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

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. In vivo data indicate that ritonavir is a weak inducer of CYP2C9 when used as a pharmacokinetic booster and may 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 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 ritonavir via modulation of, or competition for metabolic or elimination pathways.

Coadministration has not been studied but based on the metabolic data there is little potential for pharmacokinetic interactions. African potato was shown to inhibit CYP3A4 and P-gp in vitro and to activate PXR suggesting that inhibition may occur initially followed by induction of CYP3A4 and P-gp when used for extended periods. However, coadministration of African potato with lopinavir/ritonavir in healthy volunteers did not result in significant pharmacokinetic changes suggesting that boosting by ritonavir could offset the inducing effect of African potato. Similarly, no significant effect is expected on the pharmacokinetics of ritonavir.

Coadministration has not been studied. Agomelatine is metabolised predominantly by CYP1A2. Ritonavir used as a pharmacokinetic booster induces CYP1A2 and could potentially decrease agomelatine exposure. Monitor clinical effect and increase dosage if needed.

In vitro studies suggest that albendazole is predominantly metabolised by CYP450 enzymes, including CYP3A4. In a clinical study in 8 healthy volunteers, steady state ritonavir (200 mg twice daily) decreased albendazole and the active metabolite albendazole sulfoxide AUC (73% and 59% respectively) and Cmax (74% and 48% respectively). Co-administration may cause a reduction in the clinical effect of albendazole.

Coadministration has not been studied. Albuvirtide is a peptide which is eliminated by catabolism to its constituent amino acids. Based on data from studies with lopinavir/ritonavir, concentrations of ritonavir decrease but this is not expected to be clinically relevant. 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 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 and lead to severe hypotension.

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 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 ritonavir induces CYP1A2, and coadministration could potentially decrease alosetron exposure.

Alprazolam metabolism was inhibited following the introduction of ritonavir (2.5-fold increase in AUC), but at steady state no significant inhibitory effect was observed (12% decrease in AUC). Caution is warranted during the first few days of coadministration, before induction of alprazolam metabolism develops.

Coadministration of ambrisentan (5 mg once daily) and ritonavir (100 mg once daily) did not significantly modify ambrisentan exposure when administered to HIV-negative subjects for 10 days (n=42). 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. 

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. In vitro data indicate that ritonavir induces CYP1A2 and may decrease theophylline exposure. Monitor plasma concentrations and increase aminophylline dosage if needed.

Coadministration is contraindicated as it is likely to increase amiodarone concentrations and the potential for serious and/or life threatening reactions such as cardiac arrhythmias.

Coadministration has not been studied. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19. Ritonavir dosed as a pharmacokinetic booster is a weak inhibitor of CYP2D6 and therefore might increase amitriptyline exposure, although to a moderate extent. No a priori dosage adjustment is recommended if ritonavir is dosed as a pharmacokinetic booster, however, careful monitoring of therapeutic and adverse effects is recommended with full dose ritonavir.

Coadministration has not been studied. Amlodipine is metabolized by CYP3A4 and 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%. 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. Ritonavir could potentially decrease amodiaquine exposure, although to a moderate extent. No a priori dosage adjustment is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amoxicillin is mainly excreted in the urine by glomerular filtration and tubular secretion, and in vitro data indicate that it is a substrate of OAT3.

Coadministration has not been studied. Amphetamine is metabolized by CYP2D6. Ritonavir dosed as a pharmacokinetic booster is a weak CYP2D6 inhibitor and 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.

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

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

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 ritonavir is unlikely.

Coadministration has not been studied. Aripiprazole is metabolized by CYP3A4 and CYP2D6. 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.

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. Ritonavir does not interfere with this metabolic pathway.

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 is contraindicated as it is likely to increase astemizole concentrations and the risk of cardiac arrhythmias.

Coadministration of atazanavir with ritonavir in doses greater than 100 mg once daily has not been clinically evaluated. The use of higher ritonavir doses might alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and therefore is not recommended. (Note, the European product label, but not the US label, for atazanavir suggests to consider a dose increase of ritonavir to 200 mg once daily if coadministration of atazanavir/ritonavir is necessary.)

Atazanavir/cobicistat should not be administered concurrently with ritonavir due to similar effects of cobicistat and ritonavir on CYP3A4. If switching from ritonavir to cobicistat, caution is required during the first two weeks of treatment with cobicistat, particularly if doses of any coadministered medicinal products have been titrated or adjusted during use of ritonavir. Unlike ritonavir, cobicistat is not an inducer of CYPs 1A2, 2B6, 2C8, 2C9, 2C19 or UGT1A1.

Atazanavir/ritonavir should not be used in combination with medicinal products containing additional ritonavir. Coadministration of Reyataz with ritonavir at doses greater than 100 mg once daily has not been clinically evaluated. (Note, the European product label, but not the US label, for atazanavir suggests to consider a dose increase of ritonavir to 200 mg once daily if coadministration of atazanavir/ritonavir is necessary.)

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

Use with caution. The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including ritonavir, are used in combination with atorvastatin. Titrate atorvastatin dose and use the lowest possible dose with careful monitoring.

Coadministration may decrease atovaquone concentrations. Careful monitoring of serum levels or therapeutic effects is recommended.

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 ritonavir via modulation of, or competition for metabolic pathways.

Coadministration is contraindicated. Avanafil is primarily metabolized by CYP3A4. Coadministration of avanafil (50 mg single dose) and ritonavir (600 mg twice daily) increased avanafil AUC and Cmax by 13-fold and 2.4-fold.

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 with ritonavir alone has not been studied. In an interaction study of single-dose bedaquiline and multiple-dose lopinavir/ritonavir, bedaquiline AUC was increased by 22%. This increase is likely due to ritonavir and increases in bedaquiline exposure would be expected when coadministered with other ritonavir-boosted HIV protease inhibitors. The combination of bedaquiline and ritonavir should be avoided. If  the benefit of coadministration outweighs the risk and 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 coadministered 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. Benznidazole undergoes non-CYP mediated metabolism and partly CYP mediated metabolism. Renal elimination of unchanged benznidazole appears to be minimal and there is little potential for an interaction via competition for renal elimination pathways.

Coadministration is contraindicated as it is likely to increase bepridil concentrations and the potential for serious and/or life threatening reactions such as cardiac arrhythmias.

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 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 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. 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 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 of ritonavir-boosted darunavir (or indinavir) would be possible from a pharmacokinetic standpoint. Coadministration of bictegravir and darunavir/cobicistat increased bictegravir AUC by 74%. A comparable increase in bictegravir exposure is anticipated when coadministered with darunavir/ritonavir. This increase is unlikely to be clinically significant; available dose exposure data, as well as data from phase 2 and phase 3 studies (48 weeks treatment), have shown a good safety profile with up to a 2.4-fold increase in bictegravir AUC. However, darunavir/ritonavir increases tenofovir alafenamide (the prodrug of tenofovir) due to inhibition of intestinal P-gp thereby increasing the systemic concentration. Coadministration of darunavir/ritonavir (800/100 mg once daily) and tenofovir alafenamide (10 mg once daily) increased tenofovir AUC and Cmax by 105% and 142%, respectively. 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 ritonavir and drugs that prolong the PR interval, including beta blockers, have not been performed. An additive effect of 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 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 may increase bosentan concentrations. Coadministration with lopinavir/ritonavir increased bosentan trough concentrations by ~48-fold and ~5-fold on days 4 and 10, respectively. Bosentan did not affect lopinavir and ritonavir AUC or Cmax to a clinically relevant extent. The US Prescribing Information suggests for patients who have been receiving 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 ritonavir and after at least 10 days of 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. 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 ritonavir. No a priori dosage adjustment is required.

Coadministration is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and fluticasone; this could also occur with other corticosteroids metabolised by CYP3A 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 be required over a longer period.

Coadministration has not been studied. Bupivacaine is predominantly metabolized by CYP3A4. CYP3A4 inhibitors such as 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 with ritonavir (100 mg twice daily) increased concentrations of buprenorphine and its active metabolite, but this did not lead to clinically significant pharmacodynamic changes in a population of opioid tolerant patients. Dose adjustment of either drug may therefore not be necessary, but should be guided by clinical monitoring. When used in boosted regimens with buprenorphine, the SPC of the co-administered protease inhibitor should be reviewed for specific dosing information.

Coadministration is expected to decrease bupropion levels. Coadministration with ritonavir (100 mg twice daily) decreased bupropion AUC and Cmin by 22% and 21%. There was no significant interaction with bupropion after short-term administration of ritonavir (200 mg twice daily for 2 days). Reductions in bupropion concentrations may have onset several days after initiation of ritonavir. However, because ritonavir both induces and inhibits CYP2B6, the recommended dose of bupropion should not be exceeded. Patients receiving ritonavir and bupropion concurrently should be monitored for adequate clinical response to bupropion.

Coadministration has not been studied. Buspirone is metabolized by CYP3A4 but does not inhibit CYP3A4. Ritonavir could potentially increase buspirone concentrations due to inhibition of CYP3A4. A low dose of buspirone used cautiously is recommended with careful monitoring of therapeutic and adverse effects. Adjust dosage based on the clinical response.

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. Ritonavir could lead to reduced exposure to canagliflozin as a result of UGT enzyme induction 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 may increase cannabidiol concentrations due to strong inhibition of CYP3A4 by ritonavir and decrease cannabidiol concentrations due to induction of CYP2C19 by ritonavir. 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 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 clinically significant interaction is unlikely. Capecitabine is activated by sequential enzyme reactions to fluorouracil. Ritonavir does not interfere with this metabolic pathway.

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.

Use with caution. Ritonavir used as a pharmacokinetic booster may increase carbamazepine concentrations and a decrease in dose may be necessary. Careful monitoring of adverse effects and therapeutic concentration monitoring of carbamazepine is recommended. Two cases reported increased carbamazepine concentrations in patients receiving ritonavir (400 mg twice daily).

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 ritonavir and drugs that prolong the PR interval (including beta blockers) have not been performed. An additive effect of 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.

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. 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 ritonavir is a weak inducer of CYP2C9 when used as a pharmacokinetic booster. A dose adjustment is unlikely to be required for celecoxib when coadministered with ritonavir.

Coadministration with ritonavir dosed as a pharmacokinetic booster has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cetirizine is only metabolised to a limited extent and is eliminated unchanged in the urine through both glomerular filtration and tubular secretion. Furthermore, no significant electrocardiographic changes were observed when cetirizine was coadministered to 10 HIV+ subjects receiving PIs (details not given).

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 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. Chloroquine undergoes CYP mediated metabolism by CYPs 2C8, 3A4 and 2D6, and is also eliminated unchanged via the kidney (50%). Ritonavir could potentially increase chloroquine exposure by inhibition of CYPs 3A4 and 2D6. No dosage adjustment is recommended for chloroquine but monitor toxicity.

Coadministration has not been studied. Chlorphenamine is predominantly metabolized in the liver via CYP2D6. Ritonavir dosed as a pharmacokinetic booster is a weak inhibitor of CYP2D6 and could potentially increase chlorphenamine exposure, although to a moderate extent. No a priori dosage adjustment is required.

Coadministration has not been studied. Chlorpromazine is metabolized mainly by CYP2D6, but also by CYP1A2. Ritonavir dosed as a pharmacokinetic booster is a weak inhibitor of CYP2D6 and could potentially increase chlorpromazine exposure, although to a moderate extent. No a priori dosage adjustment is recommended but monitor side effects.

Coadministration has not been studied. Ciclesonide can be administered with 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 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 ciclosporin concentrations. Therapeutic concentration monitoring is recommended for ciclosporin.

Based on interaction studies with lopinavir/ritonavir and atazanavir/ritonavir, concurrent administration of a proton pump inhibitor (omeprazole) or a H2-receptor antagonist (ranitidine) does not significantly modify ritonavir efficacy as a pharmacokinetic enhancer despite a slight change of exposure of about 6-18%.

Coadministration is contraindicated as it is likely to increase cisapride concentrations and the potential for serious and/or life threatening reactions such as cardiac arrhythmias.

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. 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%). Ritonavir could potentially increase citalopram concentrations, although to a moderate extent. No a priori dosage adjustment is recommended.

Coadministration of ritonavir (200 mg twice daily) with clarithromycin (500 mg twice daily) increased ritonavir AUC (12%), Cmax (15%) and Cmin (14%). Clarithromycin AUC and Cmax increased by 77% and 31%, respectively, whilst Cmin increased 2.8-fold; 14-OH clarithromycin metabolite AUC, Cmax and Cmin all decreased by 99-100%. No dose adjustment for patients with normal renal function is necessary. For patients with creatinine clearance 30-60 ml/min reduce clarithromycin dose by 50%. For patients with creatinine clearance less than 30 ml/min reduce clarithromycin dose by 75%.

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 ritonavir may increase clobazam exposure and prolong the duration of its effect, whereas induction of CYP2C19 by 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 ritonavir.

Coadministration has not been studied. Clobetasol is a substrate of CYP3A4 and exposure may increase due to inhibition of CYP3A4 by 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.

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. Ritonavir dosed as a pharmacokinetic booster is a weak CYP2D6 inhibitor and could increase clomifene exposure, although to a moderate extent. 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.

Use with caution. Coadministration may increase clonazepam concentrations and a decrease in dose may be necessary. Therapeutic concentration monitoring of clonazepam is recommended.

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 may increase clorazepate concentrations. The European SPC contraindicates coadministration due to the risk of extreme sedation and respiratory depression; this may be more applicable for ritonavir used as an antiretroviral agent. The US Prescribing Information suggests dose reduction may be required; this may be more applicable for ritonavir used as a pharmacokinetic enhancer.

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 may increase clozapine concentrations thereby increasing the risk of serious haematologic abnormalities, or other serious adverse effects. Coadministration is contraindicated in the European SPC, but the US prescribing information does not mention the interaction. The charts reflect a cautious option based on the use of ritonavir as a pharmacokinetic enhancer.

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 ritonavir could potentially reduce the analgesic efficacy.

Coadministration of ritonavir (100 mg twice daily for 5 days) and colchicine (0.6 mg single dose) significantly increased colchicine Cmax and AUC by 2.7-fold and 3.5-fold, respectively. Coadministration is contraindicated in patients with renal or hepatic impairment. 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 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, a clinically relevant effect on ritonavir exposure 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, 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 ritonavir. A dose adjustment of cyproterone may be required.

Coadministration of dabigatran (150 mg single dose) simultaneously with or 2 h before ritonavir alone (100 mg once daily administered at steady state) was studied in HIV negative subjects. Simultaneous administration did not significantly change dabigatran PK (possibly due to mixed induction and inhibition of P-gp by ritonavir as dabigatran is a substrate of P-gp). Administration 2 hours before ritonavir decreased dabigatran AUC by 29% and Cmax by 27% (n=16). These results suggest that dabigatran can be administered simultaneously with ritonavir when used once daily as a pharmacokinetic enhancer in patients with no renal impairment, though no data are available when ritonavir is used twice daily as a pharmacokinetic enhancer. Data with verapamil (a P-gp inhibitor) and dabigatran suggest caution is needed in patients with mild or moderate renal impairment as the dabigatran dose might need to be reduced in presence of a P-gp inhibitor such as ritonavir. Note, dabigatran is not recommended in patients with severe renal impairment.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dapagliflozin is primarily metabolised by UGT1A9. Ritonavir may affect dapagliflozin due to UGT induction 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. 

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 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 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 an extra dose of ritonavir has not been studied with respect to safety, efficacy and pharmacokinetics.

Darunavir should be used in combination with 100 mg of ritonavir as a pharmacokinetic enhancer. Increasing the dose of ritonavir did not significantly affect darunavir concentrations and is not recommended.

Coadministration has not been studied but should be avoided. Dasatinib is metabolized by CYP3A4 and ritonavir may significantly increase dasatinib concentrations. If coadministration is unavoidable, close monitoring for toxicity 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 is required if prescribing ritonavir with medicines known to prolong the PR interval.

Coadministration has not been studied. 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 with a strong inhibitor of CYP3A4 (lopinavir/ritonavir) increased DM-6705 exposure by 25-30%. QTc prolongation has been reported with delamanid (and is very closely correlated with the metabolite DM-6705). A similar increase would be expected with ritonavir when used to boost other protease inhibitors and caution is advised. If coadministration is considered necessary, frequent monitoring of ECGs 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 ritonavir (100 mg twice daily) and desipramine (50 mg single dose) increased desipramine AUC by 26%. No a priori dosage adjustment is recommended when ritonavir is used as a pharmacokinetic booster.

Coadministration with a desogestrel-containing combined oral contraceptive (COC) has not been studied. Desogestrel is a prodrug that requires activation to etonogestrel. Activation to etonogestrel is by CYP2C9 (and possible CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Coadministration is predicted to increase etonogestrel due to induction of CYP2C9 and inhibition of CYP3A4. 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 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 ritonavir.

Coadministration has not been studied and is not recommended. Dextropropoxyphene has been withdrawn from most European and North American countries due to the risk of arrhythmias and fatalities. As it is metabolized mainly by CYP3A4, coadministration could markedly increase the exposure of dextropropoxyphene.

Coadministration may increase diazepam concentrations. The European SPC contraindicates coadministration due to the risk of extreme sedation and respiratory depression; this may be more applicable for ritonavir dosed as an antiretroviral agent. The US Prescribing Information suggests dose reduction may be required; this may be more applicable for ritonavir dosed as a pharmacokinetic enhancer.

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 ritonavir is a weak inducer of CYP2C9 when used as a pharmacokinetic booster. A dose adjustment is unlikely to be required for diclofenac.

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

Coadministration increases digoxin concentrations. If patients are already on ritonavir, start with the lowest dose of digoxin and monitor digoxin concentrations. Patients starting ritonavir whilst already on digoxin, should have their digoxin dose halved and their digoxin concentrations monitored. The impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including beta-adrenergic blockers) has not been evaluated. Clinical monitoring is recommended.

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. 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 is contraindicated as it is likely to increase dihydroergotamine concentrations and the 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 may increase diltiazem concentrations and a decrease in dose may be necessary. Caution is warranted and careful monitoring of therapeutic and adverse effects is recommended.

Coadministration has not been studied. Diphenhydramine is mainly metabolized by CYP2D6. Ritonavir dosed as a pharmacokinetic booster is a weak inhibitor of CYP2D6 and 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. Ritonavir used as a pharmacokinetic booster induces glucuronidation and may potentially decrease dipyridamole exposure, thereby reducing the antiplatelet effect.

Coadministration has not been studied but may increase disopyramide exposure and thereby the risk of cardiac arrhythmias. Coadministration is not recommended. Disopyramide is metabolized by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine.

Coadministration is not recommended with ritonavir ORAL SOLUTION as it contains alcohol (43% v/v). Ritonavir capsules have a lower alcohol content of 12% (w/w). Ritonavir tablets do not contain alcohol.

Coadministration has not been studied and is not recommended. Dofetilide is metabolized to a small degree by CYP3A4 and therefore ritonavir could potentially increase dofetilide exposure and thereby increase the risk of cardiac arrhythmias.

Coadministration with ritonavir alone has not been studied. Based on studies with boosted PIs, ritonavir is not expected to significantly affect dolutegravir pharmacokinetics. Using cross-study comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of ritonavir. No dosage 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 ritonavir would be possible from a pharmacokinetic standpoint. Based on studies with boosted PIs, ritonavir is not expected to significantly affect dolutegravir pharmacokinetics. Using cross-study comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of ritonavir. No interaction is expected with abacavir or lamivudine.

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 ritonavir would be possible from a pharmacokinetic standpoint. Based on studies with boosted PIs, ritonavir is not expected to significantly affect dolutegravir pharmacokinetics. Using cross-study comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of ritonavir. No interaction is expected with lamivudine.

Juluca (dolutegravir/rilpivirine) is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration with ritonavir-boosted PIs would be possible from a pharmacokinetic standpoint. Based on studies with boosted PIs, ritonavir is not expected to significantly affect dolutegravir pharmacokinetics. Using cross-study comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of ritonavir. Coadministration has not been studied but may increase rilpivirine concentrations, however, no dose adjustment is required. Rilpivirine is not expected to affect the plasma concentrations of ritonavir.

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 co-administered with antiretrovirals.

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. Coadministration of doravirine (50 mg single dose; half the recommended approved dose) with ritonavir (100 mg twice daily) increased doravirine AUC, Cmax and C24 by 254%, 31% and 191%, respectively (n=8).

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 a protease inhibitor boosted with 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 and ritonavir (100 mg twice daily with lopinavir, darunavir or saquinavir) had no significant effect on ritonavir concentrations. However, a higher risk of renal impairment has been reported in patients receiving tenofovir-DF in combination with a ritonavir boosted protease inhibitor. Close monitoring of renal function is required in these patients. 

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 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 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. Ritonavir could potentially increase doxepin exposure although to a moderate extent. No a priori dose adjustment is required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant 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, however, coadministration with protease inhibitors did not modify significantly doxorubicin exposure.

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 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 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 vivo data indicate that 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. 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.

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 of efavirenz (600 mg once daily) and ritonavir (500 mg twice daily) increased the AUC of efavirenz (21%) and ritonavir (17%) and a higher frequency of adverse events (e.g., dizziness, nausea, paraesthesia) and laboratory abnormalities (elevated liver enzymes) were observed. The magnitude of the interaction is expected to be lower when ritonavir is dosed as a pharmacokinetic booster and is expected to result in a lower risk of adverse effects.

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 ritonavir, may increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.

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 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 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 has not been studied. Tenofovir alafenamide (the prodrug of tenofovir) is a substrate of P-gp and inhibitors of P-gp such as ritonavir are expected to increase the absorption of tenofovir alafenamide, thereby increasing the systemic concentration. Descovy should be used at a dose of 200/10 mg once daily (where available).

Coadministration with emtricitabine/tenofovir-DF has not been studied. Ritonavir is metabolised by the CYP450 system and based on metabolism and clearance a clinically significant interaction with emtricitabine is unlikely. Coadministration of tenofovir-DF and ritonavir (100 mg twice daily with lopinavir, darunavir or saquinavir) had no significant effect on ritonavir concentrations. However, a higher risk of renal impairment has been reported in patients receiving tenofovir-DF in combination with a ritonavir boosted protease inhibitor. Close monitoring of renal function is required in these patients. 

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 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 is contraindicated as it is likely to increase ergometrine concentrations and the potential for serious and/or life threatening reactions such as acute ergot toxicity.

Coadministration is contraindicated as it is likely to increase ergotamine concentrations and the 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 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 may increase erythromycin concentrations. Careful monitoring of therapeutic and adverse effects is recommended.

Coadministration with low dose ritonavir has not been studied. Escitalopram is metabolized by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Ritonavir could potentially increase escitalopram concentrations although to a moderate extent. No a priori dosage adjustment 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 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 ritonavir plasma concentrations (when possible).

Based on interaction studies with lopinavir/ritonavir and atazanavir/ritonavir, concurrent administration of a proton pump inhibitor (omeprazole) or a H2-receptor antagonist(ranitidine) does not significantly modify ritonavir efficacy as a pharmacokinetic enhancer despite a slight change of exposure of about 6-18%.

Coadministration may increase estazolam concentrations. The European SPC contraindicates coadministration due to the risk of extreme sedation and respiratory depression; this may be more applicable for ritonavir dosed as an antiretroviral agent. The US Prescribing Information suggests dose reduction may be required; this may be more applicable for ritonavir dosed as a pharmacokinetic enhancer.

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.

Ritonavir is likely to change the uterine bleeding profile and reduce the effectiveness of estradiol-containing contraceptives. Coadministration of ethinylestradiol (50 µg single dose) and ritonavir (500 mg twice daily) decreased ethinyl estradiol AUC (40%) and Cmin (32%). Barrier or other non-hormonal methods of contraception should be considered. 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.

Use with caution. Coadministration may increase ethosuximide concentrations and a decrease in dose may be necessary. Therapeutic concentration monitoring of ethosuximide is recommended.

Coadministration has not been studied. Etidocaine is metabolized by CYP3A4 and concentrations may increase due to inhibition of CYP3A4 by ritonavir. Use with caution.

Coadministration with an etonogestrel-containing progestogen-only implant has not been studied. 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. Similarly, coadministration with ritonavir could potentially increase etonogestrel exposure and therefore is not expected to impair the contraceptive efficacy of etonogestrel when administered as an implant.

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. 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 ritonavir could potentially increase (inhibition of CYP3A4) or decrease (induction of UGT1A1) etoposide exposure. Close monitoring of etoposide induced toxicity is recommended. Reduce dose if clinically necessary or consider selection of an alternate non-CYP inhibiting antiretroviral regimen.

 Etravirine can be administered with low dose ritonavir in some boosted PI regimens with caution.

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 a clinically relevant effect on ritonavir exposure 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 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 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 ritonavir at least 1 hour before an exenatide injection. [Note: this interaction is not specific for ritonavir, but for any medication taken with exenatide.]

Based on interaction studies with lopinavir/ritonavir and atazanavir/ritonavir, concurrent administration of a proton pump inhibitor (omeprazole) or a H2-receptor antagonist (ranitidine) does not significantly modify ritonavir efficacy as a pharmacokinetic enhancer despite a slight change of exposure of about 6-18%.

Coadministration of ritonavir should be undertaken with caution as the impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. Clinical monitoring is recommended.

Coadministration of ritonavir (100 mg twice daily) and fenofibrate (145 mg single dose) had no significant effect on the AUC (11% decrease) or Cmax (1% decrease) of fenofibrate when administered to HIV-negative subjects. These data suggest that an interaction between fenofibrate and 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 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 ritonavir.

Coadministration has not been studied. Fexofenadine does not undergo CYP mediated metabolism but is a substrate of P-gp and OATP. 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.

Coadministration is contraindicated as it is likely to increase flecainide concentrations and the potential for serious and/or life threatening reactions such as cardiac arrhythmias.

Coadministration has not been studied. Flucloxacillin is mainly eliminated renally partly by glomerular filtration and partly by active secretion via OAT1. 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 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 of ritonavir (200 mg four times daily) with fluconazole (200 mg daily) increased ritonavir AUC (12%), Cmax (15%) and Cmin (14%). No dosage adjustment is required.

Coadministration has not been studied. Concomitant administration of 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 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 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 clinically significant 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 ritonavir via modulation of, or competition for metabolic pathways.

Coadministration with ritonavir as a pharmacokinetic booster 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. Ritonavir used as a pharmacokinetic booster could potentially increase fluoxetine concentrations although to a limited extent. No a priori dosage adjustment is recommended.

Coadministration has not been studied. Fluphenazine is metabolised by CYP2D6. Ritonavir dosed as a pharmacokinetic booster is a weak inhibitor of CYP2D6 and could potentially increase fluphenazine exposure, although to a moderate extent. 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 ritonavir with other drugs that prolong the PR interval has not been evaluated. Coadministration of 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.

Coadministration may increase flurazepam concentrations. The European SPC contraindicates coadministration due to the risk of extreme sedation and respiratory depression; this may be more applicable for ritonavir dosed as an antiretroviral agent. The US Prescribing Information suggests dose reduction may be required; this may be more applicable for ritonavir dosed as a pharmacokinetic enhancer.

Coadministration is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. Coadministration of fluticasone nasal spray (200 µg once daily) and ritonavir (100 mg twice daily) increased fluticasone AUC by ~350-fold and Cmax by ~25-fold. The significant increase in fluticasone exposure resulted in a significant decrease (86%) in plasma cortisol AUC. Systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression have been reported. A dose reduction of fluticasone 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 be required over a longer period.

The metabolism of fluvastatin is not dependent on CYP3A, and interactions are not expected with ritonavir. If treatment with a statin is indicated, pravastatin or fluvastatin are recommended.

Coadministration has not been studied. Fluvoxamine is metabolized mainly by CYP2D6 and to a lesser extent by CYP1A2. Ritonavir dosed as a pharmacokinetic booster is a weak inhibitor of CYP2D6 and could potentially increase fluvoxamine concentrations although to a moderate extent. No a priori dosage adjustment is recommended.

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. Fosinopril is hydrolysed by esterases in the GI mucosa and liver and is transported by MRP2. Ritonavir may increase fosinopril exposure due to inhibition of MRP2. 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 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 2D6 and coadministration could potentially increase gefitinib concentrations. Itraconazole (a strong CYP3A4 inhibitor) increased gefitinib exposure by 80%. A similar effect is expected with ritonavir.  If coadministration is necessary, close monitoring of gefitinib induced toxicity is recommended. 

Coadministration has not been studied. Gemfibrozil is metabolised mainly by UGT2B7. As ritonavir induces glucuronidation, coadministration could potentially decrease gemfibrozil exposure, although to a moderate extent. No a priori dosage adjustment is required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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, a clinically relevant effect on ritonavir exposure is unlikely.

Coadministration is not recommended. Concomitant use of glecaprevir/pibrentasvir with OATP1B inhibitors, such as ritonavir, may increase glecaprevir/pibrentasvir plasma concentrations.

Coadministration has not been studied. Gliclazide is metabolized mainly by CYP2C9 and to a lesser extent by CYP2C19. In vitro and in vivo data indicate that ritonavir is a weak inducer of CYP2C9 and could potentially decrease gliclazide concentrations, although to a moderate extent. Monitor clinical effect and increase gliclazide dosage if needed.

Coadministration has not been studied. Glimepiride is mainly metabolized by CYP2C9. In vitro and in vivo data indicate that ritonavir is a weak inducer of CYP2C9 and could potentially decrease glimepiride concentrations, although to a moderate extent. Monitor clinical effect and increase glimepiride dosage if needed.

Coadministration has not been studied. Glipizide is mainly metabolized by CYP2C9. In vitro and in vivo data indicate that ritonavir is a weak inducer of CYP2C9 and could potentially decrease glipizide concentrations, although to a moderate extent. Monitor clinical effect and increase glipizide dosage if needed.