13. Drug-drug interactions

A complete medication review with assessment for potential drug interactions and need for dose adjustments of concomitant medications is recommended for all patients at initiation of TB treatment. Any adjustments of doses of these medications should be reconsidered within 2 weeks of stopping TB treatment.^217–219

There are several freely available online drug interaction resources that we suggest can be helpful to guide this assessment:

Medscape (https://reference.medscape.com/drug-interactionchecker)
University of Liverpool HIV Drug Interactions (https://www.hiv-druginteractions.org/checker)
HIV/HCV Drug Therapy Guide from Toronto (https://hivclinic.ca/wp-content/plugins/php/app.php)

Rifampin is a well-documented potent inducer of hepatic and intestinal cytochrome P450 (CYP) enzymes, as well as the P-glycoprotein (P-gp) transport system. The onset of induction effects is gradual, with maximal effects on metabolizing enzymes and drug transporters by about two weeks. Induction can last for up to 4 weeks after stopping rifampin.²²⁰

Rifabutin is a less potent inducer of CYP P450 then rifampin. However, unlike rifampin, rifabutin is also a substrate of CYP3A4 and, therefore, can participate in bi-directional interactions, meaning that the metabolism of rifabutin can be altered by other drugs.⁶⁸^,²²¹

Rifapentine, when dosed weekly, exerts less induction of CYP P450 then does rifampin. However, when rifapentine is dosed daily, it appears to have an even greater inductive effect than standard-dosed rifampin.²²² Rifapentine is not a substrate for CYP3A.

Isoniazid is primarily metabolized via N-acetylation and is an inhibitor of several CYP450 isoenzymes. Isoniazid may inhibit the metabolism of concomitant agents, including some antiepileptics or benzodiazepines.²²³^,²²⁴

The absorption of quinolones is significantly affected when administered at the same time as antacids and minerals containing multivalent cations, such as aluminum, magnesium or iron. Separating administration times by at least 2 hours is recommended.²¹

EMB and PZA have a low risk of drug-drug interactions.

Good practice statement

Drug-drug interactions and altered pharmacokinetics of TB drugs are frequently encountered in people with HIV co-infection, organ transplantation, medical co-morbidities, liver disease, renal dysfunction, and advanced age. Consultation with an experienced pharmacist is recommended when treating TB in these populations.

Table 2. Common drug-drug interactions with Rifamycins (Last updated Dec 2021).

Drugs/Drug Classes Impacted	Potential Mitigation Strategy
Anticoagulants Warfarin Apixaban, dabigatran, edoxaban, rivaroxaban	Continue warfarin with frequent INR monitoring while on rifampin and for 4 weeks after stopping rifampin. Alternatively, could change to LMWH injection. ²²⁵ ^, ²²⁶ Avoid use of direct-acting oral anticoagulants with rifampin. Rifabutin may be used with dabigatran. ^227–231
Anticonvulsants carbamazepine, phenytoin, lamotrigine	Consult with neurologist to discuss the possibility of using alternative anti-epileptic agent. Levetiracetam is a preferred anticonvulsant when taking rifamycins as there are no clinically relevant interactions. Alternatively, therapeutic drug monitoring of these anti-epileptic agents with subsequent dose adjustment is required. ^232–235
Antidiabetics agents	More frequent blood glucose monitoring recommended. Potential for decrease in drug concentration of most oral antidiabetic agents in patients on rifamycins and potential for increased blood glucose levels. Dose adjustment of antidiabetic agents may be required, ^236–243 No significant interaction with metformin or insulin. ²⁴³
Antifungals Azoles (itraconazole, fluconazole, posaconazole, voriconazole, isavuconazole)	Subtherapeutic azole concentrations may occur when used with any of the rifamycins. ^244–248
Antihypertensives	Increased BP monitoring recommended with most antihypertensives. Rifampin has a strong interaction with calcium channel blockers and clinicians may be required to increase dose of the calcium channel blocker or change/add an alternate antihypertensive agent (consult provider). Rifabutin has a less potent interaction as compared to rifampin. ^249–252
Antiretroviral agents	See Text and Table 1.
Corticosteroids dexamethasone, methylprednisolone, prednisone	Monitor clinical response. May require increase in dose of corticosteroids. ^253–255
Immunosuppressive agents cyclosporine, tacrolimus	Rifabutin use is preferred over rifampin to minimize impact on concentrations of calcineurin inhibitors and to reduce the risk of allograft rejection. Monitor calcineurin inhibitor concentrations and adjust dose as required. ^256–260
Levothyroxine	Continue both agents but monitor TSH monthly. May require increase in dose of levothyroxine with rifamycins. Monitor TSH after stopping rifamycins. ^261–263
Opiate agonist therapy methadone, buprenorphine/naloxone (Suboxone)	Methadone and buprenorphine serum concentrations decrease substantially with rifampin and precipitation of withdrawal symptoms is frequent. May need preemptive OAT regimen dosage adjustment in addition to close monitoring. Discuss OAT with provider. ²⁰⁴ ^, ²⁶⁴ ^, ²⁶⁵ Rifabutin has much less impact on methadone and buprenorphine serum concentrations and is not associated with withdrawal symptoms. ²⁰⁵ ^, ²⁰⁶
Oral hormonal contraceptive ethinyl estradiol, norethindrone, etc	Add a barrier method of contraception when taking a rifamycin with oral hormonal contraceptives. ²⁶⁶

^{Abbreviations: INR, international normalized ratio; LMWH, Low molecular weight heparin; BP, blood pressure; TSH, thyroid-stimulating hormone; OAT, opiate agonist therapy.}

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TB Manual

Table 2. Common drug-drug interactions with Rifamycins (Last updated Dec 2021).

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