Coadministration of abacavir and lopinavir/ritonavir has no effect on lopinavir or ritonavir pharmacokinetics, but appears to decrease abacavir exposure by ~30%. The clinical significance of this is unknown.

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. Acenocoumarol is mainly metabolized by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. In vitro and in vivo data indicate that lopinavir/ritonavir is a weak inducer of CYP2C9. Lopinavir/ritonavir could potentially decrease acenocoumarol concentrations. Monitor INR.

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 lopinavir/ritonavir 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.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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 lopinavir/ritonavir via modulation of, or competition for metabolic or elimination pathways.

Coadministration of lopinavir/ritonavir (400/100 mg twice daily) and African potato was studied in 16 HIV-negative subjects. Relative to repeated administration of lopinavir/ritonavir alone, steady-state Cmax and AUC of lopinavir remained unchanged following concomitant administration of multiple-dose African potato. These results suggest that inhibition of CYP3A4 by ritonavir offsets any inducing effect of African potato on CYP3A4 expected when used for extended periods. 

Coadministration has not been studied. Agomelatine is metabolised predominantly by CYP1A2 which is induced by lopinavir/ritonavir. Coadministration could potentially decrease agomelatine exposure. Monitor clinical effect and increase dosage if needed.

Coadministration has not been studied. In vitro studies have demonstrated that CYP3A4 and the flavine-containing monooxygenase system are involved in formation of the active metabolite albendazole sulfoxide. Short term (2 doses) coadministration with ritonavir (200 mg) did not impact albendazole pharmacokinetics whereas long-term coadministration (8 days) decreased albendazole exposure likely due to ritonavir inducing effect. Lopinavir/ritonavir is unlikely to significantly affect albendazole exposure when used for a short duration treatment but may reduce the clinical effect of albendazole when used for a long duration treatment.

Albuvirtide is a peptide which is eliminated by catabolism to its constituent amino acids. Coadministration of albuvirtide (320 mg once weekly intravenous) and oral lopinavir/ritonavir (400/100 mg twice daily) was evaluated in HIV-infected individuals. Albuvirtide exposure was not significantly affected by lopinavir/ritonavir. However, both lopinavir and ritonavir concentrations were lower in presence of albuvirtide compared with lopinavir/ritonavir alone (lopinavir AUC, Cmax and Ctrough decreased by 37%, 33% and 35%, respectively; ritonavir AUC, Cmax and Ctrough decreased by 38%, 39% and 28%, respectively). The mean lopinavir Ctrough in presence of albuvirtide (7.1 µg/ml) remained higher than the minimal lopinavir Ctrough previously associated with efficacy. Furthermore, a randomized, phase 3 study (TALENT study) showed that albuvirtide + lopinavir/ritonavir was non-inferior to the standard second-line regimen lopinavir/ritonavir + zidovudine/tenofovir disoproxil fumarate + lamivudine in HIV infected Chinese individuals suggesting that this interaction has no clinical consequences. In vitro human microsomal studies indicate that albuvirtide has no inducing properties on P450 enzymes. In addition, albuvirtide binds to <1% of serum albumin in the range of clinical concentrations, thus the observed decrease in lopinavir and ritonavir concentrations is unlikely to result from protein binding displacement. However, binding of the albuvirtide-albumin complex to the HIV protease inhibitor cannot be excluded.

Coadministration has not been studied. Alcohol is metabolized by alcohol dehydrogenase and aldehyde dehydrogenase. The chronic use of alcohol may induce CYP2E1 and to a lesser extent CYP3A4. No a priori clinically relevant drug-drug interaction is anticipated with lopinavir/ritonavir TABLETS. However, coadministration with lopinavir/ritonavir ORAL SOLUTION is not recommended as the large amount of propylene glycol in the oral solution may compete with alcohol for the same elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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 is contraindicated as it may increase alfuzosin concentrations which may lead to severe hypotension. Furthermore, both drugs have a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website.

Coadministration has not been studied and is not recommended. Aliskiren is minimally metabolized by CYP450, however, P-gp is a major determinant of aliskiren bioavailability. A 5-6 fold increase in exposure was observed with itraconazole 100 mg twice daily (a CYP3A4 and P-gp inhibitor) and a similar interaction is possible with lopinavir/ritonavir (due to inhibition of P-gp by ritonavir). The product labels for aliskiren recommend avoiding concomitant use with CYP3A4 and P-gp inhibitors.

Coadministration has not been studied. Almotriptan is partly eliminated unchanged in the urine and partly metabolized (mainly via monoamine oxidase-A and to a lesser extent by CYP3A4, CYP2D6 and flavin monooxygenase). Coadministration may increase almotriptan concentrations due to inhibition of CYP3A4. The American product label for almotriptan recommends using an initial almotriptan dose of 6.25 mg with a strong CYP3A4 inhibitor and not exceeding 12.5 mg within a 24 hour period. It also recommends to avoid use of almotriptan and a strong CYP3A4 inhibitor in patients with impaired renal or hepatic function.

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. In vitro data indicate that alosetron is metabolized by CYPs 2C9 (30%), 3A4 (18%) and 1A2 (10%); however, in vivo data suggest that CYP1A2 plays a more prominent role. In vivo data indicate that lopinavir/ritonavir induces CYP1A2, therefore coadministration with lopinavir/ritonavir could potentially decrease alosetron exposure.

Coadministration has not been studied. 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. Ambrisentan concentrations may increase due to inhibition of OATP1B1 by lopinavir/ritonavir. Start ambrisentan at 5 mg and closely monitor the patient for tolerability.

Coadministration has not been studied. Aminophylline is a complex of theophylline and ethylenediamine and is given for its theophylline activity. Theophylline is mainly metabolized by CYP1A2 and in vitro data indicate that lopinavir/ritonavir induces CYP1A2. Lopinavir/ritonavir could potentially decrease theophylline concentrations. Monitor plasma concentrations and increase aminophylline dosage if needed.

Coadministration has not been studied. Amiodarone is metabolised by CYP3A4 and concentrations may be increased due to inhibition of CYP3A4 by lopinavir/ritonavir. Coadministration is contraindicated in European SPC but the US Prescribing Information suggests caution and concentration monitoring (if available). Furthermore, both drugs have a  risk of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for amiodarone). Caution should be exercised if coadministered. ECG monitoring is recommended.

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 (possibly via OCT).

Coadministration has not been studied. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19. Lopinavir/ritonavir could potentially increase amitriptyline exposure although to a moderate extent. No a priori dosage adjustment is recommended but monitor adverse effects. Note, both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; conditional risk for amitriptyline which may be increased in presence of an interacting drug like lopinavir/ritonavir). ECG monitoring is recommended.

Coadministration has not been studied. Amlodipine is metabolized by CYP3A4. Lopinavir/ritonavir is predicted to increase amlodipine exposure by ~2-fold based on drug-drug interactions studies with amlodipine and indinavir/ritonavir or paritaprevir/ritonavir. If coadministration is indicated, consider a dose reduction for amlodipine of 50%. Use with caution as both lopinavir/ritonavir and calcium channel blockers prolong the PR interval. Close monitoring is recommended.

Coadministration has not been studied. Amodiaquine is metabolized mainly by CYP2C8 to N-desethylamodiaquine, an active metabolite but less potent than the parent compound. Ritonavir dosed as a pharmacokinetic booster is a weak inducer of CYP2C8. Lopinavir/ritonavir could potentially decrease amodiaquine exposure, although to a moderate extent. However, coadministration of lopinavir/ritonavir and amodiaquine decreased desethylamodiaquine exposure by 51%. This drug-drug interaction was unexpected and the related mechanism is unclear. No a priori dosage adjustment is recommended.

Coadministration has not been studied. Amphetamine is metabolized by CYP2D6 and coadministration could potentially increase amphetamine exposure, although to a moderate extent. However, as dosing of recreational drugs can be variable, caution is advised.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ampicillin is predominantly eliminated unchanged via renal pathways.

Coadministration has not been studied. Anastrozole is mainly oxidized to hydroxyanastrozole by CYP3A4 (major) and glucuronidated by UGT1A4. The magnitude of the interaction is predicted to be of moderate intensity as ritonavir has an opposite effect on CYP3A4 (inhibition) and UGT1A4 (induction), which might result in a counterbalancing effect. No a priori dosage adjustment is recommended.

Lopinavir/ritonavir can be coadministered with acid reducing agents with no dose adjustment. No reduction in lopinavir or ritonavir trough concentrations were observed over 48 weeks in HIV+ subjects receiving lopinavir/ritonavir with an acid reducing agent (antacids, proton pump inhibitors or H2 receptor antagonists).

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. Concentrations of apixaban are expected to increase due to potent CYP3A4 and P-gp inhibition by lopinavir/ritonavir, thereby increasing the bleeding risk. The product labels for apixaban do not recommend the concomitant use with strong dual CYP3A4 and P-gp inhibitors, although the US label gives the option to use apixaban at a reduced dose if needed. Note, patients already receiving apixaban at a dose of 2.5 mg twice daily should avoid coadministration with strong dual CYP3A4 and P-gp inhibitors. Of interest, there are case reports of no adverse outcomes in HIV infected patients treated with a reduced dose of apixaban (2.5 mg twice daily) while on ritonavir or cobicistat boosted regimens which supports the option of dose reduction given in the US label.

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 protease inhibitors 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. However, the European SPC for lopinavir advises caution when coprescribing with drugs known to induce QT interval prolongation. Apomorphine has a possible risk of QTc prolongation on the CredibleMeds.org website. 

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 an interaction with lopinavir/ritonavir is unlikely.

Coadministration has not been studied. Aripiprazole is metabolized by CYP3A4 and CYP2D6. Lopinavir/ritonavir could potentially increase aripiprazole concentrations. Monitor adverse effects and decrease aripiprazole dosage if needed. The European SPC advises reducing the aripiprazole dose to approximately one-half of its prescribed dose when given with potent inhibitors of CYP3A4, such as HIV protease inhibitors. In addition, use with caution as both drugs have a possible risk of QTc prolongation on the CredibleMeds.org website. If coadministration is necessary, clinical monitoring including ECG assessment is recommended.

Data from clinical studies and population modelling suggest that coadministration of lopinavir/ritonavir and artesunate or artemether decreases exposure of dihydroartemisinin (the biologically active metabolite) by ~40-60%. Further studies are required to determine the clinical significance of this reduction and if dose modifications are required.

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. Lopinavir/ritonavir does not interfere with this metabolic pathway.

Coadministration has not been studied. Asenapine is metabolized by glucuronidation (UGT1A4) and oxidative metabolism (mainly CYP1A2, with minor contributions from CYP3A4 and CYP2D6). As lopinavir/ritonavir induces CYP1A2 and UGT1A4, lopinavir/ritonavir could potentially decrease asenapine exposure. Monitor the clinical effect and increase dosage if needed. Use with caution as both drugs have a possible risk of QTc prolongation on the CredibleMeds.org website.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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 of astemizole and lopinavir/ritonavir is contraindicated due to potential for serious and/or life threatening reactions such as cardiac arrhythmias. Furthermore, both drugs have a  risk of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for astemizole). Caution should be exercised if coadministered. ECG monitoring is recommended.

Coadministration of atazanavir (once daily) and lopinavir/ritonavir (twice daily) increased atazanavir Cmin (with no effect on AUC) and decreased lopinavir AUC. When used (very selected indications), the recommended dose is atazanavir 300 mg once daily plus lopinavir/ritonavir 400/100 mg twice daily. TDM of atazanavir and lopinavir should be considered. Use with caution as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; conditional risk for atazanavir). 

Atazanavir/cobicistat should not be administered concurrently with lopinavir co-formulated with ritonavir due to similar effects of cobicistat and ritonavir on CYP3A4. Furthermore, both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; conditional risk for atazanavir). 

Coadministration of atazanavir (once daily) and lopinavir/ritonavir (twice daily) increased atazanavir Cmin (with no effect on AUC) and decreased lopinavir AUC. When used (very selected indications), the recommended dose is atazanavir 300 mg once daily plus lopinavir/ritonavir 400/100 mg twice daily. TDM of atazanavir and lopinavir should be considered. Use with caution as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; conditional risk for atazanavir). 

Coadministration has not been studied. A dose adjustment of atenolol is unlikely to be required when coadministered as atenolol is eliminated by the kidney, both by glomerular filtration and active secretion via the renal transporters OCT2 and MATE1. The impact on the PR interval has not been evaluated for the coadministration of lopinavir/ritonavir and atenolol, however, no additive effect on the PR interval was noted for the coadministration of atazanavir and atenolol. Note, PR interval monitoring may be warranted in patients with underlying block or those with atrioventricular nodal blocking agents.

Coadministration of atorvastatin (20 mg once) and lopinavir/ritonavir (400/100 mg twice daily) had no significant effect on lopinavir (Cmax, AUC and Cmin decreased by 10%, 10% and 8%, respectively), but increased atorvastatin Cmax, AUC and Cmin by 4.7-fold, 5.9-fold and 2.3-fold, respectively. Coadministration is not recommended unless specifically required for patient management. Use the lowest possible dose of atorvastatin with careful monitoring (do not exceed a daily dose of 20 mg with careful safety monitoring.) or consider using other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with lopinavir/ritonavir. (Note, American treatment guidelines recommend a maximum daily dose of 20 mg for atorvastatin.)

The AUCs of single dose atovaquone/proguanil (250/100 mg) were 74% and 38% lower, respectively, in HIV-infected individuals on stable antiretroviral treatment containing lopinavir/ritonavir (400/100 mg twice daily or 800/200 mg once daily) than in healthy volunteers. 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. Consider taking atovaquone/proguanil with a high fat meal to increase its bioavailability and increase the dosage if required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely 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 lopinavir/ritonavir via modulation of, or competition for metabolic pathways.

Coadministration has not been studied and is contraindicated. Avanafil is primarily metabolized by CYP3A4. Coadministration with ritonavir (600 mg twice daily) increased avanafil AUC by 13-fold. Similarly, a large increase in avanafil exposure is predicted in the presence of lopinavir/ritonavir.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Lopinavir/ritonavir is metabolized by CYP3A. Azithromycin is not expected to have a clinically relevant effect on drugs metabolised by CYP enzymes. Azithromycin is mainly eliminated via biliary excretion and animal data suggest this may occur via P-glycoprotein and MRP2. Lopinavir/ritonavir could potentially increase azithromycin exposure (inhibition of P-gp and MRP2), however no a priori dosage adjustment is recommended for azithromycin. However, caution should be exercised as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for azithromycin). If coadministration is necessary, clinical monitoring including ECG assessment is recommended.

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.

In vitro data indicate that beclometasone is a pro-drug which is hydrolysed via esterase enzymes to the highly active metabolite beclometasone -17-monopropionate. This active metabolite is subsequently converted to inactive metabolites via CYP3A4/5. Coadministration of ritonavir (100 mg twice daily) and inhaled beclomethasone diproprionate (160 mg twice daily) increased the AUC and Cmax of beclomethasone-17-monoproprionate by 108% and 67%, respectively. However, coadministration of a boosted PI (darunavir/ritonavir, 600/100 mg twice daily) decreased the AUC and Cmax of the active metabolite by 11% and 19%, respectively. No significant effect on adrenal function was seen with either ritonavir or darunavir/ritonavir. Although statistically significant, the 2-fold increase in AUC of the active metabolite seen with ritonavir is unlikely to be of clinical significance. Use the lowest possible corticosteroid dose with caution and monitor for corticosteroid side effects.

Coadministration of bedaquiline (400 mg single dose) and lopinavir/ritonavir (400/100 mg twice daily) to 16 HIV/TB-negative subjects increased bedaquiline AUC by 22% and had no effect on Cmax. Coadministration of bedaquiline (400 mg, once daily loading dose; 200 mg once daily maintenance dose for ~3 months) with lopinavir/ritonavir increased bedaquiline AUC by 62% but had no significant effect on the pharmacokinetics of the bedaquiline M2 metabolite. Bedaquiline and lopinavir have a possible risk or QT prolongation and/or TdP on the CredibleMeds.org website. When bedaquiline is coadministered with other medicinal products that prolong the QTc interval, an additive or synergistic effect on QT prolongation cannot be excluded. Bedaquiline must be used with caution when co-administered with lopinavir/ritonavir and only if the benefit outweighs the risk. The combination of bedaquiline and moderate or strong CYP3A4 inhibitors used systemically for more than 14 consecutive days should be avoided. If coadministration is necessary, clinical monitoring including frequent electrocardiogram assessment and monitoring of transaminases is recommended. There are no clinical data on the safety and efficacy of bedaquiline when co-administered with antiretroviral agents.

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 clinically significant 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.

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

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.

Bepridil and lopinavir should not be coadministered. Coadministration has not been studied, but may increase bepridil concentrations and has the potential to produce serious and/or life-threatening adverse events. Caution is warranted and concentration monitoring is recommended if coadministered. In addition, caution should be exercised as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for bepridil).

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. Betamethasone is metabolized by CYP3A4 and coadministration may therefore lead to elevated corticosteroid levels, Cushing’s syndrome and adrenal axis suppression. A case of Cushing’s syndrome and adrenal suppression in a patient on atazanavir/ritonavir and dexamethasone 0.1% eye drops and betamethasone 0.1% eye ointment has been reported. Betamethasone is a moderate inducer of CYP3A4. Caution is needed when betamethasone is administered orally or intravenously at high doses or for a long duration as it may decrease lopinavir/ritonavir exposure.

Coadministration has not been studied. Betrixaban is largely eliminated unchanged through biliary secretion via P-gp. Coadministration with a P-gp inhibitor (such as lopinavir/ritonavir) is expected to increase betrixaban exposure. The US product label for betrixaban recommends for patients receiving or starting a strong P-gp inhibitor to reduce betrixaban dose and use an initial dose of 80 mg followed by 40 mg once daily.  Furthermore, patients should be monitored closely and any signs or symptoms of blood loss should be evaluated promptly. Betrixaban has demonstrated an exposure dependent increase in QT interval therefore caution is required when coadministering with another drug that may prolong the QTc interval (betrixaban and lopinavir have a possible risk or QT prolongation and/or TdP on the CredibleMeds.org website). Of note, coadministration of betrixaban might need to be reconsidered in patients with concomitant renal impairment (creatinine clearance <60 ml/ml) as renal impairment per se does increase betrixaban exposure. 

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.

Coadministration has not been studied and should be avoided. Bexarotene is mainly metabolized by CYP3A4 and induces CYP3A4 (after repeated administration and especially at doses greater than 300 mg/m2/day). Coadministration could potentially increase bexarotene concentrations and thus increase the risk of side effects. In addition, bexarotene could potentially decrease lopinavir/ritonavir exposure and therefore coadministration should be avoided.

Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) 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 lopinavir/ritonavir would be possible from a pharmacokinetic standpoint. Coadministration may increase bictegravir concentrations due to inhibition of CYP3A4 by lopinavir/ritonavir but this is unlikely to require dose modification. Coadministration of lopinavir/ritonavir and emtricitabine/tenofovir alafenamide had no significant effect on lopinavir and increased exposure of tenofovir alafenamide. The recommended dose of 10 mg tenofovir alafenamide with P-gp inhibitors is not possible with Biktarvy which is only available as a fixed dose combination containing 25 mg tenofovir alafenamide, but it should be noted that tenofovir alafenamide has been associated with a large clinical safety profile.

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. Coadministration could potentially increase bisoprolol concentrations, although to a moderate extent. Pharmacokinetic studies between lopinavir/ritonavir and drugs that prolong the PR interval, including beta blockers, have not been performed. An additive effect of lopinavir/ritonavir and these drugs cannot be excluded. Note, PR interval monitoring may be warranted in patients with underlying block or those with atrioventricular nodal blocking agents.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. No effect on lopinavir/ritonavir 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. Lopinavir/ritonavir could potentially increase bortezomib concentrations. Monitor for bortezomib-related side effects. The US Prescribing Information suggests considering a dose reduction of bortezomib when given with strong CYP3A4 inhibitors, such as ritonavir. Caution is advised when prescribing bortezomib and lopinavir/ritonavir as both drugs have a possible risk or QT prolongation and/or TdP on the CredibleMeds.org website. If coadministration is necessary, clinical monitoring including ECG assessment is recommended.

Caution should be exercised in administering lopinavir/ritonavir with bosentan. Coadministration with lopinavir/ritonavir increased bosentan trough concentrations by ~48-fold and ~5-fold on days 4 and 10, respectively. Lopinavir/ritonavir concentrations may decrease due to CYP3A4 induction by bosentan. When coadministered patients should be closely observed for bosentan toxicity, especially during the first week of co-administration. The US Prescribing Information suggests for patients who have been receiving lopinavir/ritonavir for at least 10 days, to start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. In patients on bosentan, it suggests to discontinue bosentan at least 36 hours prior to initiation of lopinavir/ritonavir and after at least 10 days of lopinavir/ritonavir, to resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

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. Lopinavir/ritonavir could potentially increase bromazepam concentrations although to a moderate extent. Coadministration with itraconazole (a strong CYP3A4 inhibitor) increased bromazepam AUC by ~9%. A similar effect may occur with lopinavir/ritonavir. No a priori dosage adjustment is required.

Concomitant use of lopinavir/ritonavir and glucocorticoids metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression. Systemic corticosteroid effects have been reported in patients receiving ritonavir and fluticasone; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide. A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclometasone). Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period.

Coadministration has not been studied. Bupivacaine is predominantly metabolized by CYP3A4. CYP3A4 inhibitors such as lopinavir/ritonavir may increase levels of bupivacaine. A clinical study with bupivacaine and itraconazole, a CYP3A4 inhibitor, reported a 20-25% increase in steady state concentration of bupivacaine when administered with itraconazole, compared to placebo.

Coadministration had no significant effect on the pharmacokinetics of buprenorphine and did not result in opiate withdrawal symptoms. When compared to control data, buprenorphine increased lopinavir AUC by 15%, but had no effect on Cmax or Cmin. Lopinavir/ritonavir can be coadministered with buprenorphine with no dose adjustment.

Coadministration decreased bupropion AUC and Cmax by ~57%; active metabolite AUC and Cmax decreased by 31% and 50%, respectively (data from 12 HIV- subjects). Single dose of bupropion had no effect on the pharmacokinetics of lopinavir and ritonavir. If the coadministration is judged unavoidable, this should be done under close clinical monitoring for bupropion efficacy, without exceeding the recommended bupropion dosage, despite the observed induction.

Coadministration has not been studied. Caffeine is mainly metabolized by CYP1A2. In vivo data indicate that lopinavir/ritonavir induces CYP1A2 and therefore boosted protease inhibitors could potentially decrease caffeine concentrations. However, no a priori dose adjustment is required.

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

Coadministration has not been studied. Canagliflozin is primarily metabolised by UGT1A9 and UGT2B4. Lopinavir/ritonavir could lead to reduced exposure to canagliflozin as a result of UGT enzyme induction by ritonavir as rifampicin (a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4) decreased canagliflozin AUC by 51% which may result in reduced efficacy. If coadministration is deemed necessary, increasing canagliflozin to 300 mg once daily may be considered if patients are currently tolerating canagliflozin 100 mg once daily, have an eGFR ≥60 mL/min/1.73m2 or CrCl ≥60 mL/min, and require additional glycaemic control. Other glucose-lowering therapies should be considered for patients with an eGFR 45 mL/min/1.73m2 to <60 mL/min/1.73m2 or CrCl 45 mL/min to <60 mL/min taking canagliflozin 100 mg who are receiving concurrent therapy with a UGT enzyme inducer and who require additional glycaemic control.

Coadministration has not been studied. Cannabidiol is mainly metabolized by CYP3A4 and CYP2C19. Coadministration with lopinavir/ritonavir may increase cannabidiol concentrations due to strong inhibition of CYP3A4 and decrease cannabidiol concentrations due to induction of CYP2C19. The net effect of these interactions is unknown. Monitor effect and occurrence of side effects and adjust cannabidiol dosage accordingly.

Coadministration has not been studied. Tetrahydrocannabinol (THC, the psychoactive component of cannabis) is metabolized mainly by CYP2C9 and to a lesser extent by CYP3A4. In vivo data indicate that ritonavir is a weak inducer of CYP2C9 and a strong inhibitor of CYP3A4. The net clinical effect of this interaction is difficult to predict as lopinavir/ritonavir could potentially decrease THC exposure (induction of CYP2C9) or increase THC exposure (inhibition of CYP3A4).

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. Lopinavir/ritonavir does not interfere with this metabolic pathway. However, caution is advised when prescribing capecitabine and lopinavir/ritonavir as both drugs have 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. Capreomycin is predominantly excreted via the kidneys as unchanged drug.

Lopinavir/ritonavir should not be administered once-daily in combination with carbamazepine. Coadministration may result in a marked decrease in concentrations of lopinavir/ritonavir and increased concentrations of carbamazepine. Monitor carbamazepine concentrations. An increase of lopinavir/ritonavir dosage may be envisaged, but has not been evaluated.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carbidopa is partly metabolized and partly eliminated unchanged (30% of the total urinary excretion).

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 via UGTs 1A1, 2B4 and 2B7, and metabolism via CYP2D6 and to a lesser extent CYPs 2C9 and 1A2. The net effect on carvedilol concentrations is difficult to predict but likely to be moderate in magnitude. Pharmacokinetic studies between lopinavir/ritonavir and drugs that prolong the PR interval (including beta blockers) have not been performed. An additive effect of lopinavir and these drugs cannot be excluded. Note, PR interval monitoring may be warranted in patients with underlying block or those with atrioventricular nodal blocking agents.

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 lopinavir. Coadministration should be avoided.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefalexin is predominantly eliminated unchanged via the kidneys.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefazolin is predominantly eliminated unchanged via the kidneys.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefotaxime is predominantly eliminated unchanged via the kidneys.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ceftazidime is predominantly eliminated unchanged via renal glomerular filtration.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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 has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Celecoxib is primarily metabolized by CYP2C9 and in vivo data indicate that lopinavir/ritonavir is a weak inducer of CYP2C9. A dose adjustment is unlikely to be required for celecoxib when coadministered with lopinavir/ritonavir.

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 lopinavir/ritonavir 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. Lopinavir/ritonavir is metabolised by CYP3A and inhibits CYP3A. Chloroquine is metabolised by CYPs 2C8, 3A4 and 2D6, and is also eliminated unchanged via the kidney (50%). No effect on lopinavir/ritonavir is expected, but inhibition of CYP3A by lopinavir/ritonavir may increase chloroquine concentrations (although to a moderate extent due to the multiple elimination pathways), thereby increasing the risk of QT prolongation as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (known risk for chloroquine; possible risk for lopinavir). Due to the very long half-life, the risk of QT prolongation may persist even after discontinuation of chloroquine. No dosage adjustment is recommended for chloroquine but ECG monitoring is advised.

Coadministration has not been studied. Chlorphenamine is predominantly metabolized in the liver via CYP2D6. Lopinavir/ritonavir could potentially increase chlorphenamine exposure although to a moderate extent as ritonavir is a weak inhibitor of CYP2D6. No a priori dosage adjustment is required.

Coadministration has not been studied. Chlorpromazine is metabolized mainly by CYP2D6, but also by CYP1A2. Lopinavir/ritonavir could potentially increase chlorpromazine exposure although to a moderate extent. In addition, caution should be exercised as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for chlorpromazine). If coadministration is necessary, clinical monitoring including ECG assessment is recommended.

Coadministration has not been studied. Ciclesonide can be administered with lopinavir/ritonavir without dose adjustment, but with close monitoring. There is a risk of steroid side effects occurring, particularly if a high dose is used, or in case of prolonged administration, or if used with another medicine containing corticosteroids. These side effects are also more likely during periods of physiological stress. Ciclesonide is a pro-drug activated by esterases in the lungs to des-ciclesonide which then undergoes CYP3A4-mediated metabolism. Coadministration of the strong CYP3A4 inhibitor ketoconazole (400 mg daily for 7 days) with orally inhaled ciclesonide (320 µg once daily) did not alter ciclesonide but resulted in a 3.5-fold increase in the AUC and a 2-fold increase in the Cmax of des-ciclesonide. Ciclesonide is mainly absorbed by the lungs, has a high protein binding and a high clearance resulting in a lower potential to cause systemic effects compared to some other inhaled corticosteroids. Hence, any interaction with lopinavir/ritonavir would not require any dosage/therapy adjustments, particularly if ciclesonide is administered at lower or medium clinical doses, but close monitoring for Cushing’s syndrome signs is required when using a higher dose or with prolonged administration. 

Coadministration may increase plasma concentrations of ciclosporin. More frequent therapeutic concentration monitoring is recommended until plasma levels have been stabilised.

Lopinavir/ritonavir can be coadministered with acid reducing agents with no dose adjustment. No reduction in lopinavir or ritonavir trough concentrations were observed over 48 weeks in HIV+ subjects receiving lopinavir/ritonavir with an acid reducing agent (antacids, proton pump inhibitors or H2 receptor antagonists).

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. Lopinavir/ritonavir is unlikely to inhibit OATs at clinically relevant concentrations. However, caution should be exercised as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for ciprofloxacin). If coadministration is necessary, clinical monitoring including ECG assessment is recommended.

Coadministration of cisapride and lopinavir/ritonavir is contraindicated due to potential for serious and/or life threatening reactions such as cardiac arrhythmias. Both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for cisapride).

Coadministration has not been studied. Cisplatin is eliminated renally via OCT2 and MATE1 and in vitro data indicate that ritonavir is a moderate inhibitor of MATE1. Lopinavir/ritonavir could potentially slow down cisplatin renal elimination and thus increase the risk of nephrotoxicity. Close monitoring of renal function is recommended.

Coadministration has not been studied. Citalopram is metabolized by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Lopinavir/ritonavir could potentially increase citalopram concentrations although to a moderate extent and no a priori dosage adjustment is recommended. In addition, caution should be exercised as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for citalopram). If coadministration is necessary, clinical monitoring including ECG assessment is recommended.

Particular caution must be used when prescribing lopinavir/ritonavir and medicinal products known to induce QT interval prolongation such as clarithromycin. Coadministration may increase clarithromycin concentrations. Dose reduction of clarithromycin required in patients with impaired renal function. In addition, caution should be exercised as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for clarithromycin). If coadministration is necessary, clinical monitoring including ECG assessment is recommended.

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. CYP3A4 inhibition by lopinavir/ritonavir may increase clobazam exposure and prolong the duration of its effect, whereas induction of CYP2C19 by lopinavir/ritonavir may decrease N-desmethylclobazam. The net effect of these interactions is unknown. Monitor for side effects and clinical effect. Clobazam is unlikely to significantly impact lopinavir/ritonavir.

Coadministration has not been studied. Clobetasol is a substrate of CYP3A4 and exposure may increase due to inhibition of CYP3A4 by lopinavir/ritonavir. Topical clobetasol can be used with caution. Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Clofazimine is largely excreted unchanged in the faeces, both as unabsorbed drug and via biliary excretion. Although both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (conditional risk for clofazimine; possible risk for lopinavir/ritonavir), the risk of QT interval prolongation is considered to be low as no significant pharmacokinetic interaction is expected.

Coadministration has not been studied. In vitro studies have suggested that transformation of clomifene to its active metabolite is likely to be mediated via CYP2D6. Lopinavir/ritonavir might increase clomifene exposure, although to a moderate extent, via CYP2D6 inhibition. No a priori dosage adjustment is recommended.

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. Coadministration could potentially increase clomipramine concentrations. Monitor adverse effects. Note, both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; conditional risk for clomipramine). Caution is advised as the product label for clomipramine advises to avoid coadministration with drugs that can prolong the QT interval.

Coadministration of clopidogrel and boosted regimens has been evaluated in clinical studies. Clopidogrel is a prodrug and is converted to its active metabolite via CYPs 3A4, 2B6, 2C19 and 1A2. In HIV-positive subjects, the presence of a pharmacoenhancer (ritonavir n=8; cobicistat n=1) decreased the AUC and Cmax of clopidogrel’s active metabolite both by 69% when compared to values obtained in HIV-negative subjects (n=12). In HIV-negative subjects (n=12), coadministration of clopidogrel and ritonavir (100 mg twice daily) decreased the AUC and Cmax of clopidogrel’s active metabolite by 51% and 48%. Importantly, the decrease in clopidogrel’s active metabolite lead to insufficient inhibition of platelet aggregation in 44% of the patients treated with clopidogrel and ritonavir or cobicistat. Consistently, the study in HIV-negative subjects showed that the average inhibition of platelet aggregation was decreased from 51% (clopidogrel alone) to 31% (clopidogrel + ritonavir). Of interest, the study with HIV-infected patients showed a comparable decrease in prasugrel’s active metabolite AUC (52% decrease), however this decrease did not impair prasugrel’s antiplatelet effect. The differential impact on clopidogrel and prasugrel pharmacodynamics effect is in line with clinical observations. Early thrombosis of a coronary stent was reported in a patient treated with darunavir/ritonavir concomitantly with clopidogrel while subsequent replacement of clopidogrel by prasugrel did not lead to novel stent thrombosis episodes. Taken together these data suggest that given the risk of diminished clopidogrel response, prasugrel should be preferred in presence of boosted regimens, unless the patient has a clinical condition which contraindicates its use in which case an alternative antiplatelet agent should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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, 3A4, and to a lesser extent by CYPs 2C9 and 2D6. Lopinavir/ritonavir could potentially increase clozapine exposure. Monitor patient closely for toxicity. In addition, caution should be exercised as both drugs have possible risks of QT prolongation and/or TdP on the CredibleMeds.org website.

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. Lopinavir/ritonavir could potentially increase concentrations of the parent compound. The clinical relevance is unknown as cocaine is metabolized by other non-CYP mediated pathways. Ensure the patient is aware of signs/symptoms of cocaine toxicity. In addition, caution should be exercised as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for cocaine).

Coadministration has not been studied. Codeine is a substrate of CYP2D6 (major) and CYP3A4. Ritonavir inhibits CYP2D6 at higher doses but at the 100 mg dose, ritonavir does not appear to markedly inhibit CYP2D6. While no a priori dose adjustment is required, the analgesic effect requires conversion of codeine to morphine via CYP2D6 and lopinavir/ritonavir could potentially reduce the analgesic efficacy.

Coadministration is expected to increase colchicine concentrations. Ritonavir (100 mg twice daily) significantly increased colchicine Cmax (2.7-fold) and AUC (3.5-fold) when given with a single dose of colchicine (0.6 mg). Patients with renal or hepatic impairment should not be coadministered colchicine. A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function. When coadministered for treatment of gout flares, the recommended dosage is 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. The dose is to be repeated no earlier than 3 days. When coadministered for prophylaxis of gout flares, if the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day; if the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. When coadministered for treatment of familial Mediterranean fever (FMF) do not exceed a maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

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. Inhibition of CYP3A by lopinavir/ritonavir is not expected to reduce the effect of vitamin D, but the consequence of CYP3A inhibition on the clinical effect of vitamin D is not known. However, no effect of antiretroviral therapy on the response to vitamin D supplementation was found in a PK modelling study.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Although several constituents of Piper cubeba were shown to inhibit CYP3A4 in vitro, any additional effect on exposure of lopinavir in the presence of ritonavir is unlikely.

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. Cyclophosphamide is metabolized by two pathways. Activation (major pathway) to 4-hydroxycyclophosphamide is catalyzed by CYPs 2B6 (major), 2C9 and 3A4. Inactivation (minor, 10%) to the neurotoxic chloroacetaldehyde metabolite is performed mainly by CYP3A4. In vivo data indicate that ritonavir induces CYP2B6. In theory, lopinavir/ritonavir could potentially reduce the risk of neurotoxicity and increase the amount of drug available for the activation pathway which may increase the efficacy and the toxicity of cyclophosphamide (i.e., myelosuppression, nausea, vomiting). Careful monitoring of cyclophosphamide related side effects is recommended. Adjust dose if clinically necessary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cycloserine is predominantly excreted renally via glomerular filtration.

Coadministration has not been studied. Cyproterone acetate is metabolized by CYP3A4 and concentrations may increase due to inhibition of CYP3A4 by lopinavir/ritonavir. A dose adjustment of cyproterone may be required.

A case report suggests that lopinavir/ritonavir has no clinically significant interaction with dabigatran. A reduced dabigatran dosage of 75 mg twice daily (due to the anticipated interaction with lopinavir/ritonavir) resulted in insufficient dabigatran plasma concentrations. Dabigatran concentrations comparable to historical data were achieved in this patient at a dosage of 110 mg twice daily. However, due to limited data, close clinical monitoring is recommended when ritonavir-boosted protease inhibitors are used with dabigatran particularly in patients with mild or moderate renal impairment as data with verapamil (a P-gp inhibitor) and dabigatran suggest the dabigatran dose might need to be reduced in presence of a P-gp inhibitor such as lopinavir/ritonavir. Note, dabigatran is not recommended in patients with severe renal impairment.

Coadministration has not been studied. Dacarbazine undergoes activation to MTIC primarily via CYP1A2 and to a lesser extent by CYP2E1, with CYP1A1 having a role in extrahepatic metabolism. In vitro data indicate that lopinavir/ritonavir induces CYP1A2. Lopinavir/ritonavir may increase the conversion to MTIC and thereby increase the efficacy and toxicity of dacarbazine. Monitor side effects.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dactinomycin is minimally metabolized, is concentrated in nucleated cells, and does not penetrate the blood-brain barrier. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dapagliflozin is primarily metabolised by UGT1A9. Lopinavir/ritonavir may affect dapagliflozin due to UGT induction by ritonavir but a clinically relevant effect is not expected as coadministration of dapagliflozin with rifampicin (an inducer of several UGT enzymes) decreased dapagliflozin systemic exposure by 22% but had no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended. 

Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation, and is via multiple CYP P450 enzymes. Clinically significant interactions are unlikely, but can not be excluded.

Coadministration has not been studied. Darifenacin is metabolized by CYP3A4 and CYP2D6 and coadministration is likely to increase concentrations. A 5-fold increase in darifenacin exposure was seen with ketoconazole (a strong inhibitor of CYP3A4) and the magnitude of the interaction could be even more pronounced in poor metabolizer individuals. The European Summary of Product Characteristics for darifenacin contraindicates its use with potent CYP3A4 inhibitors (such as lopinavir/ritonavir), but the US Prescribing Information recommends that the dose of darifenacin should not exceed 7.5mg when coadministered with potent CYP3A4 inhibitors.

Darunavir/cobicistat coformulations (Rezolsta; Prezcobix) should not be administered concurrently with lopinavir co-formulated with ritonavir due to similar effects of cobicistat and ritonavir on CYP3A4.

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, adding a dose of lopinavir/ritonavir has not been studied with respect to safety, efficacy and pharmacokinetics.

Coadministration of darunavir (1200 mg twice daily, with or without 100 mg ritonavir) had no significant effect on lopinavir pharmacokinetics but decreased darunavir AUC by ~40% (relative to data obtained with darunavir/ritonavir 600/100 mg alone). Due to decreased darunavir exposure, appropriate doses of the combination have not been established and it is not recommended to coadminister lopinavir/ritonavir with darunavir.

Coadministration has not been studied but should be avoided. Dasatinib is metabolized by CYP3A4 and coadministration may significantly increase exposure to dasatinib concentrations. In addition, both drugs have a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website. If coadministration is unavoidable, close monitoring for toxicity and QT prolongation is required. The US product information for dasatinib recommends a dose reduction to 20 mg daily (for patients taking dasatinib 100 mg) and to 40 mg (for patients taking dasatinib 140 mg) in presence of strong inhibitors of CYP3A4.

A clinical study reported that ritonavir had no effect on daunorubicin (liposomal) pharmacokinetics. 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. There is therefore little potential for pharmacokinetic interaction. 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. Caution must be used when prescribing lopinavir/ritonavir and medicinal products known to induce QT or PR interval prolongation.

Delamanid is primarily metabolised by albumin to DM-6705; metabolism of DM-6705 to other metabolites is thought to involve pathways mediated by CYP enzymes, including CYP3A4. Co-administration of delamanid (100 mg twice daily) and lopinavir/ritonavir (400/100 mg twice daily) had no effect on lopinavir Cmax or AUC (increases of 5% and 4%), but increased delamanid Cmax and AUC by 18% and 22%. DM-6705 exposure has been reported to increase by 25-30% with lopinavir/ritonavir. QTc prolongation has been reported with delamanid (and is very closely correlated with the metabolite DM-6705), therefore, caution is advised due to potent CYP3A4 inhibition and due to the risk of QT prolongation associated with both drugs. If coadministration is considered necessary, frequent ECG monitoring is recommended throughout the full delamanid treatment period (for example, at least fortnightly for the first month and if the QTc interval remains within normal range to reduce this to monthly thereafter).

Coadministration of lopinavir/ritonavir (400/100 mg twice daily for 10 days) and desipramine (100 mg single dose) had no clinically significant effect on desipramine (9% decrease in Cmax, 5% increase in AUC). However, caution should be exercised as both drugs have possible risks of QT prolongation and/or TdP on the CredibleMeds.org website.

Desogestrel is a prodrug that is activated to etonogestrel by CYP2C9 (and possible CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Coadministration of a combined oral contraceptive (COC) containing ethinylestradiol and desogestrel (30/150 µg once daily) with lopinavir/ritonavir (individualised dose up to 400/100 twice daily) was studied in 16 HIV positive Thai females. Lopinavir and ritonavir Ctrough decreased by 26% and 31%, respectively. When compared to historical data from HIV-negative subjects (n=14), ethinylestradiol and etonogestrel Ctrough decreased by 32% and 8%, respectively. Ovulation was reported to be suppressed, however, the study reports a high variability in hormone levels. Caution is recommended and additional contraceptives measures should be used.

Coadministration with a desogestrel-containing progestogen-only pill (POP) has not been studied. 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 is predicted to increase etonogestrel and, based on studies with norethisterone used as a POP, the contraceptive efficacy of a desogestrel POP is unlikely to be compromised by lopinavir.

Coadministration has not been studied. Dexmedetomidine undergoes extensive hepatic biotransformation through direct glucuronidation (mainly via UGT1A4, 2B10) and cytochrome P450 (mainly 2A6). Study data indicate that ritonavir decreases exposure of lamotrigine, a UGT1A4 probe substrate. Lopinavir/ritonavir could potentially decrease dexmedetomidine concentrations. No a priori dosage adjustment is recommended but monitor clinical effect. In addition, both drugs have possible risks 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. Diclofenac is partly glucuronidated by UGT2B7 and partly oxidized by CYP2C9. In vivo data indicate that lopinavir/ritonavir is a weak inducer of CYP2C9, however a dose adjustment is unlikely to be required for diclofenac.

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

Use with caution as both lopinavir/ritonavir and digoxin prolong the PR interval. Coadministration may increase digoxin concentrations due to P-gp inhibition. The increased digoxin level may lessen over time as P-gp induction develops. Caution is warranted. Clinical and therapeutic drug monitoring of digoxin concentrations is recommended, if available.

Coadministration has not been studied. 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. Lopinavir/ritonavir could potentially increase dihydrocodeine exposure (inhibition of CYP3A4 and CYP2D6) and increase the conversion to dihydrocodeine-6-glucuronide (induction of UGT2B7). The net clinical effect of this interaction is difficult to predict. 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 of dihydroergotamine and lopinavir/ritonavir is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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 has not been studied. Diltiazem is metabolized by CYP3A4 and CYP2D6, and is a moderate inhibitor of CYP3A4. Coadministration may increase diltiazem concentrations. Use with caution as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; conditional risk for diltiazem). If coadministration is necessary, clinical monitoring including ECG assessment is recommended.

Coadministration has not been studied. Diphenhydramine is mainly metabolized by CYP2D6. Lopinavir/ritonavir could potentially increase diphenhydramine concentrations although to a moderate extent. No a priori dosage adjustment is recommended.

Coadministration has not been studied. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. Coadministration could potentially decrease dipyridamole exposure due to induction of glucuronidation, thereby reducing the antiplatelet effect.

Coadministration has not been studied and is not recommended. Disopyramide is metabolized by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine. Coadministration may increase disopyramide exposure and thereby the risk of cardiac arrhythmias. Caution should be exercised as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for disopyramide).

Coadministration is contraindicated with lopinavir/ritonavir ORAL SOLUTION. No interaction expected with lopinavir/ritonavir tablets.

Coadministration with lopinavir/ritonavir may increase concentrations of docetaxel and increase the risk of severe toxicities. There have been several case reports of severe haematological and cutaneous toxicity when coadministered with ritonavir, a potent CYP3A inhibitor. Ideally avoid coadministration with boosted protease inhibitors or consider using an alternative taxane.

Coadministration has not been studied and is not recommended. Dofetilide is metabolized to a small degree by CYP3A4 and therefore lopinavir/ritonavir could potentially increase dofetilide exposure and thereby increase the risk of cardiac arrhythmias. Caution should be exercised as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for dofetilide).

Coadministration has not been studied. 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%). Coadministration could potentially increase dolasetron concentrations although this is unlikely to be clinically meaningful since CYP-mediated metabolism is minor and dolasetron has a wide therapeutic margin. However, caution should be exercised as both drugs have possible risks of QT prolongation and/or TdP on the CredibleMeds.org website.

Lopinavir/ritonavir has no clinically significant effect on the pharmacokinetics of dolutegravir. Coadministration of lopinavir/ritonavir (400/100 mg twice daily) and dolutegravir (30 mg once daily had no effect on dolutegravir Cmax, and decreased AUC and Ctrough by 3% and 6%. Coadministration with lopinavir/ritonavir and etravirine had no significant effect on dolutegravir exposure (AUC, Cmax and Ctrough increased by 10%, 7% and 28%, respectively). When compared to historical data, dolutegravir did not appear to affect the pharmacokinetics of lopinavir or ritonavir. No dose adjustment is necessary.

Triumeq (dolutegravir, abacavir, 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 lopinavir/ritonavir would be possible from a pharmacokinetic standpoint. Coadministration of lopinavir/ritonavir and dolutegravir decreased dolutegravir AUC and C24 by 4% and 6% and had no effect on Cmax; there was no effect on lopinavir or ritonavir. Coadministration of lopinavir/ritonavir and abacavir decreased abacavir AUC by 32%. No change in the pharmacokinetics of lopinavir was observed with lamivudine in clinical studies.

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 lopinavir/ritonavir would be possible from a pharmacokinetic standpoint. The European product label for Dovato advises that no dose adjustment is necessary with lopinavir/ritonavir. Coadministration of lopinavir and dolutegravir decreased dolutegravir AUC and C24 by 4% and 6% and had no effect on Cmax; there was no effect on lopinavir or ritonavir. No change in the pharmacokinetics of lopinavir was observed with stavudine and lamivudine in clinical studies.

Juluca (dolutegravir/rilpivirine) 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 lopinavir/ritonavir would be possible from a pharmacokinetic standpoint. Coadministration of lopinavir/ritonavir (400/100 mg twice daily) and dolutegravir (30 mg once daily had no effect on dolutegravir Cmax, and decreased AUC and Ctrough by 3% and 6%. Coadministration of rilpivirine (150 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) increased rilpivirine Cmax, AUC and Cmin by 29%, 52% and 74%, respectively. Lopinavir Cmax, AUC and Cmin decreased by 4%, 1% and 11%, respectively. [Note: this interaction study has been performed with a dose higher than the licensed dose for rilpivirine assessing the maximal effect on the co-administered drug. The dosing recommendation is applicable to the licensed dose of rilpivirine 25 mg once daily.] Rilpivirine has been associated with prolongation of the QTc interval at supra-therapeutic doses but equivalent rilpivirine concentrations are unlikely to occur during coadministration with lopinavir/ritonavir. However, the product labels for Juluca indicate that rilpivirine should be used with caution in combination with drugs with a known risk of Torsade de Pointes. Lopinavir has a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website.

Coadministration has not been studied and is contraindicated with potent CYP3A4 inhibitors, such as lopinavir/ritonavir. Domperidone is mainly metabolized by CYP3A4. Lopinavir/ritonavir could potentially increase domperidone exposure and increase the risk of cardiac adverse effects. Both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for domperidone).

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

Coadministration has not been studied. Coadministration with ritonavir increased doravirine AUC by 3.5 fold and Cmin by 2.9 fold. No dose adjustment of doravirine is required as phase I trials showed a good tolerability of doravirine with up to a 3-4 fold increase in exposure.

Delstrigo (doravirine, lamivudine, tenofovir-DF) 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 lopinavir/ritonavir would be possible from a pharmacokinetic standpoint, but with close monitoring for tenofovir-associated adverse events. Coadministration with ritonavir increased doravirine AUC by 3.5-fold and Cmin by 2.9-fold. No dose adjustment of doravirine is required as phase I trials showed a good tolerability of doravirine with up to a 3- to 4-fold increase in exposure. Coadministration of tenofovir-DF (300 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) increased tenofovir-DF AUC by 32%, Cmin increased by 51%, and there was no change in Cmax. A higher risk of renal impairment has been reported in patients receiving tenofovir-DF and a ritonavir boosted protease inhibitor. No dose adjustment is recommended, but close monitoring of renal function and for tenofovir-associated adverse reactions is required. 

Coadministration has not been studied. Doxazosin is metabolized mainly by CYP3A4 and coadministration may increase doxazosin exposure which can result in hypotension. For patients already taking lopinavir/ritonavir, start doxazosin at the lowest dose (i.e., 1 mg daily) and increase dose slowly based on tolerance until an effective dose is reached. For patients already taking doxazosin, monitor blood pressure and reduce doxazosin dose as needed if hypotension occurs on starting lopinavir/ritonavir.

Coadministration has not been studied. Doxepin is metabolized to nordoxepin (a metabolite with comparable pharmacological activity as the parent compound) mainly by CYP2C19. In addition, doxepin and nordoxepin are metabolized by CYP2D6. Lopinavir/ritonavir could potentially increase doxepin exposure although to a moderate extent. No a priori dose adjustment is required. Doxepin has a conditional risk of QT prolongation and/or TdP on the CredibleMeds.org website. The risk of QT prolongation when combining these drugs is considered to be small given the limited PK drug-drug interaction.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Doxorubicin is mainly eliminated in the bile 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.) Doxorubicin is a substrate of P-glycoprotein, but coadministration with protease inhibitors did not modify significantly doxorubicin exposure. However, caution is advised due to possible cardiac toxicities (ECG abnormalities and sometimes arrhythmias). Use with caution. ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. No significant metabolism of doxycycline occurs, it is cleared intact by renal and biliary mechanisms.

Coadministration has not been studied. Dronabinol is mainly metabolized by CYP2C9 and to a lesser extent by CYP3A4. In vitro and in vivo data indicate that lopinavir/ritonavir is a weak inducer of CYP2C9 and a strong inhibitor of CYP3A4. The net clinical effect of this interaction is difficult to predict as lopinavir/ritonavir could potentially decrease dronabinol concentrations (induction of CYP2C9) or increase dronabinol concentrations (inhibition of CYP3A4). No a priori dosage adjustment is recommended.

Coadministration with a drospirenone-containing combined oral contraceptive (COC) has not been studied. Drospirenone is metabolised in part by CYP3A4. Coadministration is predicted to increase drospirenone exposure and clinical monitoring is recommended due to the potential for hyperkalaemia. When used in a combined pill, the estrogen component is reduced. Given the lack of clinical data on the contraceptive efficacy, caution is recommended and additional contraceptives measures should be used.

Coadministration with drospirenone as hormone replacement therapy (HRT) has not been studied. CYP3A4 contributes to drospirenone metabolism. Coadministration is predicted to increase drospirenone exposure and clinical monitoring is recommended due to the potential for hyperkalaemia. The clinical significance of this increase in terms of overall risk of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction in postmenopausal women receiving substitution hormones is unknown. In contrast, exposure of estrogens/estradiol administered as part of HRT may decrease. Monitor for signs of hormone deficiency. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.

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 has not been studied. Duloxetine is metabolized by CYP2D6 and CYP1A2. In vitro data indicate that lopinavir/ritonavir induces CYP1A2 but inhibits CYP2D6. The net clinical effect of this interaction is difficult to predict, but is expected to be of weak intensity. No a priori dosage adjustment is required.

Coadministration has not been studied. Dutasteride is mainly metabolized by CYP3A4. Lopinavir/ritonavir could potentially increase dutasteride concentrations. A reduction of dutasteride dosing frequency can be considered if side effects are noted.

Coadministration with dydrogesterone as hormone replacement therapy (HRT) has not been studied. Dydrogesterone is metabolized to dihydrodydrogesterone (possibly via CYP3A4). Coadministration is predicted to increase dydrogesterone exposure due to inhibition of CYP3A4. The clinical significance of this increase in terms of overall risk of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction in postmenopausal women receiving substitution hormones is unknown. In contrast, exposure of estrogens/estradiol administered as part of HRT may decrease. Monitor for signs of hormone deficiency. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.

Studies using a cocktail of probe drugs in 12 HIV- subjects showed that echinacea inhibited CYP1A2 and intestinal CYP3A activity, and induced hepatic CYP3A activity. However, a study with echinacea and lopinavir/ritonavir in 13 HIV- subjects showed no clinically significant effect of echinacea on lopinavir or ritonavir pharmacokinetics.

Coadministration has not been studied. Edoxaban is a substrate for P-gp and coadministration is expected to increase edoxaban concentrations due to P-gp inhibition. The European product label for edoxaban states to consider a dose reduction of edoxaban from 60 mg to 30 mg with strong P-gp inhibitors, however, the US product label recommends no dose modification.

Coadministration decreases lopinavir concentrations by 30-40%. Efavirenz should not be coadministered with once daily lopinavir/ritonavir. Lopinavir/ritonavir tablets should be increased to 500/125 mg twice daily; lopinavir/ritonavir oral solution should be increased to 533/133 mg twice daily. Monitor closely. TDM may be useful. Furthermore, a prolongation of the QT interval may occur with efavirenz treatment in carriers of CYP2B6*6/*6. Use with caution as both drugs have 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. Eflornithine is predominantly eliminated unchanged via the kidneys.

Coadministration is contraindicated. Concomitant use of elbasvir/grazoprevir with OATP1B inhibitors, such as lopinavir/ritonavir, may increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition. Coadministration of lopinavir/ritonavir and elbasvir/grazoprevir increased grazoprevir AUC by 12.9-fold and elbasvir AUC by 3.7-fold.

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 protease inhibitors due to potential drug-drug interactions including altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir and/or the coadministered antiretroviral products. Genvoya should not be administered concurrently with products containing ritonavir or regimens containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.

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 protease inhibitors inhibitors due to potential drug-drug interactions including altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the coadministered antiretroviral products. Stribild should not be administered concurrently with products containing ritonavir or regimens containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Empagliflozin is metabolised by UGTs and is a substrate of P-gp, BCRP, OAT3 and OATP1B1/1B3. Although lopinavir/ritonavir inhibits P-gp and OATP, data with verapamil (a P-gp inhibitor) and rifampicin (an OATP1B1/1B3 inhibitor) suggest a clinically relevant effect on empagliflozin is unlikely.

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.

Coadministration of lopinavir/ritonavir (800/200 mg once daily) with emtricitabine/tenofovir alafenamide (200/10 mg, once daily) increased tenofovir AUC and Cmax by 322% and 275% (n-10). No significant effects were observed on lopinavir pharmacokinetics relative to historical controls. Coadministration of lopinavir/ritonavir (800/200 mg once daily) and tenofovir alafenamide (10 mg once daily) increased tenofovir alafenamide AUC and Cmax by 47% and 119% but had no effect on lopinavir AUC or Cmax. The recommended dose of Descovy for HIV-1 treatment is 200/10 mg once daily (where available).

Coadministration with emtricitabine/tenofovir-DF has not been studied. Based on metabolism and clearance a pharmacokinetic interaction with emtricitabine is unlikely. Coadministration of tenofovir-DF (300 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) had no significant effect on lopinavir/ritonavir pharmacokinetic parameters; tenofovir AUC increased by 32%, Cmin increased by 51%, and there was no change in Cmax. A higher risk of renal impairment has been reported in patients receiving emtricitabine/tenofovir-DF and a ritonavir or cobicistat boosted protease inhibitor. No dose adjustment is recommended, but close monitoring of renal function and for tenofovir-associated adverse reactions is required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ephedrine is predominantly eliminated unchanged via the kidneys.

Coadministration has not been studied. Epirubicin is glucuronidated by UGT2B7. Lopinavir/ritonavir could potentially reduce epirubicin concentrations (induction of UGT2B7 by ritonavir) and thus decrease the efficacy. Epirubicin may lead to cardiotoxicity consisting of tachycardia and/or ECG abnormalities. Use with caution as both drugs have a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website.

Coadministration has not been studied and is contraindicated. Eplerenone is metabolized by CYP3A4 and coadministration is expected to substantially increase eplerenone exposure due to inhibition of CYP3A4 and thereby increase the risk of hyperkalaemia. Coadministration of ketoconazole, a strong CYP3A4 inhibitor, increased eplerenone AUC by 441%. There is a case report of a patient on fosamprenavir/ritonavir developing severe hyperkalaemia when eplerenone was initiated.

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 of ergometrine and lopinavir/ritonavir is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity.

Coadministration of ergotamine and lopinavir/ritonavir is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity.

Coadministration has not been studied. Erlotinib is mainly metabolized by CYP3A4 and coadministration could potentially increase erlotinib concentrations. Ketoconazole (a strong CYP3A4 inhibitor) increased erlotinib AUC by 86%. As erlotinib is dosed at/near the maximum tolerated dose (MTD), any increase in erlotinib exposure may lead to toxicity. Coadministration of a potent CYP3A4 inhibitor, such as lopinavir/ritonavir, should be avoided, but if this is not possible, use with caution and close monitoring for erlotinib mediated toxicity is necessary. The erlotinib dose should be reduced in 50 mg increments if toxicity is observed.

Coadministration has not been studied and is not recommended. Erythromycin concentrations may increase due to inhibition of CYP3A4 by lopinavir/ritonavir. In addition, caution should be exercised as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for erythromycin). If coadministration is necessary, clinical monitoring including ECG assessment is recommended.

Coadministration has not been studied. Escitalopram is metabolized by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Lopinavir/ritonavir could potentially increase escitalopram concentrations although to a moderate extent. No a priori dosage adjustment is recommended but monitor adverse effects. In addition, caution should be exercised as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for escitalopram). If coadministration is necessary, clinical monitoring including ECG assessment is recommended.

Coadministration has not been studied. Eslicarbazepine is partly eliminated unchanged renally and partly glucuronidated by UGT2B4. Eslicarbazepine is a weak/moderate inducer of CYP3A4. Coadministration could potentially reduce lopinavir/ritonavir concentrations, leading to loss of therapeutic effect and possible development of resistance. Consider use of other anticonvulsants. If coadministration is necessary, closely monitor virological response and monitor lopinavir plasma concentrations (when possible). Eslicarbazepine has the potential to prolong the PR interval. An additive effect of lopinavir cannot be excluded therefore caution is needed. Note, PR interval monitoring may be warranted in patients with underlying block or those receiving known atrioventricular nodal blocking agents.

Lopinavir/ritonavir can be coadministered with acid reducing agents with no dose adjustment. No reduction in lopinavir or ritonavir trough concentrations were observed over 48 weeks in HIV+ subjects receiving lopinavir/ritonavir with an acid reducing agent (antacids, proton pump inhibitors or H2 receptor antagonists).

Coadministration with estradiol as hormone replacement therapy (HRT) has not been studied. Estradiol is metabolized by CYP3A4, CYP1A2 and is glucuronidated. Coadministration could potentially decrease estradiol exposure due to induction of CYP1A2 and glucuronidation (rather than increase it due to inhibition of CYP3A4). Monitor for signs of estrogen deficiency.

Ethinylestradiol AUC decreased by 42% and norethindrone AUC decreased by 17% (data from 12 HIV- subjects) when an oral contraceptive was coadministered with lopinavir/ritonavir. Coadministration of lopinavir/ritonavir and a patch contraceptive decreased ethinylestradiol AUC by 45% and increased norelgestromin AUC by 83%. Further studies are required to assess the safety and contraceptive efficacy of coadministration with a contraceptive patch. Use other contraceptive methods, i.e., barrier. Note, use of ethinylestradiol as part of gender affirming treatment is not recommended due to thrombotic risks.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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 and concentrations may increase due to inhibition of CYP3A4 by lopinavir./ritonavir Use with caution.

Etonogestrel is metabolized by CYP3A4. Coadministration of lopinavir/ritonavir and etonogestrel implants increased etonogestrel AUC, Cmax and Cmin by 52%, 61% and 34%, respectively, suggesting that lopinavir/ritonavir may not impair the efficacy of etonogestrel implants. Median serum concentrations of etonogestrel in postpartum women (n=26) with an etonogestrel implant receiving an lopinavir/ritonavir-based regimen were 428 pg/mL and were above the target minimum serum etonogestrel concentration for ovulation suppression (i.e., 90 pg/mL).

Coadministration with the etonogestrel as a combined vaginal ring (CVR) has not been studied. Etonogestrel is metabolized by CYP3A4 and is coformulated in the CVR with ethinylestradiol which is released at a dose of 0.015 mg/day. Lopinavir/ritonavir is predicted to increase etonogestrel but to reduce ethinylestradiol concentrations. Since no dosage adjustment of ethinylestradiol is possible with the CVR, alternative forms of contraception should be used.

Coadministration has not been studied. Etoposide is partly metabolized by CYP3A4 to reactive catechol metabolites. Conversion to reactive metabolites can also be mediated by prostaglandin synthase or myeloperoxidase. Furthermore, etoposide is partly glucuronidated by UGT1A1. Ketoconazole (a strong CYP3A4 inhibitor) increased etoposide exposure by 20%. The net effect of this interaction is difficult to predict as lopinavir/ritonavir could potentially increase (inhibition of CYP3A4) or decrease (induction of UGT1A1) etoposide exposure. Reduce dose if clinically necessary or consider selection of an alternate non-CYP inhibiting antiretroviral regimen.

Coadministration of lopinavir/ritonavir tablets and etravirine decreased etravirine AUC (35%), Cmax (30%) and Cmin (45%) and decreased lopinavir AUC (13%), Cmax (11%) and Cmin (20%). Etravirine and lopinavir/ritonavir can be co-administered without dose adjustments because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir. Coadministration of etravirine, saquinavir, lopinavir and ritonavir to HIV+ subjects decreased AUC, Cmax and Cmin of the PIs (saquinavir decreased by 13%, 15%, and 13%, respectively; lopinavir decreased by 18%, 16% and 8%, respectively; ritonavir decreased by 13%, 11% and 12% respectively). Etravirine pharmacokinetics were comparable to those obtained when coadministered with a single boosted PI. These changes were not considered likely to be 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 any additional effect on exposure of lopinavir in the presence of ritonavir is unlikely.

Coadministration of has not been studied but should be avoided. Everolimus is metabolized by CYP3A4. Coadministration with ketoconazole (a potent inhibitor of CYP3A4) increased everolimus exposure by 15 fold. Similarly, a large increase in everolimus exposure is predicted in presence of lopinavir/ritonavir. Coadministration is not recommended as there are currently insufficient data to allow dosing recommendations with potent CYP3A4 inhibitors.

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 has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Exemestane is metabolised by CYP3A4 but coadministration with ketoconazole (a potent CYP3A4 inhibitor) showed no clinically significant effects and no effect is expected due to inhibition of CYP3A4 by lopinavir/ritonavir. No a priori dose adjustment is required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as exenatide is primarily eliminated by glomerular filtration. However, as exenatide slows gastric emptying it is advisable to take lopinavir/ritonavir at least 1 hour before an exenatide injection. [Note: this interaction is not specific for lopinavir/ritonavir, but for any medication taken with exenatide.]

Lopinavir/ritonavir can be coadministered with acid reducing agents with no dose adjustment. No reduction in lopinavir or ritonavir trough concentrations were observed over 48 weeks in HIV+ subjects receiving lopinavir/ritonavir with an acid reducing agent (antacids, proton pump inhibitors or H2 receptor antagonists).

Coadministration of lopinavir/ritonavir and dihydropyridine calcium channel blockers, such as felodipine, may increase plasma concentrations of felodipine. Use with caution as both lopinavir/ritonavir and calcium channel blockers prolong the PR interval. Clinical monitoring of patients is recommended.

Coadministration of lopinavir/ritonavir (400/100 mg twice daily) and fenofibrate (145 mg single dose) had no significant effect on the AUC (14% decrease) or Cmax (3% decrease) of fenofibrate when administered to HIV-negative subjects. These data suggest that an interaction between fenofibrate and lopinavir/ritonavir is unlikely to occur in HIV-infected patients.

Coadministration has not been studied. Fentanyl undergoes extensive CYP3A4 metabolism. Coadministration may increase fentanyl concentrations due to inhibition of CYP3A4, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Monitor patients closely at frequent intervals and consider dosage reduction of fentanyl until stable drug effects are achieved. Discontinuation of a CYP3A4 inhibitor could decrease fentanyl concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to fentanyl. When discontinuing CYP3A4 inhibitors in fentanyl-treated patients, 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. Note, the use of fentanyl in a non-therapeutic setting (i.e., as a recreational drug) should be avoided with lopinavir/ritonavir as fentanyl exposure is expected to significantly increase and serious, life-threatening, or fatal respiratory depression may occur. Patients should be aware that recreational use could be potentially fatal.

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 increase due to inhibition of CYP3A4. The maximum daily dose of fesoterodine should not exceed 4 mg when used concomitantly with potent CYP3A4 inhibitors such as lopinavir/ritonavir.

Coadministration has not been studied. Fexofenadine does not undergo CYP mediated metabolism but is a substrate of P-gp/OATP. Lopinavir/ritonavir could potentially increase fexofenadine exposure by inhibition of P-gp. However, due to the large therapeutic index of fexofenadine, no dosage adjustment is recommended.

Flecainide and lopinavir/ritonavir should not be coadministered as it is likely to increase flecainide concentrations and has the potential to produce serious and/or life threatening reactions such as cardiac arrhythmias. Caution should be exercised as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for flecainide).

Coadministration has not been studied. Flucloxacillin is mainly eliminated renally partly by glomerular filtration and partly by active secretion via OAT1. Lopinavir/ritonavir is unlikely to inhibit OATs at clinically relevant concentrations. Flucloxacillin is thought to be a weak inducer of CYP3A4 particularly at higher doses (>2-3 g daily). A modest reduction in lopinavir/ritonavir concentrations may be observed but this is unlikely to be clinically relevant unless flucloxacillin is prescribed at higher doses for a prolonged course (> 10-14 days).

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Fluconazole is mainly eliminated renally by glomerular filtration and is a moderate inhibitor of CYP3A4. However, caution should be exercised as both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; known risk for fluconazole). If coadministration is necessary, clinical monitoring including ECG assessment is recommended.

Coadministration has not been studied. Concomitant administration of lopinavir/ritonavir and corticosteroids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Fludrocortisone is a substrate of CYP3A4 and its exposure may increase due to CYP3A4 inhibition by lopinavir/ritonavir. Use alternative treatments.

Coadministration has not been studied. Flunisolide undergoes CYP3A4-mediated metabolism and coadministration may increase flunisolide concentrations. Flunisolide has properties (low binding affinity to glucocorticoid receptors, low lipophilicity and short elimination half-life) associated with a lower propensity to cause a Cushing syndrome. If coadministered with lopinavir/ritonavir, it is recommended to use the lowest possible flunisolide dose with monitoring for corticosteroid side effects.

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 lopinavir/ritonavir via modulation of, or competition for metabolic pathways. However, use with caution as both drugs have a possible risk of QT prolongation and/or TdP on the CredibleMeds.org website.

Coadministration has not been studied. Fluoxetine is metabolized by CYPs 2D6 and 2C9 and to a lesser extent by CYPs 2C19 and 3A4 to form norfluoxetine. Lopinavir/ritonavir could potentially increase fluoxetine concentrations although to a moderate extent. No a priori dosage adjustment is recommended. Note, both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; conditional risk for fluoxetine).

Coadministration has not been studied. Fluphenazine is metabolised by CYP2D6. Lopinavir/ritonavir could potentially increase levels of fluphenazine via inhibition of CYP2D6 metabolism, increasing likelihood of adverse events. Lopinavir/ritonavir has been shown to cause modest asymptomatic PR prolongation in some healthy adult subjects. The effect of fluphenazine on QT interval is likely to be potentiated by concurrent use of other drugs that also prolong the QT interval. The impact on the PR interval of coadministration with lopinavir/ritonavir with other drugs that prolong the PR interval has not been evaluated. Coadministration of lopinavir/ritonavir and fluphenazine should be undertaken with caution. The European SPC for fluphenazine contraindicates the concurrent use of other drugs that also prolong the QT interval.

Concomitant use of lopinavir/ritonavir and glucocorticoids metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression. Systemic corticosteroid effects have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclometasone). Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluvastatin is partially metabolised by CYP2C9 and is a substrate of OATP1B1.

Coadministration has not been studied. Fluvoxamine is metabolized mainly by CYP2D6 and to a lesser extent by CYP1A2. Lopinavir/ritonavir could potentially increase fluvoxamine concentrations although to a moderate extent. No a priori dosage adjustment is recommended. Note, both drugs have risks of QT prolongation and/or TdP on the CredibleMeds.org website (possible risk for lopinavir; conditional risk for fluvoxamine).

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. 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 prolong the QT interval and the European SPC for lopinavir/ritonavir advises caution when coprescribing with drugs known to induce QT interval prolongation.

Coadministration has not been studied. Fosinopril is hydrolysed by esterases in the GI mucosa and liver and is transported by MRP2. Lopinavir/ritonavir may increase fosinopril exposure due to inhibition of MRP2 by ritonavir. The clinical relevance of this interaction is unknown.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as gabapentin is cleared mainly by glomerular filtration.

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 lopinavir/ritonavir could be decreased via induction of CYP3A4 and/or P-gp. Patients should be advised against the use of garlic supplements.

Coadministration has not been studied. Gefitinib is metabolized by CYP3A4 and CYP2D6 and coadministration could potentially increase gefitinib concentrations. Itraconazole (a strong CYP3A4 inhibitor) increased gefitinib exposure by 80%. A similar effect is expected with lopinavir/ritonavir. If coadministration is unavoidable, close monitoring of gefitinib induced toxicity is recommended..

Gemfibrozil is metabolised mainly by UGT2B7. Coadministration decreased the AUC of gemfibrozil by 41% and decreased Cmax by 33%, possibly through induction of glucuronidation by lopinavir/ritonavir. No a priori dosage adjustment is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gentamicin is predominantly eliminated unchanged via the kidneys.

Coadministration with a gestodene-containing combined oral contraceptive (COC) has not been studied. Gestodene is metabolized by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Coadministration is predicted to increase gestodene exposure. When used in a combined pill, the estrogen component is reduced. Given the lack of clinical data on the contraceptive efficacy, caution is recommended and additional contraceptives measures should be used.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Although gingerols moderately inhibit CYP3A4 in vitro, any additional effect on exposure of lopinavir in the presence of ritonavir is unlikely.

Coadministration Ginkgo biloba extract (120 mg twice daily for 4 weeks) and lopinavir/ritonavir (400/100 mg twice daily) had no effect on the steady state pharmacokinetics of lopinavir or ritonavir (n=14).

Coadministration is not recommended. Concomitant use of glecaprevir/pibrentasvir with OATP1B inhibitors, such as lopinavir/ritonavir, may increase the risk of ALT elevations due to a significant increase in glecaprevir/pibrentasvir plasma concentrations caused by OATP1B1/3 inhibition. Coadministration of lopinavir/ritonavir and glecaprevir/pibrentasvir increased glecaprevir Cmax, AUC and Cmin by 2.55-fold, 4.38-fold and 18.6-fold; pibrentasvir Cmax, AUC and Cmin increased by 1.40-fold, 2.46-fold and 5.24-fold, respectively (n=21).