidated guidelines on tuberculosis. Module 1: Prevention. Geneva: World Health Organization; 2020. https://www.who.int/publications/i/item/9789240001503 , [9]Citation 9.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[10]Citation 10.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[11]Citation 11.World Health Organization. WHO Consolidated guidelines on tuberculosis. Module 1: Prevention. Geneva: World Health Organization; 2020. https://www.who.int/publications/i/item/9789240001503 , [12]Citation 12.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[13]Citation 13.University of Liverpool HIV Drug Interaction Checker. https://www.hiv-druginteractions.org/checker, [14]Citation 14.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.

TB drugs

NRTI

(ABC, 3TC, TDF, AZT)

INI

(DTG, RAL)

NNRTI

(NVP, EFV)

Boosted PI

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

R[8]Citation 8.World Health Organization. WHO Consolidated guidelines on tuberculosis. Module 1: Prevention. Geneva: World Health Organization; 2020.
https://www.who.int/publications/i/item/9789240001503 , [9]Citation 9.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[10]Citation 10.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[11]Citation 11.World Health Organization. WHO Consolidated guidelines on tuberculosis. Module 1: Prevention. Geneva: World Health Organization; 2020.
https://www.who.int/publications/i/item/9789240001503 , [12]Citation 12.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[13]Citation 13.University of Liverpool HIV Drug Interaction Checker.
https://www.hiv-druginteractions.org/checker, [14]Citation 14.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.

aDTG: administer 50 mg 2 times daily, rather than the usual dose of 50 mg once daily.
bRAL: e.g. administer 12 mg/kg 2 times daily, rather than the usual dose of 6 mg/kg 2 times daily.
cLPV/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).

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[15]Citation 15.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, Mfx^h, 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.

المراجع

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.
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
3.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
4.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
5.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
6.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
7.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
8.World Health Organization. WHO Consolidated guidelines on tuberculosis. Module 1: Prevention. Geneva: World Health Organization; 2020.
https://www.who.int/publications/i/item/9789240001503
9.University of Liverpool HIV Drug Interaction Checker.
https://www.hiv-druginteractions.org/checker
10.University of Liverpool HIV Drug Interaction Checker.
https://www.hiv-druginteractions.org/checker
11.World Health Organization. WHO Consolidated guidelines on tuberculosis. Module 1: Prevention. Geneva: World Health Organization; 2020.
https://www.who.int/publications/i/item/9789240001503
12.University of Liverpool HIV Drug Interaction Checker.
https://www.hiv-druginteractions.org/checker
13.University of Liverpool HIV Drug Interaction Checker.
https://www.hiv-druginteractions.org/checker
14.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
15.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