Specific interaction studies have not been performed with efavirenz and abacavir. Clinically significant interactions would not be expected with abacavir since the NRTIs are metabolised via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways. Abacavir had no effect on efavirenz pharmacokinetics when abacavir. efavirenz and indinavir were coadministered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Acamprosate is eliminated unchanged in the urine.

Coadministration has not been studied but may increase or decrease acenocoumarol concentrations. Monitor INR. A case report described an HIV-infected patient who required an increase in average acenocoumarol dose to maintain INR in the target range whilst on either an efavirenz-based or an atazanavir/ritonavir-based regimen; eventually the patient was stabilised on a raltegravir regimen.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Acetazolamide is primarily excreted unchanged via the kidneys, there is therefore little potential for interaction with efavirenz via modulation of, or competition for metabolic pathways.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aclidinium bromide is rapidly and extensively hydrolyzed (non-enzymatic and enzymatic transformation by esterases and butylrylcholineesterases) to its pharmacologically inactive metabolites with only a minor role for CYP metabolism.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Adalimumab is a monoclonal IgG antibody. Elimination is similar to endogenous IgG and occurs primarily via proteolytic catabolism throughout the body.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Adrenaline is rapidly inactivated, mostly in the liver by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). There is therefore little potential for interaction with efavirenz via modulation of, or competition for metabolic or elimination pathways.

The effect of multiple doses of an African potato preparation on a single dose of efavirenz (600 mg) was studied in 10 HIV-negative subjects. Coadministration had no significant effect on efavirenz AUC or Cmax.

Coadministration has not been studied. In vitro studies have demonstrated that CYP3A4 is involved in formation of the active metabolite albendazole sulfoxide. When antiepileptics (phenytoin, carbamazepine and phenobarbital) were coadministered with albendazole, significantly reduced levels of the active metabolite albendazole sulfoxide were observed, apparently due to induction of CYP3A4. Similarly, coadministration with efavirenz could reduce albendazole exposure; however, the clinical relevance is unknown as the antihelmintic action is thought to be mainly intra-intestinal.

Coadministration has not been studied but based on metabolism and clearance, as well as limited drug-drug interaction data, a clinically significant interaction is unlikely. Efavirenz is metabolized by CYP3A4 and CYP2B6. In vitro human microsomal studies and limited in vivo drug-drug interaction data indicate that albuvirtide has no inhibiting or inducing properties on P450 enzymes. Induction of CYP3A4 by efavirenz is unlikely to affect albuvirtide, a peptide which is eliminated by catabolism to its constituent amino acids.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs there is little potential for interaction. Alcuronium is predominantly eliminated unchanged via the kidneys.

If taken at the same time, it is likely that food and beverages (including mineral water), calcium supplements, antacids, and some oral medicinal products will interfere with absorption of alendronate. Therefore, patients must wait at least 30 minutes after taking alendronate before taking any other oral medicinal product.

Coadministration has not been studied. Alfuzosin is metabolised mainly by CYP3A4. Efavirenz, an inducer of CYP3A4, could potentially decrease alfuzosin exposure. Monitor clinical effect and increase dosage if needed. Alfuzosin has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Aloe vera is only a weak inhibitor of CYPs in vitro and therefore is unlikely to cause clinically significant interactions. It does not inhibit P-gp and there is no evidence to suggest it impacts UGTs.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Amantadine is mainly eliminated renally by glomerular filtration and active secretion. A bicarbonate dependent organic cation transporter has been identified as the major uptake transporter of amantadine in the renal proximal tubule. Amantadine has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ambrisentan is mainly glucuronidated by UGT1A9, UGT2B7, UGT1A3 and is metabolized to a lesser extent by CYP3A4. Ambrisentan is also a substrate of P-gp and OATP1B1. Efavirenz induces UGT1A1 but this is not involved in ambrisentan glucuronidation. Furthermore, induction of CYP3A4 by efavirenz is unlikely to significantly impact ambrisentan exposure as CYP3A4 does not play a major role in ambrisentan metabolism.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aminophylline is a complex of theophylline and ethylenediamine and is given for its theophylline activity. Theophylline is mainly metabolized by CYP1A2.

Coadministration has not been studied and the nature of the interaction is difficult to predict. Amiodarone is metabolized by CYP2C8 and 3A4. Efavirenz is an inducer of CYP3A4, but in vitro data suggest that it inhibits CYP2C8. Amiodarone concentrations could potentially decrease due to induction of CYP3A4 or increase due to inhibition of CYP2C8. Close monitoring of the therapeutic effect is recommended. Amiodarone has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As efavirenz has the potential to increase amiodarone exposure, this interaction reflects the more cautious option.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amisulpride is weakly metabolized and is primarily eliminated renally. Amisulpride has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely as amitriptyline is metabolized predominantly by CYP2D6 and CYP2C19. Amitriptyline has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely as amphotericin is not appreciably metabolized and is eliminated to a large extent in the bile. Amphotericin B has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Ampicillin is predominantly eliminated unchanged via renal pathways.

Coadministration of efavirenz with medicinal products that alter gastric pH would not be expected to affect efavirenz absorption. Coadministration of an antacid containing aluminium hydroxide-magnesium hydroxide-simethicone (Maalox, 30 ml single dose) and efavirenz (400 mg single dose) did not alter the absorption of efavirenz. Coadministration with antacids containing calcium carbonate has not been studied. No dosage adjustment is recommended when efavirenz is given with antacids.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Thymoglobulins are cleared by the reticuloendothelial system.

Coadministration has not been studied. Apixaban is metabolized by CYP3A4 and to a lesser extent by CYP1A2, CYP2C8, CYP2C9 and CYP2C19. Efavirenz could potentially decrease apixaban exposure resulting in diminished efficacy.

Coadministration has not been studied. Apomorphine is metabolized by several pathways that include mainly glucuronidation and sulfation and to a lesser extent N-demethylation. Although some NNRTIs have the potential to induce glucuronidation, the clinical relevance of such an interaction is unknown considering the numerous pathways contributing to apomorphine metabolism. No a priori dosage adjustment is required. Apomorphine has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Argatroban undergoes metabolism in the liver via hydroxylation and aromatization. In vitro studies indicate that CYP3A4 plays a role in argatroban metabolism however, human drug-drug interactions studies suggest that metabolism via CYP3A4 is not a major elimination pathway in vivo. Erythromycin (a strong CYP3A4 inhibitor) had no effect on argatroban pharmacokinetics and pharmacodynamics and it is unlikely that efavirenz will significantly reduce argatroban exposure due to induction of CYP3A4.

Coadministration has not been studied. Aripiprazole is metabolized by CYP3A4 and CYP2D6. Efavirenz could potentially decrease aripiprazole concentrations. Monitor therapeutic effect and adjust aripiprazole dosage if needed. The European SmPC advises doubling the aripiprazole dose when given with potent inducers of CYP3A4, such as efavirenz. Aripiprazole has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration of efavirenz and artemeter/lumefantrine has been investigated in two studies. Both studies showed decreases in artemether exposure (51% and 79%), dihydroartemisinin exposure (46% and 75%) and lumefantrine exposure by (21% and 56%). Lumefantrine had no significant effect on efavirenz exposure in either study. Use with caution as decreased concentrations of artemether, dihydroartemisinin, or lumefantrine may result in a decrease of antimalarial efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely with vitamin C when given alone or in multivitamins. Ascorbic acid is oxidised to dehydroascorbic acid where some is metabolised to oxalic acid and the inactive ascorbate-2-sulphate. Large doses are rapidly excreted in the urine when in excess of the requirements of the body. There is therefore little potential for interaction with efavirenz via modulation of, or competition for metabolic pathways.

Coadministration has not been studied. Asenapine is metabolized by glucuronidation (UGT1A4) and oxidative metabolism (mainly CYP1A2, with minor contributions from CYP3A4 and CYP2D6). Efavirenz has been shown to induce UGT1A4 and CYP3A4 and could potentially decrease asenapine exposure. Monitor the clinical effect and increase dosage if needed. Asenapine has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

This interaction has not been studied. Based on the metabolic profiles of both drugs, there is little potential for pharmacokinetic interaction. Limited data suggest that asparaginase is likely to be eliminated by the reticuloendothelial system.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aspirin is rapidly deacetylated to salicylic acid and then further metabolized mainly by glucuronidation (by several UGT, major UGT1A6).

Coadministration has not been studied. Astemizole is metabolized by CYPs 2D6, 2J2 and 3A4. Efavirenz, an inducer of CYP3A4, could potentially decrease astemizole exposure. However, the European SPC (but no longer the US Prescribing Information) for efavirenz contraindicates coadministration due to potential serious and/or life-threatening adverse events such as cardiac arrhythmias citing competition for CYP3A4 by efavirenz as a potential mechanism for inhibition of astemizole metabolism. Coadministration should be avoided or used with caution. Astemizole has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered.

Coadministration with atazanavir alone is not recommended as efavirenz decreases atazanavir exposure. Coadministration of atazanavir (400 mg once daily) and efavirenz (600 mg once daily) decreased atazanavir AUC, Cmax and Cmin by 74%, 59% and 93%, respectively. Furthermore, a prolongation of the QT interval may occur with efavirenz treatment in carriers of CYP2B6*6/*6. The product label for atazanavir advises caution when prescribing atazanavir with medicinal products which have the potential to increase the QT interval. Efavirenz has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website.

Coadministration is not recommended. Coadministration of cobicistat (150 mg once daily) and efavirenz (600 mg single dose) had no significant effect on efavirenz (Cmax and AUC decreased by 13% and 7%, respectively). However, coadministration is expected to decrease cobicistat plasma concentrations and consequently those of atazanavir being boosted, leading to loss of therapeutic effect and possible development of resistance. The European SmPC and US Prescribing Information do not recommend coadministration of atazanavir/cobicistat with efavirenz. Furthermore, a prolongation of the QT interval may occur with efavirenz treatment in carriers of CYP2B6*6/*6. The product label for atazanavir advises caution when prescribing atazanavir with medicinal products which have the potential to increase the QT interval. Efavirenz has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website.

Coadministration has not been studied. The European product label for atazanavir does not recommend coadministration, but if the combination is required suggests to consider increasing atazanavir/ritonavir to 400/200 mg once daily with close clinical monitoring. Based on historical comparison, atazanavir AUC, Cmax and Cmin were unchanged with coadministration of atazanavir/ritonavir (400/200 mg once daily) and efavirenz (600 mg once daily). The US Prescribing Information suggests atazanavir/ritonavir 400/100 mg for treatment naive patients, but advises not to coadminister to treatment experienced patients. Coadministration of atazanavir/ritonavir (400/100 mg once daily) and efavirenz (600 mg once daily) had no effect on atazanavir AUC, increased Cmax by 17% and decreased Cmin by 42%. Furthermore, a prolongation of the QT interval may occur with efavirenz treatment in carriers of CYP2B6*6/*6. The product label for atazanavir advises caution when prescribing atazanavir with medicinal products which have the potential to increase the QT interval. Efavirenz has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as atenolol is mainly eliminated unchanged by the kidney, both by glomerular filtration and active secretion via the renal transporters OCT2 and MATE1.

Coadministration of atorvastatin (10 mg once daily) and efavirenz (600 mg once daily) decreased atorvastatin Cmax (14%), AUC (43%) and Cmin (69%). Total active drug (including metabolites) decreased by 15% (Cmax), 32% (AUC) and 48% (Cmin). There was no change in efavirenz Cmax, AUC or Cmin. Given the decrease in exposure of total active drug, an increase in atorvastatin dose might be needed in presence of efavirenz. Monitor lipid values and adjust the atorvastatin dose based on the clinical response.

Coadministration of atovaquone/proguanil (250/100 mg single dose) and efavirenz (600 mg once daily) decreased atovaquone AUC and Cmax by 75% and 44%. Proguanil AUC decreased by 44% but there was no change in Cmax. The clinical relevance of this interaction is unknown due to the lack of data on the minimal effective atovaquone plasma concentration in the setting of malaria prophylaxis. Concomitant administration of atovaquone/proguanil with efavirenz should be avoided whenever possible. If coadministration is judged necessary, consider taking atovaquone/proguanil with a high fat meal to increase its bioavailability and increase the dosage if required.

This interaction has not been studied. Based on the metabolism/elimination profiles of both drugs, there is little potential for interaction when atropine is used either systemically or as eye drops. Although metabolism of atropine is not fully elucidated, up to 50% is excreted unchanged via the kidneys. There is therefore little potential for clinically significant interactions with efavirenz via modulation of, or competition for metabolic pathways.

Coadministration has not been studied but is not recommended. Avanafil is primarily metabolized by CYP3A4 and concentrations (and efficacy) may decrease due to induction of CYP3A4 by efavirenz.

Coadministration of azithromycin (600 mg single dose) with efavirenz (400 mg once daily) increased azithromycin Cmax by 22%, but had no effect on azithromycin AUC or efavirenz Cmax, AUC or Cmin. No dosage adjustment is necessary. Azithromycin has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Basiliximab is a monoclonal IgG antibody. Elimination is similar to endogenous IgG and occurs primarily via proteolytic catabolism throughout the body.

Coadministration of bedaquiline (400 mg single dose) and efavirenz (600 mg once daily) to 33 HIV/TB-negative subjects decreased bedaquiline AUC by 18% and had no effect on Cmax. Efavirenz pharmacokinetics were similar to historical data from HIV-infected subjects. A reduction in bedaquiline exposure may result in loss of activity and coadministration is not recommended. There are no clinical data on the safety and efficacy of bedaquiline when co-administered with antiretroviral agents. Bedaquiline has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Belatacept is a protein that undergoes non-CYP mediated metabolism in the liver.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Benazepril is rapidly hydrolyzed to its active metabolite benazeprilat which is eliminated predominantly renally.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Bendroflumethiazide is mainly eliminated by hepatic metabolism (70%), although the exact pathway is not known. It is unlikely that CYP enzymes are involved in this process and no transporter interactions have been described. There is no evidence that bendroflumethiazide inhibits or induces CYP450 enzymes. Bendroflumethiazide has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Benznidazole undergoes non-CYP mediated metabolism and partly CYP mediated metabolism. Renal elimination of unchanged benznidazole appears to be minimal and there is little potential for an interaction via competition for renal elimination pathways.

Coadministration has not been studied and is contraindicated. Bepridil is metabolised mainly by CYP2D6 and to a lesser extent by CYP3A4. Efavirenz, an inducer of CYP3A4, could potentially decrease bepridil exposure. However, the European SPC (but no longer the US Prescribing Information) for efavirenz contraindicates coadministration due to potential serious and/or life-threatening adverse events such as cardiac arrhythmias citing competition for CYP3A4 by efavirenz as a potential mechanism for inhibition of bepridil metabolism. Coadministration should be avoided or used with caution. Bepridil has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As efavirenz has the potential to increase bepridil exposure, this interaction reflects the more cautious option. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Betahistine is metabolized by monoamine oxidase. Betahistine does not induce or inhibit CYP450 enzymes.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Betrixaban is largely eliminated unchanged through biliary secretion via P-gp. In vitro data indicate that efavirenz does not induce or inhibit P-gp in the range of clinical concentrations. Betrixaban has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant pharmacokinetic interaction is unlikely as bevacizumab is metabolized via proteolytic catabolism.

Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and should not be administered with other antiretroviral products. In addition, efavirenz is an inducer of CYP3A4 and is expected to decrease bictegravir exposure which may result in loss of therapeutic effect and development of resistance. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Although limited human data suggest biperiden undergoes hydroxylation in the liver, there are no known or documented interactions with other drugs that have an effect on metabolism or transport.

Coadministration has not been studied. Bisoprolol is partly metabolized by CYP3A4 and CYP2D6 and partly eliminated unchanged in the urine. Efavirenz could potentially decrease bisoprolol exposure, although to a moderate extent. No a priori dosage adjustment is required.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. No effect on efavirenz is expected as black cohosh had no significant effect on the pharmacokinetics of midazolam (a CYP3A4 substrate) or digoxin (a P-gp substrate).

Coadministration has not been studied. Bortezomib is mainly metabolized by CYP3A4 and 2C19 and to a lesser extent by CYPs 1A2, 2D6 and 2C9. Efavirenz could potentially decrease bortezomib concentrations and thus potentially reduce the clinical effect. Bortezomib has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied. Bosentan is a substrate and inducer of CYP3A4 and CYP2C9. Efavirenz, a CYP3A4 inducer, could potentially decrease bosentan exposure and the clinical effect of bosentan should be monitored.

Coadministration has not been studied. Bromazepam undergoes oxidative biotransformation. Drug-drug interaction studies indicate that CYP3A4 plays a minor role in bromazepam metabolism, but other cytochromes such as CYP2D6 or CYP1A2 may play a role. Bromazepam does not inhibit CYP3A4. Efavirenz could potentially decrease bromazepam concentrations although to a moderate extent. No a priori dosage adjustment is required.

Coadministration of efavirenz (600 mg once daily) significantly decreased buprenorphine AUC by 50% in HIV- subjects; however, no subject developed an opioid withdrawal syndrome. Efavirenz concentrations remained in the therapeutic range. Dose adjustments are unlikely to be required, but consider monitoring for withdrawal symptoms. Buprenorphine has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration of efavirenz and a single dose of bupropion decreased bupropion AUC (55%) and Cmax (34%). The AUC of an active metabolite, hydroxybupropion, was unchanged, but Cmax increased by 50% and half life decreased from 24 h to 16 h. The 55% decrease in bupropion exposure may be clinically significant. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. No dose adjustment is necessary for efavirenz.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Canagliflozin is primarily metabolised by UGT1A9 and UGT2B4 and efavirenz has been shown to inhibit UGT1A9 in vitro. The clinical relevance of this inhibition is unknown but a significant interaction is unlikely as UGT1A9 contributes only partly to canagliflozin metabolism.

Coadministration has not been studied. Cannabidiol is mainly metabolized by CYP3A4 and CYP2C19 and is unlikely to significantly inhibit or induce CYP2B6 and therefore no effect is expected on efavirenz. However, efavirenz induces both CYP3A4 and CYP2C19, which may decrease cannabidiol exposure. A careful dose increase of cannabidiol might be needed. In addition, a careful titration might be needed within the two weeks following cessation of efavirenz.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Capecitabine is activated by sequential enzyme reactions to fluorouracil. Capecitabine has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Capreomycin is predominantly excreted via the kidneys as unchanged drug.

Coadministration of carbamazepine (400 mg once daily) and efavirenz (600 mg once daily) decreased carbamazepine Cmax (20%), AUC (27%) and Cmin (35%); carbamazepine epoxide Cmin decreased by 13%, but there was no change in Cmax or AUC. Efavirenz Cmax, AUC and Cmin decreased by 21%, 36% and 47%, respectively. There are no data from coadministration of higher doses of either drug. No dose recommendation can be made and alternative anticonvulsant treatment should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carboplatin is excreted primarily by renal glomerular filtration and therefore there is little potential for a pharmacokinetic interaction.

Coadministration has not been studied. Carvedilol undergoes glucuronidation and additional metabolism via CYP2D6 and to a lesser extent CYPs 2C9 and 1A2. Efavirenz could potentially increase carvedilol concentrations via CYP2C9 inhibition or decrease carvedilol concentrations via induction of glucuronidation (UGT1A1). The net effect on carvedilol concentrations is difficult to predict but likely to be moderate in magnitude. No a priori dosage adjustment is required.

Coadministration has not been studied. Cat’s claw is a strong inhibitor of CYP3A4 in vitro but has also been shown to induce CYP3A4 activity in vitro. Increased concentrations of atazanavir, saquinavir and ritonavir were reported in a patient receiving Cat’s claw. Similar increases would be expected for other CYP3A4 substrates, such as efavirenz. Coadministration should be avoided.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Cefalexin is predominantly eliminated unchanged via the kidneys.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Cefazolin is predominantly eliminated unchanged via the kidneys.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Approximately 50% of the absorbed dose is excreted unchanged in the urine; there is no evidence of metabolism of cefixime in vivo. In vitro studies have shown that cefixime does not inhibit/induce major cytochrome P450 metabolic enzymes, and would not be expected to cause clinically significant interactions with other drugs, which are metabolized by CYP450 enzymes.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Cefotaxime is predominantly eliminated unchanged via the kidneys.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Ceftazidime is predominantly eliminated unchanged via renal glomerular filtration.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Ceftriaxone is eliminated mainly as unchanged drug; approximately 60% of the dose being excreted in the urine, almost exclusively by glomerular filtration, and the remainder via the biliary and intestinal tracts.

Coadministration of a single dose of cetirizine (10 mg) with efavirenz (600 mg) decreased cetirizine Cmax by 24% but caused no change in AUC. Efavirenz Cmax, AUC and Cmin were unaltered. No dosage adjustment is necessary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cetuximab is a monoclonal IgG antibody. Elimination is similar to endogenous IgG and occurs primarily via proteolytic catabolism throughout the body.

Coadministration has not been studied. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYP3A4. Coadministration of chloramphenicol may potentially increase levels of efavirenz via this mechanism, increasing the risk of adverse events. The clinical significance of this interaction is unknown. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the concentrations used are unlikely to cause a clinically significant interaction.

Coadministration has not been studied. Chloroquine undergoes CYP mediated metabolism by CYPs 2C8, 3A4 and 2D6, and is also eliminated unchanged via the kidney (50%). Efavirenz could potentially increase chloroquine exposure (inhibition CYP2C8) or decrease chloroquine exposure (induction CYP3A4) although to a moderate extent due to the multiple elimination pathways. No dosage adjustment is recommended but monitor toxicity and efficacy of the antimalarial. Chloroquine has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlorphenamine is predominantly metabolized in the liver via CYP2D6.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Chlorpromazine is metabolized mainly by CYP2D6, but also CYP1A2. Chlorpromazine has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ciclesonide is a pro-drug activated by esterases in the lungs to des-ciclesonide which then undergoes CYP3A4-mediated metabolism. Efavirenz is unlikely to have clinically significant effect on ciclesonide metabolism.

Coadministration may decrease ciclosporin concentration. Case reports have shown efavirenz concentrations to be similar to historical data, but ciclosporin concentrations to be lower when coadministered. Close monitoring is recommended with appropriate dose adjustment of ciclosporin.

Co-administration of efavirenz with medicinal products that alter gastric pH would not be expected to affect efavirenz absorption. Cimetidine has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ciprofloxacin is primarily eliminated unchanged by the kidneys by glomerular filtration and tubular secretion via OAT3. It is also metabolized and partially cleared through the bile and intestine. Ciprofloxacin has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied. Cisapride is metabolised mainly by CYP3A4. Efavirenz, an inducer of CYP3A4, could potentially decrease cisapride exposure. However, the European SmPC (but no longer the US Prescribing Information) for efavirenz contraindicates coadministration due to potential serious and/or life-threatening adverse events such as cardiac arrhythmias citing competition for CYP3A4 by efavirenz as a potential mechanism for inhibition of cisapride metabolism. Coadministration should be avoided or used with caution. Cisapride has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered.

Coadministration has not been studied. Citalopram is metabolized by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Efavirenz could potentially decrease citalopram concentrations, although to a moderate extent. No a priori dosage adjustment is recommended. Citalopram has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration of clarithromycin (500 mg every 12 hours) and efavirenz (400 mg once daily) decreased clarithromycin Cmax (26%), AUC (39%) and Cmin (53%) and increased 14-OH clarithromycin Cmax (49%), AUC (34%) and Cmin (26%). Efavirenz Cmax increased by 11%, but AUC and Cmin were unaltered. The clinical significance of the decreases in clarithromycin is unknown. In uninfected individuals, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of efavirenz is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Clarithromycin has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied. Clindamycin is metabolized by CYP3A4 and some metabolites have antibacterial activity. Efavirenz could potentially decrease clindamycin exposure which could impact efficacy.

Coadministration has not been studied. Clobazam is metabolised by CYP3A4 (major) and CYP2B6 and CYP2C19 (minor) to the active metabolite N-desmethylclobazam, which is metabolised by CYP2C19. Efavirenz induces CYP3A4, CYP2B6 and CYP2C19 which may decrease clobazam exposure. Monitor for anticonvulsant effect and adjust clobazam dosage if needed. Clobazam is unlikely to affect efavirenz.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Clofazimine is largely excreted unchanged in the faeces, both as unabsorbed drug and via biliary excretion. Clofazimine has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. In vitro studies have suggested that CYP3A4 does not affect conversion of clomifene to its active metabolite, and that this transformation is likely to be mediated via CYP2D6. There is therefore little potential for efavirenz to affect this metabolic pathway.

Coadministration has not been studied. Clomipramine is metabolized by CYPs 3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. In addition, clomipramine and desmethylclomipramine are metabolized by CYP2D6. Efavirenz could potentially decrease clomipramine concentrations but increase the formation of the active metabolite. The clinical relevance is unknown. Monitor clinical effect. Clomopramine has a conditional of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied. Clopidogrel is a prodrug and is converted to its active metabolites via CYPs 3A4, 2B6, 2C19 and 1A2. Recurrent drug-eluting in-stent restenosis was described in a HIV patient treated concurrently with etravirine and clopidogrel (possibly due to inhibition of CYP2C19 and thereby decreased conversion of clopidogrel to its active metabolite). Since efavirenz is an inhibitor of CYP2C19, a similar effect cannot be excluded, therefore coadministration is not recommended. Furthermore, clopidogrel is an inhibitor of CYP2B6 and has been shown to increase efavirenz exposure (17% increase in AUC, 31% increase in Cmax).

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Cloxacillin is metabolised to a limited extent, and the unchanged drug and metabolites are excreted in the urine by glomerular filtration and renal tubular secretion.

Coadministration has not been studied. Clozapine is metabolized by CYPs 1A2, 2C19 and 3A4. Efavirenz may decrease clozapine concentrations, leading to reduced efficacy. No a priori dosage adjustment is recommended, but monitor therapeutic effect.Clozapine has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied. Cocaine is metabolized by several pathways, with metabolism to norcocaine by CYP3A4 being less than 10% of the overall metabolic clearance. Norcocaine is further transformed to a hepatotoxic metabolite. Efavirenz could potentially increase the serum level of the hepatotoxic metabolite. Cocaine has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but efavirenz could potentially decrease codeine exposure and increase the conversion to norcodeine, a metabolite that does not have analgesic properties. Codeine is converted to morphine (active metabolite) via CYP2D6 and inactivated to codeine-6-glucuronide via glucuronidation (major pathway) as well as to norcodeine via CYP3A4. No a priori dosage adjustment is recommended but monitoring the analgesic effect may be considered.

Colchicine is a substrate of CYP3A4 and P-gp. Coadministration with efavirenz (an inducer of CYP3A4) has not been studied but may reduce colchicine concentrations. The clinical relevance of this potential interaction is unknown.

Coadministration has not been studied. No interaction is expected with vitamin D when given with calcium or in a multivitamin preparation. Metabolism of vitamin D to active metabolites occurs in the liver and kidneys, and is thought to involve CYP3A4 and CYP24A1. In vitro studies have shown rifampicin (an enzyme inducer) increased metabolism of vitamin D and introduction of 6',7'-dihydroxybergamottin (a CYP3A4 inhibitor in grapefruit juice) reversed the effects of rifampicin on vitamin D clearance. These studies suggest that inducers of CYP3A4 (such as efavirenz) may increase metabolism of vitamin D and therefore reduce its effect. Various observational studies have reported increased risk for vitamin D deficiency in patients taking efavirenz containing regimens. However, no effect of efavirenz on the response to vitamin D supplementation was observed in a clinical study nor found in a PK modelling study.

Coadministration has not been studied. Piperine, a constituent of piper cubeba was shown to inhibit nevirapine metabolism, increasing nevirapine AUC and Cmin by 170% and 146%, respectively, however, the treatments were well tolerated. No a priori dose adjustment of efavirenz is required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely with cyanocobalamin when given alone or in multivitamins. Cyanocobalamin undergoes enterohepatic recycling and is excreted almost entirely in the urine.

Coadministration has not been studied and is difficult to predict. Cyclophosphamide is activated to 4-hydroxycyclophosphamide by CYPs 2B6 (major), 2C9, and 3A4. The inactivation pathway (minor, 10%) to the neurotoxic chloroacetaldehyde metabolite is mainly by CYP3A4. Efavirenz could either potentially increase the conversion to the active metabolite or increase the amount of drug converted to the inactive neurotoxic metabolite. Careful monitoring of cyclophosphamide efficacy and toxicity is recommended.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Cycloserine is predominantly excreted renally via glomerular filtration.

Coadministration has not been studied. Cyproterone acetate is metabolized by CYP3A4 and concentrations may decrease due to induction of CYP3A4 by efavirenz. A dose adjustment of cyproterone may be required.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dapagliflozin is primarily metabolised by UGT1A9. Efavirenz has been shown to inhibit this enzyme in vitro, but a clinically relevant effect is not expected as coadministration of dapagliflozin with mefenamic acid (which is also an inhibitor of UGT1A9), increased dapagliflozin systemic exposure by 55%, but had no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended.

Coadministration has not been studied. Darifenacin is metabolized by CYP3A4 and CYP2D6 and could potentially decrease darifenacin exposure due to induction of CYP3A4. Monitor the effect.

Coadministration has not been studied and is not recommended because it is expected to decrease darunavir/cobicistat exposure which may result in loss of therapeutic effect and development of resistance to darunavir. 

Symtuza (darunavir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. Furthermore, efavirenz is expected to decrease darunavir/cobicistat exposure which may result in loss of therapeutic effect and development of resistance to darunavir.

Efavirenz in combination with darunavir/ritonavir 800/100 mg once daily may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used. Coadministration of efavirenz (600 mg once daily) and darunavir/ritonavir at a dose lower than that licensed (300/100 mg twice daily) decreased darunavir Cmax (15%), AUC (13%) and Cmin (31%). Efavirenz Cmax, AUC and Cmin increased by 15%, 21% and 17%, respectively. The clinical significance has not been established. Coadministration of efavirenz and once daily darunavir/ritonavir (900/100 mg once daily) decreased darunavir AUC (14%), Cmax (8%) and Ctrough (57%). Ritonavir AUC and Ctrough were significantly reduced, but there was no significant effect on efavirenz AUC, Cmax or Ctrough. The combination should be used with caution. Clinical monitoring for CNS toxicity associated with increased efavirenz exposure may be indicated.

This interaction has not been studied. Dasatinib is metabolized by CYP3A4 and coadministration could potentially decrease dasatinib concentrations. Consider alternatives, but if coadministration is unavoidable, monitoring of dasatinib therapeutic effect is recommended. Dasatinib has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. An in vitro study has shown that daunorubicin was able to inhibit metabolism mediated by CYP3A4, but was unlikely to cause clinically significant drug interactions via this mechanism. However, damage to the myocardium is one of the major risks of daunorubicin treatment and may include dose-independent supraventricular arrhythmias (sinus tachycardia, premature ventricular contractions, AV-block) and/or non-specific ECG abnormalities. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

No clinically significant interaction was observed when efavirenz (600 mg daily) and delamanid (100 mg twice daily) were coadministered. There was no change in delamanid Cmax and a 3% decrease in AUC; efavirenz Cmax and AUC both decreased by 6%. However, the overall incidence of adverse effects was higher during concomitant dosing with delamanid and efavirenz compared to either medication alone. A higher rate of neuropsychiatric adverse effects (e.g., euphoric mood and abnormal dreams) was observed with delamanid plus efavirenz compared to either drug alone, but no subject discontinued the study because of neuropsychiatric events or had serious neuropsychiatric adverse effects. Delamanid has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely as desipramine is metabolized by CYP2D6. Desipramine has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration is expected to reduce the contraceptive efficacy of desogestrel and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives. Desogestrel is a prodrug that requires activation to etonogestrel. Activation to etonogestrel is by CYP2C9 (and possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Coadministration of efavirenz and desogestrel was administered as a COC to HIV+ women (n=16). An increased risk of contraceptive failure (evaluated by measuring serum progesterone) was observed and efavirenz C12 concentrations decreased by 22% and were below the target of 1000 ng/ml in 3/16 subjects. When compared to values obtained from administration without efavirenz to HIV-negative women (n=14), etonogestrel trough concentrations decreased by 61% in HIV+ women administered desogestrel/ethinylestradiol and efavirenz (n=16). In addition, efavirenz has been shown to reduce the exposure of progestogens and unintended pregnancy have been observed when used with levonorgestrel or etonogestrel containing implants.

Coadministration with a desogestrel-containing progestogen-only pill (POP) has not been studied but is expected to reduce the contraceptive efficacy of desogestrel and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives. Desogestrel is a prodrug that requires activation to etonogestrel. Activation to etonogestrel is by CYP2C9 (and possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Efavirenz has been shown to reduce the exposure of progestogens and unintended pregnancies have been observed when used with levonorgestrel or etonogestrel containing implants. In addition, an increased risk of contraceptive failure (evaluated by measuring serum progesterone) was observed when efavirenz was coadministered with a combined oral contraceptive containing desogestrel and ethinylestradiol.

Coadministration has not been studied. Dexmedetomidine undergoes extensive hepatic biostranformation through direct glucuronidation (mainly via UGT1A4, 2B10) and cytochrome P450 (mainly 2A6). Efavirenz has been shown to decrease exposure of another UGT1A4 substrate (posaconazole) and could potentially decrease dexmedetomidine concentrations. The clinical relevance of this interaction is unknown. Dexmedetomidine has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

This interaction has not been studied. Based on limited data concerning the metabolism/elimination and toxicity profile of diethylcarbamazine, there is little potential for interaction with efavirenz.

Coadministration has not been studied and the net effect of this interaction is difficult to predict. Dihydrocodeine is converted to dihydromorphine (active metabolite) via CYP2D6, to dihydrocodeine-6-glucuronide via UGT2B7 (major pathway) and to nordihydrocodeine via CYP3A4. The analgesic effect appears to be primarily due to the parent compound. Efavirenz could potentially increase the formation of nordihydrocodeine (via induction CYP3A4) and reduce the conversion to dihydrocodeine-6-glucuronide (via competition or inhibition of UGT2B7). No a priori dose adjustment is required, but monitoring for analgesic effect and for signs of opiate toxicity may be required as clinically indicated.

Coadministration has not been studied. Dihydroergotamine is a substrate and inhibitor of CYP3A4. Efavirenz, an inducer of CYP3A4, could potentially decrease dihydroergotamine exposure. However, coadministration is contraindicated in the European SmPC (but no longer the US Prescribing Information) for efavirenz due to potential serious and/or life-threatening adverse events, such as acute ergot toxicity, citing competition for CYP3A4 by efavirenz as a potential mechanism for inhibition of dihydroergotamine metabolism. Coadministration should be avoided or used with caution.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Diloxanide furoate is largely hydrolysed under the combined action of bacterial and gut esterases and consequently glucuronidated. No clinically-significant drug interactions are known, and significant interactions with antiretrovirals are unlikely.

Coadministration of diltiazem (240 mg once daily) and efavirenz (600 mg for 14 days) decreased diltiazem Cmax (60%), AUC (69%) and Cmin (63%). Reductions in Cmax, AUC and Cmin were also observed for the metabolites desacetyl diltiazem (64%, 75%, 62%, respectively) and N-monodesmethyl diltiazem (28%, 37%, 37%, respectively). Efavirenz Cmax, AUC and Cmin increased by 16%, 11% and 13%, respectively. Diltiazem dose adjustments should be guided by clinical response but no dose adjustment of efavirenz is necessary. Diltiazem has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diphenhydramine is mainly metabolized by CYP2D6 which is not inhibited or induced by efavirenz. Diphenhydramine has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. Efavirenz induces UGT1A1 and could potentially decrease dipyridamole exposure, thereby reducing the antiplatelet effect.

Coadministration has not been studied but efavirenz may decrease disopyramide concentrations. Caution is warranted and therapeutic concentration monitoring is recommended for the antiarrhythmic if available. Disopyramide has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration of disulfiram (62.5 mg or 250 mg once daily) with efavirenz (600 mg once daily) had no significant effect on efavirenz pharmacokinetics at either dose. Disulfiram is converted to an active metabolite by CYP3A4 and UGT. Coadministration with efavirenz (an inducer of CYP3A4) was associated with a moderate increase in disulfiram‐associated inhibition of ALDH activity. No dose adjustments for efavirenz or disulfiram are necessary.

Coadministration with CYP3A inducers (i.e. efavirenz, etravirine, nevirapine) may decrease concentrations of docetaxel.

Coadministration has not been studied. Dofetilide is metabolized to a small degree by CYP3A4 and therefore efavirenz could potentially decrease dofetilide exposure. Dose adjustment may be needed and should be done with caution due to the narrow therapeutic index of dofetilide. Dofetilide has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dolasetron is converted by carbonyl reductase to its active metabolite, hydrodolasetron, which is mainly glucuronidated (60%) and metabolized by CYP2D6 (10-20%) and CYP3A4 (<1%). Dolasetron has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration decreases dolutegravir exposure and a dose increase of dolutegravir is recommended. Coadministration of efavirenz (600 mg once daily) and dolutegravir (50 mg once daily) decreased dolutegravir Cmax, AUC and Ctrough by 39%, 57% and 75%, respectively. When compared to historical data, dolutegravir did not appear to affect the pharmacokinetics of efavirenz. In treatment-naïve or INSTI-naïve patients, a dose adjustment of dolutegravir to 50 mg twice daily is recommended. Alternative combinations that do not include metabolic inducers should be considered where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. Switching from efavirenz to dolutegravir decreased dolutegravir Ctrough by 60% and 85% in CYP2B6 normal and slow/intermediate metabolizers, respectively. CYP2B6 slow metabolizers experienced more prolonged subtherapeutic dolutegravir concentrations. When switching from efavirenz to dolutegravir, consider administering dolutegravir 50 mg twice daily for 2 weeks  in patients who are not virologically suppressed, or who have resistance to efavirenz, or in patients who are CYP2B6 slow metabolizers.

Triumeq (dolutegravir, abacavir, lamivudine) is indicated for use as a complete regimen for the treatment of HIV-1 infection and coadministration with efavirenz is expected to decrease dolutegravir exposure. The European product label for Triumeq does not recommend coadministration with efavirenz. However, the US product label for Triumeq recommends that an additional dolutegravir 50 mg tablet, separated by 12 hours from Triumeq, should be taken. Coadministration of efavirenz (600 mg once daily) and dolutegravir (50 mg once daily) decreased dolutegravir Cmax, AUC and Ctrough by 39%, 57% and 75%, respectively. When compared to historical data, dolutegravir did not appear to affect the pharmacokinetics of efavirenz. Coadministration of lamivudine (150 mg twice daily) with efavirenz (600 mg once daily) increased lamivudine Cmin by 265%, but had no effect on lamivudine Cmax or AUC. Abacavir had no effect on efavirenz pharmacokinetics when abacavir, efavirenz and indinavir were coadministered. Switching from efavirenz to dolutegravir decreased dolutegravir Ctrough by 60% and 85% in CYP2B6 normal and slow/intermediate metabolizers, respectively. CYP2B6 slow metabolizers experienced more prolonged subtherapeutic dolutegravir concentrations. When switching from efavirenz to dolutegravir, consider administering dolutegravir 50 mg twice daily for 2 weeks (as an additional 50 mg tablet of dolutegravir administered approximately 12 hours after Triumeq) in patients who are not virologically suppressed, or who have resistance to efavirenz, or in patients who are CYP2B6 slow metabolizers.

Dovato (dolutegravir/lamivudine) is indicated for use as a complete regimen for the treatment of HIV 1 infection. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration with efavirenz would be possible from a pharmacokinetic standpoint. The European product label for Dovato recommends an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Dovato, during coadministration with efavirenz. Coadministration of dolutegravir and efavirenz decreased dolutegravir AUC, Cmax and Cmin by 57%, 39% and 75%, respectively. There was no change in efavirenz when compared to historical controls. Coadministration of lamivudine (150 mg twice daily) with efavirenz (600 mg once daily) increased lamivudine Cmin by 265%, but had no effect on lamivudine Cmax or AUC. Switching from efavirenz to dolutegravir decreased dolutegravir Ctrough by 60% and 85% in CYP2B6 normal and slow/intermediate metabolizers, respectively. CYP2B6 slow metabolizers experienced more prolonged subtherapeutic dolutegravir concentrations. When switching from efavirenz to dolutegravir, consider administering dolutegravir 50 mg twice daily for 2 weeks (as an additional 50 mg tablet of dolutegravir administered approximately 12 hours after Dovato) in patients who are not virologically suppressed, or who have resistance to efavirenz, or in patients who are CYP2B6 slow metabolizers.

Juluca (dolutegravir/rilpivirine) is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. Furthermore, coadministration may decrease dolutegravir and rilpivirine concentrations and combining two NNRTIs (i.e., efavirenz and rilpivirine) has not been shown to be beneficial. Coadministration of efavirenz (600 mg once daily) and dolutegravir (50 mg once daily) decreased dolutegravir Cmax, AUC and Ctrough by 39%, 57% and 75%, respectively. When compared to historical data, dolutegravir did not appear to affect the pharmacokinetics of efavirenz. Furthermore, rilpivirine has been associated with prolongation of the QTc interval at supra-therapeutic doses but these are unlikely to occur during coadministration with efavirenz. However, the product labels for rilpivirine indicate that rilpivirine should be used with caution in combination with drugs with a known risk of Torsade de Pointes. Efavirenz has a possible risk of QTc prolongation and/or TdP on the CredibleMeds.org website.

Coadministration has not been studied. Domperidone is metabolised mainly by CYP3A4. Efavirenz, an inducer of CYP3A4, could potentially decrease domperidone exposure. A dose adjustment may be needed. Domperidone has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs there is little potential for interaction. Dopamine is metabolised in the liver, kidneys, and plasma by monoamine oxidase (MAO) and catechol-O-methyltransferase to inactive compounds. About 25% of a dose of dopamine is metabolised to norepinephrine within the adrenergic nerve terminals. There is little potential for dopamine to affect disposition of antiretrovirals, or to be affected if co-administered with antiretrovirals.

Doravirine should not be administered with another NNRTI. Furthermore, coadministration is expected to decrease doravirine exposure. Note: switching from efavirenz to doravirine resulted in a transient decrease in doravirine exposure (doravirine AUC, Cmax and Cmin decreased by 52%, 35% and 85%, respectively, one day after stopping efavirenz and by 32%, 14% and 50%, respectively, 14 days after stopping efavirenz). Dose adjustment may not be necessary to maintain therapeutic concentrations of at least one drug during switching in a virologically suppressed individual.

Delstrigo (doravirine, lamivudine, tenofovir-DF) is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products. Note: switching from efavirenz to doravirine resulted in a transient decrease in doravirine exposure (doravirine AUC, Cmax and Cmin decreased by 52%, 35% and 85%, respectively, one day after stopping efavirenz and by 32%, 14% and 50%, respectively, 14 days after stopping efavirenz). Dose adjustment may not be necessary to maintain therapeutic concentrations of at least one drug during switching in a virologically suppressed individual.

Coadministration has not been studied. Doxazosin is metabolised mainly by CYP3A4 and concentrations may decrease due to induction of CYP3A4 by efavirenz. Monitor clinical effect. For the treatment of benign prostatic hyperplasia (BPH), depending on the patient’s urodynamics and BPH symptomatology, doxazosin dose may be increased from 1 mg/day to 2 mg/day and thereafter 4 mg/day with a maximum recommended dose of 8 mg/day. The recommended titration interval is 1-2 weeks with routine blood pressure monitoring.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Doxepin is metabolized mainly by CYP2C19 to nordoxepin, an active metabolite. In addition, doxepin and nordoxepin are metabolized by CYP2D6. Doxepin has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on the metabolism/elimination and toxicity profiles of both drugs there is little potential for a pharmacokinetic interaction. Doxorubicin is mainly eliminated in the bile by P-gp and BCRP and does not undergo CYP-mediated metabolism. (Some product labels suggest doxorubicin is a substrate of CYP3A4, however, there are no strong data supporting the role of CYP3A4 in doxorubicin metabolism.) However, possible cardiac toxicities (ECG abnormalities and sometimes arrhythmias) have been reported with doxorubicin. Use with caution. ECG monitoring is recommended. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration with a drospirenone-containing combined oral contraceptive (COC) has not been studied but is expected to reduce the contraceptive efficacy of drospirenone/ethinylestradiol and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives. Drospirenone is metabolised in part by CYP3A4. Efavirenz has been shown to reduce the exposure of progestogens and unintended pregnancies have been observed when used with levonorgestrel or etonogestrel containing implants. In addition, coadministration of efavirenz and a desogestrel-containing COC decreased etonogestrel exposure by 61% and an increased risk of contraceptive failure (evaluated by measuring serum progesterone) was observed.

Coadministration with drospirenone as hormone replacement therapy (HRT) has not been studied. CYP3A4 contributes to drospirenone metabolism. Coadministration is predicted to decrease drospirenone exposure. In addition, exposure of estrogens/estradiol administered as part of HRT may also decrease. Monitor for signs of hormone deficiency.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as dulaglutide is presumed to be degraded by general protein catabolism pathways. Dulaglutide delays gastric emptying and has the potential to impact the rate of absorption of concomitantly administered oral medicinal products. However, interaction studies did not result in any clinically relevant effects and no dose adjustment of comedications is recommended.

Coadministration with dydrogesterone as hormone replacement therapy (HRT) has not been studied. Dydrogesterone is metabolized to dihydrodydrogesterone (possibly via CYP3A4). Coadministration is predicted to decrease dydrogesterone exposure. In addition, exposure of estrogens/estradiol administered as part of HRT may also decrease. Monitor for signs of hormone deficiency.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Edoxaban is a substrate for P-gp and in vitro data indicate that efavirenz does not induce or inhibit P-glycoprotein in the range of clinical concentrations.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Eflornithine is predominantly eliminated unchanged via the kidneys.

Coadministration is contraindicated. The effect of efavirenz, a moderate inducer of CYP3A/P-gp, on grazoprevir and elbasvir steady-state pharmacokinetics was evaluated in separate studies and decreased elbasvir and grazoprevir AUCs by 54% and 83%, respectively. This may lead to reduced therapeutic effect of elbasvir/grazoprevir.

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products. Genvoya should not be used in conjunction with non-nucleoside reverse transcriptase inhibitors due to potential drug-drug interactions including altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir and/or the coadministered antiretroviral products. When switching patients who are CYP2B6 poor metabolisers from an efavirenz containing regimen to Genvoya, there is a potential for lower elvitegravir exposure due to prolonged CYP3A induction by efavirenz. Monitoring of viral load is recommended for these patients during the first month after switching treatment to Genvoya.

Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir-DF) is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products. Stribild should not be used in conjunction with non-nucleoside reverse transcriptase inhibitors due to potential drug-drug interactions including altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the coadministered antiretroviral products. When switching patients who are CYP2B6 poor metabolisers from an efavirenz containing regimen to Stribild, there is a potential for lower elvitegravir exposure due to prolonged CYP3A induction by efavirenz. Monitoring of viral load is recommended for these patients during the first month after switching treatment to Stribild.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Empagliflozin is mainly glucuronidated by UGTs 1A3, 1A8, 1A9 and 2B7. It is a substrate of P-gp and BCRP, and also a substrate of the renal transporter OAT3 and the hepatic transporters OATP1B1 and OATP1B3. Empagliflozin does not inhibit or induce CYPs and does not inhibit UGTs. There is no evidence that efavirenz induces the UGTs involved in empagliflozin metabolism or interacts to a significant level with the transporters involved in empagliflozin disposition.

Based on the results of in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low. The coadministration of emtricitabine, didanosine and efavirenz was studied in 9 treatment naive, HIV+ patients. When compared to historical data for each drug alone, the pharmacokinetics of emtricitabine were not affected, didanosine AUC and Cmax were higher than expected and efavirenz Cmax, Cmin and AUC were lower than expected. However, efavirenz concentrations may have been underestimated as dosing was delayed by 12 hours for ease of sampling.

Coadministration of efavirenz (600 mg once daily) and emtricitabine/tenofovir alafenamide (200/40 mg once daily decreased tenofovir alafenamide AUC and Cmax by 14% and 22%; tenofovir AUC and Cmax decreased by 20% and 24% (n=11). The recommended dose of Descovy for HIV-1 treatment is 200/25 mg once daily.

Coadministration with emtricitabine/tenofovir-DF has not been studied. Based on metabolism and clearance a clinically significant interaction with emtricitabine is unlikely. Coadministration of emtricitabine and efavirenz in the presence of didanosine was studied in 9 treatment naive, HIV+ patients. When compared to historical data for each drug alone, the pharmacokinetics of emtricitabine were not affected, didanosine AUC and Cmax were higher than expected and efavirenz Cmax, Cmin and AUC were lower than expected. However, efavirenz concentrations may have been underestimated as dosing was delayed by 12 hours for ease of sampling. Coadministration of tenofovir-DF and efavirenz decreased efavirenz AUC and Cmax both by 4%; tenofovir AUC decreased by 1% and Cmax increased by 7%. No dosage adjustment of efavirenz is necessary.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Ephedrine is predominantly eliminated unchanged via the kidneys.

Coadministration has not been studied. Epirubicin is glucuronidated by UGT2B7. In vitro data indicate that efavirenz inhibits UGT2B7 and could potentially increase epirubicin concentrations, thus increasing the risk of side effects. Epirubicin has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied. Eplerenone is metabolized by CYP3A4. Efavirenz could potentially decrease eplerenone exposure due to induction of CYP3A4 and thereby reduce the efficacy of eplerenone.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Epoprostenol is rapidly hydrolyzed in the blood.

Coadministration has not been studied. Ergometrine is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, could potentially decrease ergometrine exposure. However, coadministration is contraindicated in the European SmPC (but no longer the US Prescribing Information) for efavirenz due to potential serious and/or life-threatening adverse events, such as acute ergot toxicity, citing competition for CYP3A4 by efavirenz as a potential mechanism for inhibition of ergometrine metabolism. Coadministration should be avoided or used with caution.

Coadministration has not been studied. Ergotamine is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, could potentially decrease ergotamine exposure. However, coadministration is contraindicated in the European SmPC (but no longer the US Prescribing Information) for efavirenz due to potential serious and/or life-threatening adverse events, such as acute ergot toxicity, citing competition for CYP3A4 by efavirenz as a potential mechanism for inhibition of ergotamine metabolism. Coadministration should be avoided or used with caution.

Erythromycin has not been studied in combination with efavirenz but may increase efavirenz concentrations. No data are available to make a dose recommendation. Erythromycin has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied. Escitalopram is metabolized by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Efavirenz could potentially decrease escitalopram concentrations although to a moderate extent. No a priori dosage adjustment is recommended. Escitalopram has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied. Eslicarbazepine is partly eliminated unchanged renally and partly glucuronidated by UGT2B4. Eslicarbazepine is a weak/moderate inducer but is unlikely to reduce significantly efavirenz exposure considering that strong inducers (rifampicin, carbamazepine) caused only a 20-30% decrease in efavirenz exposure.

Co-administration of efavirenz with medicinal products that alter gastric pH would not be expected to affect efavirenz absorption. Esomeprazole has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied. Estazolam is metabolized to its major metabolite 4-hydroxyestazolam via CYP3A4. Efavirenz, an inducer of CYP3A4, could potentially decrease estazolam exposure. Monitor clinical effect and withdrawal symptoms.

Coadministration with estradiol as hormone replacement therapy (HRT) has not been studied. Estradiol is metabolized by CYP3A4, CYP1A2 and is glucuronidated. Efavirenz, an inducer of CYP3A4, could potentially decrease estradiol exposure. Monitor for signs of estrogen deficiency. When estradiol was administered as part of feminizing hormone therapy (FHT) to 20 HIV-infected transgender women receiving efavirenz and emtricitabine/tenofovir-DF, estradiol AUC, Cmax and C24 decreased by 28%, 19% and 36%, respectively, and there was no significant change in efavirenz pharmacokinetics.

Coadministration of efavirenz and ethambutol alone has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%). Coadministration of TB treatment containing ethambutol (with rifampicin, isoniazid and pyrazinamide) and efavirenz (with emtricitabine and tenofovir-DF) increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; there was no effect on ethambutol concentrations.

The effect of efavirenz on ethinylestradiol exposure varies according to the hormonal contraceptive method. Coadministration of a combined oral contraceptive (COC) containing ethinylestradiol/norgestimate (0.035/0.25 mg once daily) and efavirenz (600 mg once daily) for 14 days had no effect on the Cmax, AUC or Cmin of ethinylestradiol or efavirenz. However, coadministration of a vaginal ring releasing etonogestrel/ethinylestradiol (120/15 µg/day) in HIV positive women treated with efavirenz containing regimen (600 mg once daily) decreased in ethinylestradiol exposure by 53-57%. With both methods, progestogen levels were markedly decreased and therefore use with efavirenz is not recommended as it may impair the contraceptive efficacy. Note, use of ethinylestradiol as part of gender affirming treatment is not recommended due to thrombotic risks.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Ethionamide is extensively metabolized in the liver, animal studies suggest involvement of flavin-containing monooxygenases. Ethionamide does not affect metabolism mediated by CYP450 enzymes in vitro.

Coadministration has not been studied. Etidocaine is metabolized by CYP3A4. Inducers of CYP3A4, such as efavirenz, may decrease concentrations of etidocaine and potentially decrease its efficacy. The clinical relevance of this interaction is unknown.

Etonogestrel is metabolized by CYP3A4. In a pharmacokinetic study, coadministration of efavirenz and etonogestrel implants decreased etonogestrel AUC, Cmax, and Cmin by 63%, 54%, and 70%, respectively). Data from a small number of subjects (n=3) with etonogestrel implants showed that efavirenz decreased etonogestrel concentrations by 49% when compared to a control group of subjects (n=22). A study in Botswanan HIV-infected women with etonogestrel implants showed that 9/15 women receiving efavirenz-based antiretroviral treatment had etonogestrel concentrations below 90 pg/mL, the threshold for ovulation suppression. The use of etonogestrel implants or vaginal rings is not recommended in women on long-term treatment with hepatic enzyme-inducing drugs. There have been post-marketing reports of contraceptive failure with etonogestrel-containing implants in efavirenz-exposed patients. Doubling the etonogestrel implant dose (i.e., 2 x 68 mg) in the presence of efavirenz resulted in etonogestrel concentrations more than 2-fold higher when compared to using one etonogestrel implant dose (i.e., 1 x 68 mg) in the presence of efavirenz. Furthermore, the two etonogestrel implant dose reduced the odds of ovulation by 97.7% over 48 weeks compared to the use of the one etonogestrel implant dose in presence of efavirenz. Note, although women using implants and efavirenz-based antiretroviral regimens have a risk of contraceptive failure, the failure rate is still lower in comparison to other contraceptive methods (i.e., depo-medroxyprogesterone or combined oral contraceptives) due to the higher efficacy of implants.

The use of a vaginal ring releasing etonogestrel/ethinylestradiol (120/15 µg/day) in HIV positive women treated with an efavirenz containing regimen (600 mg once daily) decreased etonogestrel exposure by 76-79% and ethinylestradiol exposure by 53-57% compared to exposure of hormones in HIV positive women not yet on ART. There was no clinically significant effect on efavirenz pharmacokinetics (Cmin and AUC decreased by 36% and 13%). Given the substantial decrease in hormone exposure, a reliable method barrier contraception must be used in addition to hormonal contraceptives. Efavirenz has been shown to reduce the exposure of progestogens and unintended pregnancies have been observed when used with levonorgestrel or etonogestrel containing implants. In addition, coadministration of efavirenz and desogestrel/ethinylestradiol administered as a COC decreased etonogestrel exposure by 61% and increased the risk of contraceptive failure.

Coadministration decreased etravirine AUC by 41% and Cmax by 18%. Coadministration is contraindicated as it significantly decreases etravirine concentrations. Combining two NNRTIs has not been shown to be beneficial. If switching from efavirenz to etravirine, the inducing effect of efavirenz has been shown to persist up to 14 days after stopping drug intake, resulting in decreases in etravirine AUC, Cmax and Cmin (32%, 22% and 42% for once daily; 26%, 19% and 34% for twice daily). The decrease in etravirine is comparable to that determined in the presence of darunavir/ritonavir and is not considered clinically significant.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Eucalyptus is only a weak inhibitor of CYP3A4 and is unlikely to impact the exposure of efavirenz given that CYP3A4 is already induced by efavirenz.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Evolocumab is a monoclonal IgG antibody. Elimination is similar to endogenous IgG and occurs primarily via proteolytic catabolism throughout the body.

Coadministration of famotidine (40 mg single dose) and efavirenz (400 mg single dose) had no effect on efavirenz Cmax or AUC. Famotidine has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration may decrease felodipine concentrations. Dose adjustments should be guided by clinical response.

Coadministration has not been studied. Fentanyl undergoes extensive CYP3A4 metabolism. Coadministration could decrease fentanyl concentrations due to induction of CYP3A4, which could decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When using fentanyl with CYP3A4 inducers, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur. Discontinuation of a concomitantly used CYP3A4 inducer may increase in fentanyl concentrations which could result in a fatal overdose of fentanyl. When discontinuing CYP3A4 inducers in fentanyl-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of fentanyl until stable drug effects are achieved. 

Coadministration has not been studied. Fesoterodine is rapidly hydrolysed to its active metabolite which is subsequently metabolized by CYP2D6 and CYP3A4. Concentrations of the active metabolite of fesoterodine are likely to decrease due to induction of CYP3A4. Monitor the effect.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Flecainide is metabolized mainly via CYP2D6, with a large proportion of the parent drug also eliminated unchanged really. Flecainide has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flucloxacillin is mainly eliminated renally partly by glomerular filtration and partly by active secretion via OAT1. Flucloxacillin is thought to be a weak inducer of CYP3A4 particularly at higher doses (>2-3 g daily), but is unlikely to alter efavirenz exposure significantly as rifampicin (a strong inducer) had only a modest effect on efavirenz exposure.

Coadministration of fluconazole (200 mg once daily) with efavirenz (400 mg once daily) had no effect on fluconazole Cmax, AUC or Cmin. Efavirenz Cmax was unaltered, AUC increased by 16% and Cmin increased by 22%. No dose adjustment is recommended. Fluconazole has a known risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied. Flunisolide undergoes CYP3A4-mediated metabolism and coadministration may decrease flunisolide concentrations. Monitor steroid effect and adjust dosage if needed. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Fluorouracil is metabolised via the same mechanisms as endogenous uracil, including via dihydropyrimidine dehydrogenase. There is therefore little potential for an interaction with efavirenz via modulation of, or competition for metabolic pathways. Fluorouracil has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Based on data with paroxetine, no pharmacokinetic interaction is expected with fluoxetine and efavirenz. Population pharmacokinetics of efavirenz in patients receiving selective serotonin reuptake inhibitors (fluoxetine, paroxetine and sertraline) showed that they did not appear to significantly affect efavirenz plasma levels. Fluoxetine has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Fluphenazine is metabolised by CYP2D6. However, fluphenazine may prolong the QT interval and some European product labels have advised against concurrent use of drugs that prolong the QT interval. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied. Fluvastatin is metabolised mainly by CYP2C9. In vitro data suggest that efavirenz is an inhibitor of CYP2C9 and could potentially increase fluvastatin concentrations. No a priori dosage adjustment is recommended but monitor for fluvastatin toxicity.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Fluvoxamine is metabolized mainly by CYP2D6 and to a lesser extent by CYP1A2. Fluvoxamine has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Folic acid is metabolized to dihydrofolic acid and tetrahydrofolic acid with the aid of reduced diphosphopyridine nucleotide and folate reductases.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely when folic acid is administered in a multivitamin preparation. Folic acid is metabolized to dihydrofolic acid and tetrahydrofolic acid with the aid of reduced diphosphopyridine nucleotide and folate reductases.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fondaparinux does not undergo cytochrome metabolism but is eliminated predominantly renally.

Coadministration has not been studied but based on metabolism and clearance, a pharmacokinetic interaction is unlikely. Formoterol is eliminated primarily by direct glucuronidation, with O-demethylation (by CYPs 2D6, 2C19, 2C9, and 2A6) followed by further glucuronidation being another pathway. As multiple CYP450 and UGT enzymes catalyze the transformation the potential for a pharmacokinetic interaction is low. However, formoterol may induce prolongation of the QT interval and the product label for formoterol advises caution in patients treated with drugs affecting the QT interval. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fosinopril is hydrolysed by esterases in the GI mucosa and liver. Fosinopril does not inhibit or induce CYP450 enzymes.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Furosemide is glucuronidated mainly in the kidney (UGT1A9) and to a lesser extent in the liver (UGT1A1). A large proportion of furosemide is also eliminated unchanged really. Furosemide has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. Efavirenz was shown to prolong the QT interval above the regulatory threshold of concern in homozygous carriers of the CYP2B6*6/*6 allele (i.e. 516T variant in the gene encoding CYP2B6). The European product label for efavirenz contraindicates coadministration with a drug with a known risk of Torsade de Pointes whereas the American product label for efavirenz recommends that alternatives should be considered. As the potential risk of a QT interval prolongation relates specifically to homozygous carriers of CYP2B6*6/*6 and given the accumulated years of safety data with efavirenz and such drugs, the contraindication is not reflected in the colour coding of this interaction summary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as gabapentin is exclusively eliminated unchanged in the urine.

Coadministration has not been studied. Garlic supplements have been shown to decrease unboosted saquinavir AUC by 50% in a clinical trial and there is a case report of treatment failure due to garlic cloves (six garlic cloves three times weekly) decreasing ritonavir-boosted atazanavir trough concentrations by ~70%. Similarly, concentrations of efavirenz could be decreased via induction of CYP3A4 and/or P-gp. Patients should be advised against the use of garlic supplements.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. Gentamicin is predominantly eliminated unchanged via the kidneys.

Coadministration with a gestodene-containing combined oral contraceptive (COC) has not been studied but is expected to reduce the efficacy of the contraceptive method and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives. Gestodene is metabolized by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Efavirenz has been shown to reduce the exposure of progestogens and unintended pregnancies have been observed when used with levonorgestrel or etonogestrel containing implants. In addition, coadministration of efavirenz and a desogestrel-containing COC decreased etonogestrel exposure by 61% and an increased risk of contraceptive failure (evaluated by measuring serum progesterone) was observed.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Although gingerols moderately inhibit CYP3A4 in vitro this is unlikely to impact the exposure of efavirenz.

Coadministration is not recommended as efavirenz concentrations may be decreased. A case report described lower efavirenz plasma concentrations in a patient who started taking Gingko biloba, which coincided with an increasing viral load.

Coadministration with efavirenz alone has not been studied and is not recommended as efavirenz may reduce glecaprevir/pibrentasvir concentrations which may lead to reduced therapeutic effect. Coadministration of glecaprevir/pibrentasvir and efavirenz/emtricitabine/tenofovir-DF (600/200/300 mg once daily) was studied in 12 HIV+ /HCV- subjects. When compared to historical data, glecaprevir and pibrentasvir AUC were at least 47% lower than in other antiretroviral interaction studies. Coadministration increased efavirenz Cmax, AUC and Ctrough  by 6%, 3% and 1%, respectively; emtricitabine Cmax, AUC and Ctrough increased by 4%, 7% and 13%, respectively; tenofovir Cmax, AUC and Ctroughincreased by 22%, 29% and 38%, respectively.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glyceryl trinitrate is metabolised by aldehyde dehydrogenase-2. Glyceryl trinitrate is not known to induce or inhibit CYP450 enzymes.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glycopyrronium bromide is mainly eliminated renally (active secretion via organic cation transporter) and is also partly hydroxylated via multiple CYPs. Inhibition or induction of its metabolism is unlikely to result in a significant change in exposure.