Coadministration of tipranavir/ritonavir decreased abacavir exposure by ~40%. The clinical relevance of the reduction in abacavir levels has not been established. Coadministration is not recommended unless there are no other available NRTIs suitable for patient management. In such cases no dosage adjustment of abacavir can be recommended.

Coadministration has been studied but is contraindicated. Abemaciclib is metabolized by CYP3A4 and is a substrate of P-gp and BCRP. Ketoconazole (a strong CYP3A4 and P-gp inhibitor) has been predicted to increase abemaciclib AUC by 1470% and to increase the AUC of abemaciclib’s active metabolites (sum of 3 metabolites) by 615%. A similar effect is expected with tipranavir and therefore coadministration should be avoided.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Abiraterone is metabolized by CYP3A4 and SULT2A1. A 15% increase in abiraterone exposure has been reported in presence of ketoconazole (a strong CYP3A4 inhibitor) and a similar effect is expected with tipranavir/ritonavir, but this is not considered to be clinically relevant.

Coadministration has not been studied but should be avoided. Acalabrutinib is metabolized by CYP3A4. Itraconazole (a CYP3A4 inhibitor) increased acalabrutinib AUC and Cmax by 5.1- and 3.9-fold, respectively. A similar effect may occur with tipranavir/ritonavir. Increased acalabrutinib concentrations may result in increased toxicity, therefore, coadministration should be avoided.

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

Coadministration has not been studied. Acenocoumarol is mainly metabolized by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. In vitro and in vivo data indicate that ritonavir is a modest inducer of CYP2C9. Tipranavir/ritonavir could potentially decrease acenocoumarol concentrations. Monitor INR.

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

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

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

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

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

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 tipranavir/ritonavir may 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.

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

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

Coadministration is contraindicated as it may increase alfuzosin concentrations which may lead to severe hypotension.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alogliptin is primarily excreted unchanged in the urine and undergoes negligible CYP-mediated metabolism. Alogliptin was shown to have no inhibitory or inducing effect on CYPs at concentrations achieved with the recommended dose of 25 mg alogliptin.

Coadministration has not been studied. Ambrisentan is mainly glucuronidated by UGT1A9, UGT2B7, UGT1A3 and is metabolized to a lesser extent by CYP3A4. Ambrisentan is also a substrate of P-gp and OATP1B1. Ambrisentan concentrations may increase due to inhibition of OATP1B1 by tipranavir. Start ambrisentan at 5 mg and closely monitor the patient for tolerability.

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

Coadministration is contraindicated due to potential increase in amiodarone concentrations, which could result in serious and/or life-threatening reactions such as cardiac arrhythmias.

Coadministration with tipranavir/ritonavir has not been studied. The effect of tipranavir/ritonavir on calcium channel blockers that are dual substrates of CYP 3A and P-gp can not be predicted due to the conflicting effect of tipranavir/ritonavir on CYP 3A and P-gp. Caution is warranted and clinical monitoring of patients is recommended.

Coadministration has not been studied. Amphetamine is metabolized by CYP2D6 and coadministration could potentially increase amphetamine exposure. Caution is advised.

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

Coadministration 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 of tipranavir/ritonavir (500/200 mg twice daily) with an antacid containing aluminium and magnesium (20 ml single dose) decreased tipranavir AUC, Cmax and Cmin by 25-29%. Coadministration with antacids containing calcium carbonate has not been studied. Dosing of tipranavir/ritonavir with antacids should be separated by at least two hours.

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 and is not recommended. Concentrations of apixaban are expected to increase due to potent CYP3A4 and P-gp inhibition by ritonavir. Increased concentrations of apixaban increase the bleeding risk and the combination should be avoided if possible.

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. Apremilast is metabolized by multiple pathways involving hydrolysis, glucuronidation and oxidation by CYP3A4. Coadministration of apremilast with ketoconazole (a strong CYP3A4 inhibitor) increased apremilast AUC by 36%. This effect is not considered to be clinically significant and warrant a dosage adjustment of apremilast. Similarly, tipranavir/ritonavir is unlikely to significantly alter apremilast exposure. Furthermore, apremilast has no inhibitory or inducing effects on CYPs or drug transporters. Note: severe diarrhoea, nausea and vomiting can occur within the first few weeks after initiating apremilast treatment. Patients should be instructed to contact their healthcare provider if they experience severe diarrhoea, nausea or vomiting as this could potentially alter the absorption of orally administered antiretroviral drugs.

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 tipranavir is unlikely.

Coadministration has not been studied. Aripiprazole is metabolized by CYP3A4 and CYP2D6. Tipranavir/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. 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. Tipranavir does not interfere with this metabolic pathway.

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. Tipranavir does not interfere with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Ashwagandha extracts had no effect on CYP enzymes in vitro.

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

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

Coadministration is contraindicated due to potential increase in astemizole concentrations, which could result in serious and/or life-threatening reactions such as cardiac arrhythmias.

Coadministration of atazanavir/ritonavir (300/100 mg once daily) with tipranavir/ritonavir (500/100 mg twice daily) decreased atazanavir Cmax, AUC and Cmin by 57%, 68% and 81%, and increased tipranavir Cmax, AUC and Cmin by 8%, 20% and 75%. Coadministration is not recommended but if considered necessary, monitor atazanavir concentrations and the safety of tipranavir.

Coadministration has not been studied and is not recommended. Appropriate doses of this combination with respect to safety, efficacy and pharmacokinetics have not been established.

Coadministration has not been studied and is not recommended. Appropriate doses of this combination with respect to safety, efficacy and pharmacokinetics have not been established.

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.

Coadministration has not been studied. Atomoxetine is metabolized by CYP2D6 and concentrations may increase due to inhibition of CYP2D6 by tipranavir. Slower titration and a final lower dosage of atomoxetine may be necessary in presence of tipranavir/ritonavir.

This combination is not recommended. Coadministration of tipranavir/ritonavir increased plasma concentrations of a single dose atorvastatin by approximately 8-10 fold and reduced the AUCs of its metabolites by approximately 85%. There was no significant change the AUC, Cmax or Cmin of tipranavir. Other statins should be considered such as pravastatin, fluvastatin or rosuvastatin. However, if atorvastatin is specifically required for patient management, start with the lowest possible dose of atorvastatin with careful monitoring.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Avelumab is primarily metabolized through catabolic pathways and drug-drug interactions are not expected.

Coadministration has not been studied. Ayahuasca preparations contain N,N-dimethyltryptamine (DMT, a psychedelic substance along with monoamine oxidase inhibitors (MAOI) which attenuates the breakdown of DMT. MAOI are substrate of MRP2 which is inhibited by tipranavir thereby potentially increasing DMT toxicity by slowing its breakdown. Given the narrow therapeutic index of DMT, caution is advised. Harma alkaloids found in ayahuasca preparations may cause weak/moderate inhibition of CYP3A4 which is unlikely to alter exposure of tipranavir.

Coadministration has not been studied. Azilsartan is metabolized mainly by CYP2C9. In vitro and in vivo data indicate that ritonavir is a modest inducer of CYP2C9. Tipranavir/ritonavir could potentially decrease azilsartan concentrations, however, the clinical relevance of this is unknown. No a priori dose adjustment is required.

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

Coadministration with bazedoxifene alone or coformulated with conjugated estrogens as hormone replacement therapy (HRT) has not been studied. Bazedoxifene is glucuronidated by UGT1A1/8/10 and conjugated estrogens are metabolized by CYP3A4, CYP1A2 and are glucuronidated. Coadministration could potentially decrease exposure of bazedoxifene and conjugated estrogens due to induction of CYP1A2 and glucuronidation. Monitor for signs of estrogen deficiency.

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 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. Benazepril is rapidly hydrolyzed to its active metabolite benazeprilat. Benazeprilat is a substrate of UGTs (the specific UGTs have not been well described) and concentrations may decrease due to induction of UGTs by tipranavir. Adjust benazepril dosage based on the clinical response.

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 due to potential increase in bepridil concentrations, which could result in 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 tipranavir/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 tipranavir) 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. 

Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and should not be administered with other antiretroviral products. Furthermore, tipranavir is expected to decrease the absorption (and thereby plasma concentrations) of tenofovir alafenamide due to induction of P-gp which may result in loss of therapeutic effect and development of resistance.

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. An indirect effect of blinatumomab on CYPs may occur due to transient release of cytokines during the first days of therapy which can inhibit CYP450 metabolism, however, this is unlikely to be clinically relevant. The metabolic pathway of blinatumomab has not been characterised. Like other protein therapeutics, blinatumomab is expected to be degraded into small peptides and amino acids via catabolic pathways.

Coadministration is not recommended due to the marked hepatotoxicity of bosentan and the potential for increasing the liver toxicity associated with tipranavir. Coadministration may increase bosentan concentrations. The US Prescribing Information suggests when starting bosentan in patients already receiving tipranavir/ritonavir to start at a dose of 62.5 mg once daily or every other day based upon individual tolerability. When starting tipranavir/ritonavir in patients on bosentan, it recommends discontinuing bosentan at least 36 hours prior to starting tipranavir/ritonavir and resuming bosentan at 62.5 mg once daily or every other day based upon individual tolerability at least 10 days after the initiation of tipranavir/ritonavir.

Coadministration has not been studied but should be avoided. Bosutinib is metabolized by CYP3A4. Ketoconazole (a strong CYP3A4 inhibitor) increased bosutinib AUC by 8.6-fold. A similar effect may occur with tipranavir/ritonavir. Use an alternative antiretroviral drug with no inhibitory or inducing effects.

Coadministration has not been studied but should be used with caution. Brentuximab vedotin is an antibody-drug conjugate comprising a monoclonal antibody and monomethyl auristatin E (MMAE), a potent chemotherapeutic agent. The monoclonal antibody undergoes elimination via intracellular catabolism and does not interact with tipranavir/ritonavir. However, MMAE is a substrate of CYP3A4 and P-gp, therefore tipranavir/ritonavir may increase concentrations of MMAE and the incidence of neutropenia. Coadministration of brentuximab vedotin and ketoconazole (a strong inhibitor of CYP3A4 and P-gp) increased MMAE AUC by 34%. The increase in MMAE exposure might be less with tipranavir/ritonavir given its mixed inhibitory effect on CYP3A4 and inducing effect on P-gp. Patients receiving tipranavir/ritonavir concomitantly with brentuximab vedotin should be closely monitored for adverse reactions of brentuximab vedotin. If neutropenia develops, refer to dosing recommendations for neutropenia in the product label for brentuximab vedotin.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Brimonidine is metabolized mainly by aldehyde oxidase.

Coadministration has not been studied. Brincidofovir is a prodrug converted to cidofovir which is eliminated renally via glomerular filtration and active renal secretion by OAT1 and OAT3. Tipranavir/ritonavir does not interfere with this pathway. However, brincidofovir is a substrate of OATP1B1 and concentrations may increase due to inhibition of OATP1B1 by tipranavir/ritonavir. If concomitant use with brincidofovir is necessary, increase the monitoring for adverse reactions associated with brincidofovir (i.e. elevations in transaminases and bilirubin, diarrhoea, or other gastro-intestinal adverse events) and postpone the dosing of tipranavir/ritonavir for at least 3 hours after brincidofovir administration.

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. Tipranavir/ritonavir could potentially increase bromazepam concentrations. Start at the lowest dosage and titrate dosage until the desired response is achieved.

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

Coadministration has not been studied. Bupivacaine is predominantly metabolized by CYP3A4. CYP3A4 inhibitors such as boosted tipranavir 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 of tipranavir/ritonavir (500/200 mg twice daily) and buprenorphine/naloxone had no effect (<6%) on buprenorphine AUC or Cmin, but decreased Cmax by 14%. The AUC, Cmax and Cmin of norbuprenorphine (the major metabolite) decreased by ~80%. The AUC, Cmax and Cmin of naloxone decreased by 44%, 36% and 20%, respectively. There was no evidence of opioid withdrawal and no need to modify the dose of buprenorphine. When compared to historical data, there was no effect (<6%) on tipranavir Cmax, but AUC and Cmin decreased by 26% and 39%, respectively. Ritonavir Cmin was similar to historical data, but AUC decreased by 35% and Cmax decreased by 40-50%. Caution should be used as tipranavir may be less effective due to decreased concentrations. Patients should be monitored for signs of opioid withdrawal.

Coadministration of tipranavir/ritonavir decreased bupropion exposure by ~50%; exposure of the active metabolite decreased by ~25%. If coadministration is judged unavoidable, this should be done under close clinical monitoring for bupropion efficacy, without exceeding the recommended dosage.

Coadministration has not been studied and should be used with caution. Cabazitaxel is metabolized by CYP3A4. Coadministration with ketoconazole (a strong CYP3A4 inhibitor) increased cabazitaxel exposure by 25% and a similar effect is expected with tipranavir/ritonavir. Thus, coadministration should be avoided but if coadministration is required, consider a dose reduction of cabazitaxel of up to 25% and monitor for cabazitaxel toxicity.

Coadministration has not been studied. Cabergoline is extensively metabolized by the liver, predominantly via hydrolysis (non-CYP mediated metabolism), and is a substrate of P-gp. Cabergoline exposure increased by 2.6- to 4-fold in the presence of the strong P-gp inhibitors itraconazole or clarithromycin. Similarly, coadministration with tipranavir is expected to increase cabergoline exposure. Consider a reduction in cabergoline dose if the patient presents with adverse drug effects. No effect on tipranavir is expected as cabergoline does not inhibit or induce drug metabolizing enzymes. 

Coadministration has not been studied but a clinically significant interaction is unlikely when cabergoline is administered as a single dose to suppress lactation. Cabergoline is extensively metabolized by the liver, predominantly via hydrolysis (non-CYP mediated metabolism), and is a substrate of P-gp. Cabergoline exposure was shown to increased 2.6- to 4-fold in the presence of the strong P-gp inhibitors itraconazole or clarithromycin. Although tipranavir inhibits P-gp, no dose adjustment of cabergoline is required when cabergoline is administered as a single dose to suppress lactation. No effect on tipranavir is expected as cabergoline does not inhibit or induce drug metabolizing enzymes.

Coadministration has not been studied. Coadministration of rifampicin (600 mg once daily) and oral cabotegravir (30 mg once daily) decreased cabotegravir AUC by 59%. Tipranavir has inducing properties and is predicted to significantly reduce cabotegravir exposure. Coadministration with intramuscular cabotegravir is contraindicated due to the potential for loss of therapeutic effect and development of resistance. Residual concentrations of cabotegravir may remain in the systemic circulation for prolonged periods (up to 12 months or longer) but are not expected to affect the exposure of antiretroviral drugs initiated after discontinuation of Apretude.

Coadministration has not been studied. Coadministration of rifampicin (600 mg once daily) and oral cabotegravir (30 mg once daily) decreased cabotegravir AUC by 59%. Tipranavir has inducing properties and is predicted to reduce cabotegravir exposure. Coadministration with oral cabotegravir is contraindicated due to the potential for loss of therapeutic effect and development of resistance. Cabotegravir is not expected to alter concentrations of other antiretroviral products. 

Cabenuva (cabotegravir LA, rilpivirine LA) is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. In addition, tipranavir has inducing properties and therefore has the potential to reduce cabotegravir and rilpivirine exposures. Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for a prolonged period after discontinuation of intramuscular cabotegravir/rilpivirine but are not expected to affect exposure of antiretroviral drugs.

Coadministration has not been studied but should be used with caution. Cabozantinib is metabolized by CYP3A4. Ketoconazole (a strong CYP3A4 inhibitor) increased cabozantinib AUC by 38%. A similar effect may occur with tipranavir/ritonavir. Avoid concomitant use with strong inhibitors if possible. If a strong CYP3A4 inhibitor must be used, reduce the cabozantinib daily dose by 20 mg. Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2-3 days after discontinuation of the strong inhibitor

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Calcitonin is primarily metabolized via proteolysis in the kidney. Tipranavir does not interfere with this pathway.

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. Tipranavir/ritonavir could lead to reduced exposure to canagliflozin as a result of UGT enzyme induction by ritonavir as rifampicin (a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4) decreased canagliflozin AUC by 51% which may result in reduced efficacy. If coadministration is deemed necessary, increasing canagliflozin to 300 mg once daily may be considered if patients are currently tolerating canagliflozin 100 mg once daily, have an eGFR ≥60 mL/min/1.73m2 or CrCl ≥60 mL/min, and require additional glycaemic control. Other glucose-lowering therapies should be considered for patients with an eGFR 45 mL/min/1.73m2 to <60 mL/min/1.73m2 or CrCl 45 mL/min to <60 mL/min taking canagliflozin 100 mg who are receiving concurrent therapy with a UGT enzyme inducer and who require additional glycaemic control.

Coadministration has not been studied. Cannabidiol is mainly metabolized by CYP3A4 and CYP2C19. Coadministration may increase cannabidiol concentrations due to strong inhibition of CYP3A4 by tipranavir + 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 modest inducer of CYP2C9. Tipranavir/ritonavir could potentially decrease THC exposure although to a moderate extent. 

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

Caution should be used when prescribing carbamazepine. Tipranavir may be less effective due to decreased tipranavir concentrations. Coadministration with carbamazepine (200 mg twice daily) decreased tipranavir Cmin by 61% when compared to historical controls. Carbamazepine AUC, Cmax and Cmin were increased by 26%, 22% and 35%, respectively, but this is not expected to have clinical consequences.

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 additionally metabolism via CYP2D6 and to a lesser extent CYPs 2C9 and 1A2. Tipranavir/ritonavir could potentially increase carvedilol concentrations via CYP2D6 inhibition or decrease carvedilol concentrations via induction of glucuronidation. The net effect on carvedilol concentrations is difficult to predict but likely to be moderate in magnitude. No a priori dosage adjustment is required.

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

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

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

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

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

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

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

Coadministration 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 tipranavir 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 with a chlormadinone-containing combined oral contraceptive (COC) has not been studied. Chlormadinone undergoes extensive hepatic metabolism by hydroxylation (likely CYP mediated). Coadministration is predicted to increase exposure of chlormadinone. 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. Chlorphenamine is predominantly metabolized in the liver via CYP2D6. Tipranavir/ritonavir could potentially increase chlorphenamine exposure. Start at the lowest dosage and titrate dosage until the desired response is achieved.

Coadministration has not been studied. Chlorpromazine is metabolized mainly by CYP2D6, but also by CYP1A2. Tipranavir/ritonavir could potentially increase chlorpromazine exposure although to a moderate extent. No a priori dosage adjustment is recommended.

Coadministration has not been studied. Ciclesonide can be administered with tipranavir 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 tipranavir 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 with tipranavir/ritonavir has not been studied. The effect of tipranavir/ritonavir on immunosuppressants can not be predicted due to the conflicting effect of tipranavir/ritonavir on CYP 3A and P-gp. Increased concentration monitoring of the immunosuppressant is recommended until blood levels have been stabilized.

This interaction has not been studied, but any increase in gastric pH that may result from H2-receptor antagonist therapy is not expected to have an impact on tipranavir plasma concentrations.

Coadministration is contraindicated due to potential increase in cisapride concentrations, which could result in 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 of tipranavir/ritonavir (500/200 mg twice daily) and clarithromycin (500 mg twice daily) increased tipranavir AUC (66%), Cmax (40%) and Cmin (100%). Clarithromycin AUC increased by 19% and metabolite AUC decreased by 95%. No dose adjustment of tipranavir or clarithromycin for patients with normal renal function is necessary. For patients with renal impairment, consider the following dosage adjustments: CLCR 30-60 ml/min , reduce clarithromycin by 50%; CLCR less than 30 ml/min reduce clarithromycin 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 tipranavir/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 tipranavir/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.

This interaction has not been studied. In vitro studies have suggested that transformation of clomifene to its active metabolite is likely to be mediated via CYP2D6. As tipranavir/ritonavir may inhibit CYP2D6 metabolism, there is potential for interaction if ritonavir boosted tipranavir is administered with clomifene, although the clinical significance is unknown.

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.

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.

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

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

Coadministration has not been studied. 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 tipranavir 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. 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 tipranavir 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. Colestyramine may delay or reduce the absorption of drugs. Administration of other drugs should be at least 1 hour before or 4-6 hours after colestyramine. [Note: this interaction is not specific for tipranavir, but for any medication taken with colestyramine.]

Coadministration with conjugated estrogens as hormone replacement therapy (HRT) has not been studied. Conjugated estrogens are metabolized by CYP3A4, CYP1A2 and are glucuronidated. Coadministration could potentially decrease exposure of conjugated estrogens due to induction of CYP1A2 and glucuronidation (rather than increase it due to inhibition of CYP3A4). Monitor for signs of estrogen deficiency. In contrast exposure of progestogens administered as part of HRT may increase. The clinical relevance of this is unknown but increased progestogen concentrations may be associated with a higher incidence of side effects. Note, use of conjugated estrogens as part of gender affirming treatment should be avoided as they are associated with high thromboembolic risk.

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

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

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.

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

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

Coadministration with tipranavir has not been studied. 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 tipranavir/ritonavir. Note, dabigatran is not recommended in patients with severe renal impairment.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tipranavir/ritonavir is metabolized by CYP3A. Tipranavir has inducing properties. Dapivirine is metabolized mainly by CYP3A4 and to a lesser extent by glucuronidation. However, the risk of drug-drug interactions is low with the dapivirine vaginal ring due to its low systemic exposure. Furthermore, dapivirine concentrations in vaginal fluid exceed the in vitro HIV IC99 by 1000-fold.

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.

The coadministration of darunavir/ritonavir and PIs other than lopinavir/ritonavir, saquinavir, atazanavir, and indinavir has not been studied. Therefore, such coadministration is not recommended.

Symtuza is (darunavir, cobicistat, emtricitabine, tenofovir alafenamide) indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. Furthermore, tipranavir is expected to decrease the absorption (and thereby plasma concentrations) of tenofovir alafenamide due to induction of P-gp which may result in loss of therapeutic effect and development of resistance.

Coadministration has not been studied is currently not recommended. Appropriate doses of this combination with respect to safety, efficacy and pharmacokinetics have not been established.

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. Ritonavir should be used with caution in patients taking medicines known to prolong the PR interval. Tipranavir/ritonavir may prolong the QT interval at supratherapeutic doses.

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 tipranavir/ritonavir 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 has not been studied but is expected to increase concentrations of desipramine. Dosage reduction and concentration monitoring of desipramine is recommended.

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 tipranavir.

Coadministration has not been studied. The effect on dexlansoprazole concentrations is difficult to predict due to CYP3A4 inhibition and CYP2C19 induction by tipranavir/ritonavir. Coadministration is not recommended, but if judged unavoidable, this should be done under close clinical monitoring.

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

Coadministration may increase digoxin concentrations after a single dose of tipranavir/ritonavir, but digoxin concentrations may be decreased slightly once tipranavir/ritonavir is at steady state. Monitoring digoxin concentrations is recommended until steady state has been obtained.

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. Tipranavir/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 due to potential increase in dihydroergotamine concentrations, which could result in serious and/or life-threatening reactions such as acute ergot toxicity.

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

Coadministration with tipranavir/ritonavir has not been studied. The effect of tipranavir/ritonavir on calcium channel blockers that are dual substrates of CYP 3A and P-gp can not be predicted due to the conflicting effect of tipranavir/ritonavir on CYP 3A and P-gp. Caution is warranted and clinical monitoring of patients is recommended.

Coadministration has not been studied. Diphenhydramine is mainly metabolized by CYP2D6. Tipranavir/ritonavir could potentially increase diphenhydramine. Use with caution.

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

Coadministration has not been studied 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.

Tipranavir capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram.

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

Coadministration decreases dolutegravir concentrations and a dose adjustment of dolutegravir is recommended. Coadministration of tipranavir/ritonavir (500/200 mg twice daily) and dolutegravir (50 mg once daily) decreased dolutegravir Cmax, AUC and Ctrough by 46%, 59% and 76%, respectively. When coadministered with tipranavir/ritonavir, a dose adjustment of dolutegravir to 50 mg twice daily is recommended in the absence of integrase class resistance. In the presence of integrase class resistance this combination should be avoided.

Triumeq (dolutegravir, abacavir, lamivudine) is indicated for use as a complete regimen for the treatment of HIV-1 infection and coadministration with tipranavir is expected to decrease dolutegravir exposure. If intensification of HIV treatment is needed, alternatives to tipranavir should be considered as appropriate doses of this combination with respect to safety, efficacy and pharmacokinetics of dolutegravir have not been established. The European product label for Triumeq does not recommend coadministration with tipranavir. However, the US product label for Triumeq recommends that an additional dolutegravir 50 mg tablet, separated by 12 hours from Triumeq, should be taken. Coadministration of tipranavir/ritonavir and dolutegravir decreased dolutegravir AUC, Cmax and Ctrough by 59%, 47% and 76%, respectively; there was no effect on tipranavir or ritonavir. Coadministration of tipranavir/ritonavir decreased abacavir exposure by ~40%. The clinical relevance of the reduction in abacavir levels has not been established. Coadministration of tipranavir/ritonavir and lamivudine had no significant effect on lamivudine AUC or Cmax.

Dovato (dolutegravir/lamivudine) is indicated for use as a complete regimen for the treatment of HIV 1 infection. If intensification of HIV treatment is needed, alternatives to tipranavir should be considered as appropriate doses of this combination with respect to safety, efficacy and pharmacokinetics of dolutegravir have not been established. Coadministration with other antiretroviral drugs for the treatment of HIV-1 infection is not recommended in the US Prescribing Information for Dovato. However, the European product label for Dovato recommends an additional 50 mg tablet of dolutegravir should be administered, approximately 12 hours after Dovato, during coadministration with tipranavir. Coadministration of dolutegravir and tipranavir decreased dolutegravir AUC, Cmax and Cmin by 59%, 47% and 76%, respectively. There was no change in tipranavir or ritonavir pharmacokinetics.

Juluca (dolutegravir/rilpivirine) is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. Furthermore, tipranavir decreases dolutegravir concentrations and could potentially decrease rilpivirine exposure and thereby result in loss of efficacy.

Coadministration has not been studied. Donepezil is metabolized by CYP3A4 and CYP2D6 (minor). A 30% increase in donepezil exposure has been reported in presence of ketoconazole, a strong CYP3A4 inhibitor. A similar effect is expected with tipranavir/ritonavir. No a priori dose modification is required but monitoring for increased side effects is recommended.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs there is little potential for interaction. 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 has not been studied. Coadministration with ritonavir increased doravirine AUC by 3.5 fold and Cmin by 2.9 fold. No dose adjustment of doravirine is required as phase I trials showed a good tolerability of doravirine with up to a 3-4 fold increase in exposure.

Delstrigo (doravirine, lamivudine, tenofovir-DF) is indicated for use as a complete regimen for the treatment of HIV-1 infection and coadministration with other antiretroviral agents is not recommended in Delstrigo product labels. If intensification of HIV treatment is needed, alternatives to tipranavir should be considered as appropriate doses of this combination with respect to safety, efficacy and pharmacokinetics of doravirine have not been established.

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 tipranavir, 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 tipranavir.

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. Tipranavir/ritonavir could potentially decrease doxepin concentrations (induction of CYP2C19) but increase nordoxepin concentrations (inhibition of CYP2D6). No a priori dosage adjustment is recommended.

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.

This interaction has not been studied. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for interaction. 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 3A4. In vitro and in vivo data indicate that ritonavir is a modest inducer of CYP2C9. Tipranavir/ritonavir could potentially decrease dronabinol exposure although to a moderate extent. 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. 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. 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 with a drospirenone progestogen-only pill (POP) has not been studied. CYP3A4 contributes to drospirenone metabolism. Coadministration is predicted to increase drospirenone and therefore, based on studies with norethisterone used as a progestogen only pill, the contraceptive efficacy of a drospirenone POP is unlikely to be compromised by tipranavir.

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

Coadministration has not been studied. Duloxetine is metabolized by CYP2D6 and CYP1A2. In vitro data indicate that 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. Tipranavir/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.

Coadmninstration of tipranavir/ritonavir (500/200 mg twice daily) and efavirenz (600 mg once daily) had no effect at steady state on tipranavir AUC and Cmax. Cmin increased by 19%, but this was not considered clinically relevant. No significant changes in efavirenz concentrations have been observed.

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

Coadministration is contraindicated. Concomitant use of elbasvir/grazoprevir with OATP1B inhibitors, such as tipranavir, may increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.

Coadministration has not been studied and is not recommended. Eletriptan is metabolised by CYP3A4 and concentrations may increase due to inhibition of CYP3A4 by tipranavir. Coadministration with ketoconazole (a strong CYP3A4 inhibitor) increased eletriptan Cmax and AUC by 2.7 and 5.9 fold, respectively. The US product label for eletriptan contraindicates its use with potent CYP3A4 inhibitors whereas the European product label advises that it should not be used with potent CYP3A4 inhibitors.

Genvoya (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products. Genvoya should not be used in conjunction with protease inhibitors due to potential drug-drug interactions including altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir and/or the coadministered antiretroviral products. Genvoya should not be administered concurrently with products containing ritonavir or regimens containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.

Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir-DF) is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products. Stribild should not be used in conjunction with protease inhibitors inhibitors due to potential drug-drug interactions including altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the coadministered antiretroviral products. Stribild should not be administered concurrently with products containing ritonavir or regimens containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Empagliflozin is metabolised by UGTs and is a substrate of P-gp, BCRP, OAT3 and OATP1B1/1B3. Although tipranavir/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 is not recommended. Tipranavir/ritonavir results in P-glycoprotein induction and therefore is expected to decrease the absorption of tenofovir alafenamide and thereby plasma concentrations which may result in loss of therapeutic effect and development of resistance.

Emtricitabine and tenofovir alafenamide used as PrEP are not expected to be coadministered with antiretrovirals. Coadministration is not recommended. Tipranavir/ritonavir results in P-glycoprotein induction and therefore is expected to decrease the absorption of tenofovir alafenamide and thereby plasma concentrations which may result in loss of therapeutic effect and development of resistance.

Coadministration with emtricitabine/tenofovir-DF has not been studied. Tipranavir is primarily metabolised by CYP3A4 and based on metabolism and clearance a clinically significant interaction with emtricitabine is unlikely. Coadministration of tenofovir (300 mg once daily) and tipranavir/ritonavir (500/100 mg twice daily) decreased tenofovir Cmax and AUC by 23% and 2%, but increased Cmin by 7%; tipranavir Cmax, AUC and Cmin decreased by 17%, 18% and 21%, respectively (n=22). Coadministration of tenofovir (300 mg once daily) and tipranavir/ritonavir (750/200 mg twice daily) decreased tenofovir Cmax by 38%, but increased AUC and Cmin by 2% and 14%; tipranavir Cmax, AUC and Cmin decreased by 11%, 9% and 12%, respectively (n=20). No dosage adjustment is necessary. 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.

Data from Phase 3 trials show steady state trough tipranavir concentrations to be ~45% higher in patients coadministered enfuvirtide, however, no a priori dose adjustment is recommended. A pharmacokinetic interaction is mechanistically unexpected and the interaction has not been confirmed in a controlled interaction study. Conflicting data from two studies - data from 55 HIV+ subjects (27 with enfuvirtide, 28 without enfuvirtide) showed higher tipranavir concentrations (50% increase) in the enfuvirtide group, but data from 15 HIV+ patients (11 with and 4 without enfuvirtide) showed no significant effect of enfuvirtide on tipranavir trough concentrations or full 12 hour pharmacokinetic profiles.

Coadministration has not been studied but is not recommended. Enzalutamide is primarily metabolized by CYP2C8 and to a lesser extent by CYP3A4. Enzalutamide concentrations may significantly increase as tipranavir is a strong inhibitor of CYP2C8. However, tipranavir/ritonavir is metabolized by CYP3A4 and enzalutamide is a strong inducer of CYP3A4 and may significantly decrease tipranavir/ritonavir exposure leading to loss of therapeutic effect and possible development of resistance. 

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

Coadministration has not been studied 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 due to potential increase in ergometrine concentrations, which could result in serious and/or life-threatening reactions such as acute ergot toxicity.

Coadministration is contraindicated due to potential increase in ergotamine concentrations, which could result in serious and/or life-threatening reactions such as acute ergot toxicity.

Coadministration has not been studied. Escitalopram is metabolized by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Tipranavir/ritonavir could potentially increase escitalopram concentrations. Start at the lowest dosage and titrate dosage until the desired response is achieved.

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 tipranavir 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 tipranavir plasma concentrations (when possible).

Coadministration of omeprazole decreases omeprazole AUC and Cmax by 70% and 73%, respectively. Similar effects were observed for the S-enantiomer, esomeprazole. There was no effect on tipranavir AUC or Cmax. Coadministration is not recommended, but if unavoidable, dose increases of esomeprazole may be considered based on clinical response.

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.

Coadministration of tipranavir/ritonavir with a single dose of an oral contraceptive (ethinylestradiol/norethindrone 0.035/1.0 mg) decreased ethinylestradiol AUC by 40-50% (formal interaction studies performed with different doses of tipranavir/ritonavir - 250/200, 500/100, 750/100, 750/200 mg). There was no change in tipranavir AUC. Alternative or additional methods of non-hormonal contraception should be used when estrogen based oral contraceptives are co-administered with tipranavir/ritonavir. Women using estrogens may have an increased risk of non serious rash. Note, use of ethinylestradiol as part of gender affirming treatment is not recommended due to thrombotic risks.

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

Coadministration has not been studied. Etidocaine is metabolized by CYP3A4 and concentrations may increase due to inhibition of CYP3A4 by tipranavir. 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 tipranavir 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. Tipranavir 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.

Etravirine and tipranavir/ritonavir should not be coadministered due to decreased etravirine exposure. Coadministration of tipranavir/ritonavir (500/200 mg twice daily) and etravirine decreased etravirine Cmax, AUC and Cmin by 71%, 76% and 82% respectively; tipranavir Cmax, AUC and Cmin increased by 14%, 18% and 24%, respectively.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Eucalyptus is only a weak inhibitor of CYP3A4 and any additional effect on exposure of tipranavir in the presence of ritonavir is unlikely.

Coadministration 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 tipranavir/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 tipranavir/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 tipranavir at least 1 hour before an exenatide injection. [Note: this interaction is not specific for tipranavir, but for any medication taken with exenatide.]

This interaction has not been studied, but any increase in gastric pH that may result from H2-receptor antagonist therapy is not expected to have an impact on tipranavir plasma concentrations.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fampridine is metabolized by CYP2E1 but is predominantly eliminated unchanged by the kidney with active secretion by OCT2. Tipranavir does not interfere with fampridine elimination pathway.

Coadministration with tipranavir/ritonavir has not been studied, but may increase felodipine concentrations. Caution is warranted and clinical monitoring of patients is recommended.

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 tipranavir 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 but based on metabolism and clearance a clinically significant interaction is unlikely.

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/OATP. Tipranavir/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 has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Filgrastim is eliminated mainly by neutrophil-mediated clearance and renal excretion.

Coadministration is contraindicated due to potential increase in flecainide concentrations, which could result in serious and/or life-threatening reactions such as cardiac arrhythmias.