Coadministration of ombitasvir/paritaprevir/ritonavir + dasabuvir and abacavir/lamivudine (600/300 mg once daily) was studied in 12 HIV/HCV-negative subjects and had no clinically significant effect on the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, dasabuvir, abacavir or lamivudine. No dose adjustment is required for ombitasvir/paritaprevir/ritonavir + dasabuvir or abacavir during coadministration.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Abiraterone has multiple metabolic pathways and is an inhibitor of CYP2D6. Ritonavir is an inhibitor of CYP3A4, but data from ketoconazole have shown a negligible effect of CYP3A4 inhibitors on abiraterone.

Coadministration has not been studied but should be avoided. Acalabrutinib is a CYP3A4 and P-gp substrate. Acalabrutinib concentrations may increase due to inhibition of CYP3A4 by ritonavir. Itraconazole (a CYP3A4 inhibitor) increased acalabrutinib AUC and Cmax by 5.1- and 3.9-fold, respectively, and a similar effect could be expected with ritonavir.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely as acamprosate does not undergo significant metabolism.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aceclofenac is metabolised by CYP2C9 which is not affected by ombitasvir/paritaprevir/ritonavir + dasabuvir.

Coadministration has not been studied. Acenocoumarol is a substrate of CYP2C9 and CYP1A2. Ombitasvir/paritaprevir/ritonavir at steady-state did not affect the plasma exposures of the anticoagulant warfarin which is metabolised in a similar way. However, a case report describes a patient who required a significant increase in acenocoumarol weekly dose probably due to an interaction with ombitasvir/paritaprevir/ritonavir and/or dasabuvir. Ombitasvir/paritaprevir/ritonavir and acenocoumarol can be coadministered but with close monitoring of international normalized ratio (INR) as dose modifications may be necessary in some patients.

Coadministration has not been studied. Activated charcoal absorbs substances in the stomach and intestines and may decrease absorption of orally administered medications. If coadministration is required, administration of activated charcoal and ombitasvir/paritaprevir/ritonavir + dasabuvir should be separated by 4 hours. [Note: this interaction is not specific for ombitasvir/paritaprevir/ritonavir + dasabuvir, but for any medication taken with activated charcoal.]

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. Ombitasvir/paritaprevir/ritonavir + dasabuvir is not expected to interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. CYP3A4/5, CYP2D6 and CYP2C8 are involved in the metabolism of ombitasvir, paritaprevir, ritonavir and dasabuvir. The potential for hepatically metabolised interactions with adefovir is low. Adefovir is eliminated renally via glomerular filtration and active renal secretion by OAT1. Ombitasvir/paritaprevir/ritonavir and dasabuvir do not interfere with this pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as agomelatine is metabolized predominantly by CYP1A2. [Note, agomelatine is contraindicated in hepatic impairment as increases in exposure of 140-fold have been seen in cirrhotic patients.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Albiglutide is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by ubiquitous proteolytic enzymes. Albiglutide slows gastric emptying, but this is unlikely to have a clinically relevant effect on ombitasvir/paritaprevir/r + dasabuvir.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alcohol is metabolized by alcohol dehydrogenase and aldehyde dehydrogenase. Acute alcohol use inhibits CYP2E1. Chronic use may induce CYP2E1 and to a lesser extent CYP3A4 but this is unlikely to be clinically relevant in the context of ritonavir, a potent CYP3A4 inhibitor. Additionally, a study of over 15,000 veterans treated with DAAs found no association between alcohol use and SVR12, suggesting that alcohol does not affect the efficacy of DAAs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as alemtuzumab is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by widely distributed proteolytic enzymes.

Coadministration has not been studied but alendronate can be administered with ombitasvir/paritaprevir/ritonavir + dasabuvir and no dose alteration is required. Alendronate is not metabolised and is cleared from the plasma by uptake into bone and elimination via renal excretion. Although no pharmacokinetic interaction is expected, alendronate should be separated from food or other medicinal products and therefore should be separated from ombitasvir/paritaprevir/ritonavir + dasabuvir administration. [Note: this interaction is not specific for ombitasvir/paritaprevir/ritonavir + dasabuvir, but for any medication taken with alendronic acid.]

Coadministration has not been studied but alfentanil concentrations may be increased since it is a substrate of CYP3A4. Close monitoring of therapeutic response and adverse effects (including respiratory depression) is recommended, especially at initiation of treatment. A dosage adjustment of alfentanil may be required.

Coadministration has not been studied but allopurinol can be administered with ombitasvir/paritaprevir/ritonavir + dasabuvir and no dose alteration is required. Allopurinol is a substrate of xanthine oxidase and no interaction is expected. [Note, the European SmPC and US Prescribing Information for allopurinol recommend a reduced dose in hepatic impairment.]

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 does not undergo extensive metabolism and is excreted mainly unchanged in the urine and metabolism by CYPs is minimal. No transporter interactions have been described.

Coadministration increased alprazolam AUC by 34% with no significant effect on exposures of ombitasvir, paritaprevir, ritonavir or dasabuvir. Close monitoring of patients is recommended. A decrease in dose may be considered based on clinical response.

Coadministration has not been studied but based on limited understanding of metabolism and clearance a clinically significant interaction is unlikely. However as alverine citrate affects gastric motility, an effect on the absorption of ombitasvir/paritaprevir/ritonavir + dasabuvir cannot be ruled out. Doses of ombitasvir/paritaprevir/ritonavir + dasabuvir and alverine should be separated by 4 hours if possible. [Note: this interaction is not specific for ombitasvir/paritaprevir/ritonavir + dasabuvir, but for any medication taken with alverine citrate.]

Coadministration has not been studied. Ambrisentan is glucuronidated by several UGT isoenzymes and metabolised to a lesser extent by CYP3A4. Ambrisentan is also a substrate of P-gp and OATP1B1. An effect on ambrisentan exposure is not anticipated due to CYP3A4/P-gp inhibition by ritonavir. However, coadministration with ciclosporin resulted in a 2-fold increase in ambrisentan exposure (possibly due to OATP1B1 inhibition). A similar effect may occur due to inhibition of OATP1B1 by paritaprevir. Advise patient to be aware of the potential for increased side effects during coadministration.

Amlodipine is a substrate of CYP3A4 and coadministration increased amlodipine AUC by 2.6-fold. Caution is warranted. Consider a dose reduction for amlodipine (a dose reduction of 50% is recommended in the European SPC). Close monitoring is recommended.

Coadministration has not been studied and is not recommended. Amobarbital induces CYP3A4 and P-gp and could decrease concentrations of ombitasvir/paritaprevir/ritonavir + dasabuvir. This may result in loss of efficacy and potential virological failure.

Coadministration has not been studied. Amodiaquine is metabolized mainly by CYP2C8 to N-desethylamodiaquine, a metabolite responsible for almost all of the antimalarial effect. Ritonavir is a weak inducer of CYP2C8. Ombitasvir/paritaprevir are inhibitors of CYP2C8 in vitro. Coadministration of a ritonavir-boosted HIV protease inhibitor (lopinavir/ritonavir) and amodiaquine decreased desethylamodiaquine exposure by 51%. This drug-drug interaction was unexpected and the related mechanism is unclear. A similar effect cannot be excluded with ombitasvir/paritaprevir/ritonavir + dasabuvir and this could compromise the efficacy of the antimalarial treatment. Consider using an alternative antimalarial drug.

Coadministration has not been studied. Angarelide is metabolised by CYP1A2 and concentrations may decrease due to induction of CYP1A2 by ritonavir. Close monitoring for efficacy is recommended. Consider a dose increase if clinically indicated.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ombitasvir is primarily metabolized by amide hydrolysis followed by oxidative metabolism, with only a minor contribution from CYP enzymes. Paritaprevir is metabolized by CYP3A4 and CYP3A5. Ritonavir is metabolized by CYP3A and CYP2D6. Dasabuvir is metabolized by CYP2C8 and CYP3A4. Anakinra does not interact with these pathways. Anakinra is an IL-1 receptor antagonist and is eliminated by glomerular filtration and subsequent tubular metabolism.

Coadministration has not been studied. 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. The European SmPC for apixaban says that coadministration is not recommended, but the US prescribing information advises a 50 % dose reduction for apixaban. Refer to the apixaban product label for details. Of interest, no adverse outcomes were reported in six HIV infected patients treated with a reduced dose of apixaban (2.5 mg twice daily) while on ritonavir boosted regimens. No effect on ombitasvir/paritaprevir/ritonavir + dasabuvir is expected.

Coadministration has not been studied. Aprepitant is a substrate, inhibitor and inducer of CYP3A4 and also inhibits CYP2C9. Aprepitant exposure may increase due to CYP3A4 inhibition by ritonavir. Close monitoring is recommended. A decrease in aprepitant dose may be needed.

Coadministration has not been studied. Aripiprazole is a substrate of CYP3A4 and CYP2D6. Aripiprazole exposure may increase due to CYP3A4 inhibition by ritonavir. Close monitoring is recommended. A decrease in aripiprazole dose may be needed. The aripiprazole label suggests decreasing the dose by one-half when administered with CYP3A4 inhibitors like ketoconazole.

Coadministration has not been studied. Artemether is a substrate of CYP3A4 and exposure may increase due to CYP3A4 inhibition by ritonavir. Close monitoring for increased side effects is recommended.

Coadministration has not been studied. Artemisinins undergo rapid metabolism via several CYP450 (CYPs 3A4, 2A6, 2B6). The active metabolite (dihydroartemisinin, which has greater potency than the parent drug) is further metabolized via UGTs 1A9 and 2B7 and has been shown to induce CYP3A4. There is the possibility of a decrease in exposure of ombitasvir/paritaprevir/ritonavir + dasabuvir although it is difficult to judge the clinical relevance. Close monitoring for therapeutic effect is recommended.

Coadministration has not been studied. Dihydroartemisinin (the active metabolite of artesunate) is further metabolised via UGTs 1A9 and 2B7 and has been shown to induce CYP3A4. There is the possibility of a decrease in exposure of ombitasvir/paritaprevir/ritonavir + dasabuvir although it is difficult to judge the clinical relevance. Close monitoring for therapeutic effect is recommended.

Coadministration has not been studied. Asenapine is metabolized by glucuronidation (UGT1A4) and oxidative metabolism (mainly CYP1A2, with minor contributions from CYP3A4 and CYP2D6). As ritonavir induces CYP1A2 and UGT1A4, it could potentially decrease asenapine exposure. Monitor the clinical effect and increase dosage if needed.

Atazanavir/ritonavir should not be used in combination with medicinal products also containing ritonavir.

Atazanavir should be taken without additional ritonavir with ombitasvir/paritaprevir/ritonavir + dasabuvir since ritonavir 100 mg once daily is provided as part of the ombitasvir/paritaprevir/ritonavir fixed dose combination. Atazanavir plus additional ritonavir is not recommended with ombitasvir/paritaprevir/ritonavir + dasabuvir.

Atazanavir/cobicistat should not be used in combination with medicinal products containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.

Coadministration has not been studied. Atomoxetine is a substrate of CYP2D6 but at 100 mg dose ritonavir does not markedly inhibit CYP2D6. Subjects may require monitoring as clinically indicated. A decrease in atomoxetine dose may be needed.

Atovaquone exposure may decrease when co-administered with ritonavir. The co-administration of lopinavir/ritonavir with atovaquone led to a decrease in atovaquone AUC of 74%. Close monitoring is recommended. An increase in atovaquone dose may be needed.

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

Coadministration has not been studied but would not be recommended. Axitinib is a metabolised by CYP3A and coadministration with strong CYP3A4/5 inhibitors such as ritonavir may increase axitinib plasma concentrations and an alternative should be considered. Coadministration of ketoconazole (another strong inhibitor of CYP3A4/5) increased axitinib AUC and Cmax by 2-fold and 1.5-fold, respectively. If coadministration cannot be avoided, a dose decrease of axitinib to approximately half the dose is recommended. If coadministration of the strong inhibitor is discontinued, a return to the axitinib dose used prior to initiation of the strong CYP3A4/5 inhibitor should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug interaction is unlikely. Aztreonam is only minimally metabolised and is eliminated mainly unchanged in the urine.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Multiple CYP enzymes and drug transporters, including P-gp, BCRP, and OATP1B are involved in the metabolism and elimination of ombitasvir/paritaprevir/ritonavir + dasabuvir. Ritonavir is a strong inhibitor of CYP3A4. Bamlanivimab and etesevimab are IgG1 monoclonal antibodies and are likely to be eliminated via intracellular catabolism, similarly to endogenous IgG. Bamlanivimab and etesevimab are not metabolized by CYP enzymes. Interactions with concomitant medications that are substrates, inducers, or inhibitors of CYP enzymes are unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Multiple CYP enzymes and drug transporters, including P-gp, BCRP, and OATP1B are involved in the metabolism and elimination of ombitasvir/paritaprevir/ritonavir + dasabuvir. Baricitinib is not expected to have a clinically relevant effect on drugs metabolised by CYP enzymes. Ritonavir is a strong inhibitor of CYP3A4 but CYP3A4 contributes to less than 10% to baricitinib overall metabolism. Coadministration with ketoconazole (a strong CYP3A4 inhibitor) had no significant impact on baricitinib exposure.

Coadministration has not been studied. Bedaquiline is metabolized by CYP3A4 and concentrations may increase due to inhibition of CYP3A4 by ritonavir. In a parallel group interaction study, steady state coadministration of bedaquiline (200 mg three times weekly, n=17) and ritonavir (as lopinavir/ritonavir, n=14) increased bedaquiline AUC by 62%. Coadministration of bedaquiline and ritonavir should be avoided. If the benefit of coadministration outweighs the risk and coadministration is necessary, clinical monitoring including frequent ECG assessment and monitoring of transaminases is recommended.

Coadministration has not been studied. Benazepril is a substrate of UGTs (the specific UGTs have not been well described) and its exposure may increase due to UGT inhibition by ombitasvir/paritaprevir/ritonavir + dasabuvir. The exposure of raltegravir (a UGT substrate) was increased by up to 2-fold with ombitasvir/paritaprevir/ritonavir + dasabuvir; a similar interaction is possible with other UGT substrates. In the absence of further data, close monitoring of cardiac parameters and for increased side effects is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bendroflumethiazide is mainly eliminated by hepatic metabolism, 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.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Benralizumab is a humanised IgG1 monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body and not restricted to hepatic tissue.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Benztropine is primarily metabolised by CYP2D6, with minor involvement from CYP3A4. Ritonavir inhibits CYP2D6 at higher doses but at the 100 mg dose ritonavir does not markedly inhibit CYP2D6.

Coadministration has not been studied but based on metabolism and clearance a clinically significant pharmacokinetic interaction is unlikely. Betahistine undergoes nearly complete metabolism by monoamine oxidase. Based on in-vitro data, no inhibition of cytochrome P450 enzymes by betahistine is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bevacizumab biotransformation involves proteolytic catabolism throughout the body, including endothelial cells, and does not rely primarily on elimination through the kidneys and liver.

Coadministration has not been studied. Bezafibrate is metabolised by hydroxylation, glucuronidation and renal elimination (~50%). Due to involvement of multiple metabolic pathways and renal elimination, a clinically significant interaction is not expected with ombitasvir/paritaprevir/ritonavir + dasabuvir. [Note, the European SPC for bezafibrate contraindicates its use in significant hepatic disease.]

Coadministration has not been studied. Ritonavir is a strong inhibitor of CYP3A4 and is predicted to increase bictegravir concentrations but to a modest extent as bictegravir is metabolized equally by CYP3A4 and UGT1A1. 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, 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 systemic concentrations. 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. No interactions are anticipated since although the drug is metabolised, the systemic concentrations of bimatoprost are extremely low (less than 0.2 ng/ml) following ocular dosing with bimatoprost.

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. Bisacodyl increases colonic mass movements and may affect absorption of ombitasvir/paritaprevir/ritonavir + dasabuvir. The potential interaction can be resolved by giving bisacodyl at least 4 hours after ombitasvir/paritaprevir/ritonavir + dasabuvir. [Note: this interaction is not specific for ombitasvir/paritaprevir/ritonavir + dasabuvir, but for any medication taken with bisacodyl.]

Coadministration has not been studied. Bisoprolol is a substrate of CYP3A4 and its exposure may increase due to CYP3A4 inhibition by ritonavir. Close monitoring is recommended. A decrease in bisoprolol dose may be needed. [Note, the European product label for bisoprolol recommends a maximum of 10 mg in severe hepatic impairment; the US Prescribing Information recommends an initial 2.5 mg in hepatic impairment with caution in further dose titration.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Black cohosh does not appear to be involved in drug metabolism to a clinically significant effect. Standardized black cohosh supplements, when taken at recommended doses, pose little risk for herb-drug interactions.

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, a clinically relevant interaction is unlikely. 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 has not been studied. Bosutinib is metabolised principally by CYP3A4. Data with ketoconazole showed a 8.6-fold increase in bosutinib AUC and a similar effect may occur with ritonavir. Coadministration is not recommended.

Coadministration has not been studied. Brentuximab vedotin releases the active species MMAE within the tumour cell; MMAE is a substrate of CYP3A4 and possibly CYP2D6 and a weak inhibitor of CYP3A4. Ritonavir is an inhibitor of CYP3A4 and may increase MMAE concentrations and the incidence of neutropenia. No a priori dose adjustment is recommended, however, patients who are receiving strong CYP3A4 inhibitors concomitantly with brentuximab vedotin should be closely monitored for adverse reactions. If neutropenia develops, refer to dosing recommendations for neutropenia.

Coadministration has not been studied. Brincidofovir is a substrate of OATP1B1/3 and concentrations may increase due to OATP1B1/3 inhibition by ombitasvir/paritaprevir/r + dasabuvir. If concomitant use with brincidofovir is necessary, increase the monitoring for adverse reactions associated with brincidofovir (i.e. elevations in transaminases and bilirubin, diarrhea, or other gastro-intestinal adverse events) and postpone the dosing of ombitasvir/paritaprevir/r + dasabuvir for at least 3 hours after brincidofovir administration.

Coadministration has not been studied. Brinzolamide is metabolised by CYP3A4 and concentrations may increase due to inhibition of CYP3A4 by ritonavir. Caution is advised, and a dose reduction could be considered at higher doses. Monitor for increased side effects such as blurred vision and consider intraocular pressure checks if co-prescribed within first week. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Brodalumab is degraded into small peptides. Brodalumab may modulate serum levels of some cytokines and may modestly increase the exposure of CYP450 substrates such as ombitasvir/paritaprevir/ritonavir + dasabuvir. However, based on data with midazolam (AUC increased by 24%), this is unlikely to be clinically significant.

Coadministration has not been studied. Bromocritpine is a substrate of CYP3A4 and concentrations may increase due to inhibition of CYP3A4 by ritonavir. Close monitoring is recommended. A decrease in bromocriptine dose may be needed.

Coadministration has not been studied. Bromperidol is metabolised by CYP3A4 and concentrations may increase due to inhibition of CYP3A4 by ritonavir. Close monitoring for signs and symptoms of increased concentrations is recommended.

Concomitant administration of ritonavir and glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Cushing's syndrome and adrenal suppression have been reported when ritonavir has been co-administered with inhaled or intranasally administered budesonide. Use beclometasone as an alternative. Budesonide is a substrate and inhibitor of CYP3A4 and its exposure may increase due to CYP3A4 inhibition by ritonavir causing a decrease in plasma cortisol leading to Cushing's syndrome.

Coadministration has not been studied. Bupivacaine is metabolised by UGT1A1, CYP1A2 and CYP3A4, and amide hydrolysis. Due to the involvement of UGT1A1 and CYP3A4 an increase in bupivacaine concentrations may occur. Close monitoring is recommended and consider dose reduction.

Buprenorphine can be administered with ombitasvir/paritaprevir/ritonavir + dasabuvir and no a priori dose alteration is required. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). Coadministration with buprenorphine (4-24 mg once daily) and naloxone (1-6 mg once daily) increased buprenorphine Cmax, AUC and Cmin by 2.18-, 2.07- and 3.12-fold, respectively; values for norbuprenorphine increased by 2.07-, 1.84- and 2.10-fold, respectively. These changes in PK values did not translate into any pharmacodynamic changes. There was no change in exposure of ombitasvir, paritaprevir or dasabuvir based on cross-study comparison. However, prescribers should be aware to look out for signs of sedation and cognitive effects, particularly on initiation and discontinuation of treatment.

Coadministration has not been studied. No interaction was observed between ombitasvir/paritaprevir/ritonavir + dasabuvir and methadone (CYP2B6 substrate). Hence, it is not expected to interact with other CYP2B6 substrates. Short-term ritonavir (200 mg; 4 doses over 2 days) dosing has only minimal impact on the pharmacokinetics of bupropion while long term administration of low dose ritonavir (100 mg twice daily) doses has shown only ≤22% decrease in bupropion exposures. Monitoring may be required. Adjust bupropion dose if clinically indicated.

Coadministration has not been studied but may increase concentrations of buspirone due to inhibition of CYP3A4 by ritonavir. Using the lowest dose possible of buspirone is recommended, starting at 2.5mg. Close monitoring is recommended for increased side effects such as impaired psychomotor performance, nausea, vomiting, dizziness, drowsiness and miosis and decrease dose if symptomatic. Use with caution in cirrhosis.

Coadministration has not been formally studied but based on current knowledge of the effect of vaccines on drug disposition a clinically significant interaction is considered unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Calcium carbimide is a prodrug requiring catalase and hydrogen peroxide to generate the active metabolite. Calcium carbimide is an inhibitor of ALDH but this enzyme is not involved in the metabolism of ombitasvir, paritaprevir, ritonavir or dasabuvir.

Coadministration has not been studied. Canagliflozin is primarily metabolised by UGTs 1A9 and 2B4. Rifampicin (a non-selective inducer of several UGT enzymes, including UGTs 1A9 and 2B4) decreased canagliflozin AUC by 51% which may result in reduced efficacy. Ritonavir could lead to reduced exposure to canagliflozin as a result of UGT enzyme induction. No interaction is anticipated with ombitasvir, paritaprevir or dasabuvir. If coadministration is deemed necessary, increasing the dose to 300 mg once daily may be considered if patients are currently tolerating canagliflozin 100 mg once daily, have an eGFR ≥60 mL/min/1.73 m2 or CrCl ≥60 mL/min, and require additional glycaemic control. In patients with an eGFR 45 mL/min/1.73 m2 to <60 mL/min/1.73 m2 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, other glucose-lowering therapies should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Candesartan is mainly eliminated unchanged in urine and bile. [Note, use of candesartan in severe hepatic impairment is contraindicated in the European SmPC; the US Prescribing Information recommends caution in moderate hepatic impairment.]

Coadministration has not been studied. Cannabidiol is mainly metabolized by CYP3A4 and CYP2C19. Coadministration is expected to significantly increase cannabidiol exposure (inhibition of CYP3A4 by ritonavir) which may result in a greater risk of adverse reactions. Consider a dose reduction of cannabidiol. Advise patients to be aware of adverse reactions to cannabidiol.

Coadministration has not been studied. Tetrahydrocannabinol (THC, the psychoactive component of cannabis) is metabolised mainly by CYP2C9 and to a lesser extent by CYP3A4. Coadministration with ombitasvir/paritaprevir/ritonavir + dasabuvir may increase concentrations of THC due to inhibition of CYP3A4 by ritonavir. The patient should be made aware of potential increased side effects.

Coadministration is contraindicated. Carbamazepine is a substrate and inducer of CYPs 3A4, 2C8 and 1A2. Ombitasvir/paritaprevir/ritonavir + dasabuvir exposures show significant decreases when administered with carbamazepine (ombitasvir Cmax and AUC both decreased by 31%; paritaprevir Cmax and AUC decreased by 66% and 70%) which may lead to virologic failure.

Coadministration has not been studied and is not recommended. Carfentanil is expected to be metabolized by CYP3A4/5. Ritonavir is a strong inhibitor of CYP3A4 and could increase carfentanil exposure, causing serious and/or life-threatening reactions such as respiratory depression. Carfentanil is an extremely strong opiate, reported to be up to 10,000 times more potent than morphine, and multiple deaths have resulted from its use. Advise patients to avoid.

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. The net effect on carvedilol concentrations is difficult to predict. Ombitasvir/paritaprevir/ritonavir + dasabuvir could potentially increase carvedilol concentrations. Close monitoring is recommended. [Note, the US Prescribing Information contraindicates carvedilol in patients with severe liver impairment and the European SmPC contraindicates it in patients with hepatic dysfunction.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Multiple CYP enzymes and drug transporters, including P-gp, BCRP, and OATP1B are involved in the metabolism and elimination of ombitasvir/paritaprevir/ritonavir + dasabuvir. Ritonavir is a strong inhibitor of CYP3A4. Casirivimab and imdevimab are IgG1 monoclonal antibodies and are likely to be eliminated via intracellular catabolism, similarly to endogenous IgG. Casirivimab and imdevimab are not metabolized by CYP enzymes. Interactions with concomitant medications that are substrates, inducers, or inhibitors of CYP enzymes are unlikely.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely as caspofungin undergoes spontaneous chemical degradation and non-CYP medicated metabolism. [Note, no dose adjustment is required in patients with normal hepatic function but a dose reduction of caspofungin daily dose to 35 mg is recommended for adults with moderate hepatic impairment. There is no clinical experience in adults with severe hepatic impairment.]

Coadministration has not been studied but, based on limited information and case reports, is not recommended. Cat’s claw is a strong inhibitor of CYP3A4 in vitro and increased concentrations of ombitasvir/paritaprevir/ritonavir + dasabuvir may be expected. Coadministration should be avoided in the absence of further data.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug interaction is unlikely. Cefadroxil is not metabolised and is predominantly eliminated unchanged by the kidneys.

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug interaction is unlikely. Cefradine is not metabolised and is predominantly eliminated unchanged by the kidneys.

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug interaction is unlikely. Ceftaroline is not metabolised by CYP enzymes and is primarily eliminated by the kidneys.

Coadministration has not been studied but celecoxib can be administered with ombitasvir/paritaprevir/ritonavir + dasabuvir and no dose alteration is required. Celecoxib is a substrate of CYP2C9. There was no interaction between ombitasvir/paritaprevir/ritonavir + dasabuvir and warfarin, a CYP2C9 substrate so no interaction is expected with celecoxib. [Note, use in patients with severe liver impairment is contraindicated in the European SmPC and not recommended in the US Prescribing Information. In patients with moderate liver impairment (serum albumin 25-35 g/L, Child-Pugh Class B), celecoxib treatment should be started at half the recommended dose.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Like other protein therapeutics, cetuximab is expected to be degraded into small peptides and amino acids via catabolic pathways.

Coadministration has not been studied but a clinically significant interaction is considered unlikely. Very little has been described about chlorambucil metabolism in humans but CYP450 enzymes are not involved.

Coadministration has not been studied. Following administration, chloroquine is rapidly metabolised by CYPs 2C8, 3A and 2D6 to desethylchloroquine and bisdesethylchloroquine which have activity similar to chloroquine. Chloroquine is also renally eliminated. Inhibition of CYP3A4 by ritonavir may decrease exposure to the active metabolites, but this may not affect overall activity. No a priori dosage adjustment is recommended for chloroquine. Note, the European SPC and US Prescribing Information for chloroquine both recommend caution in impaired hepatic function.

Coadministration has not been studied. Chlorphenamine is a substrate of CYP2D6 with possible involvement of CYP3A4. Ritonavir inhibits CYP2D6 at higher doses but at the 100 mg dose, ritonavir does not appear to markedly inhibit CYP2D6. No a priori dose adjustment is required.

Coadministration has not been studied. Chlorpromazine is a substrate of CYPs 2D6 (major), 1A2, and 3A4 in vitro. Chlorpromazine exposure may increase due to CYP3A4 and possibly CYP2D6 inhibition by ritonavir. No a priori dose modification is needed but monitoring for side effects may be required as clinically indicated. [Note, the European SmPC for chlorpromazine advises that its use should be avoided in patients with hepatic dysfunction.]

Coadministration has not been studied. Chlorprothixene is metabolised by CYP2D6 and although ritonavir inhibits CYP2D6 at higher doses, at the 100 mg dose it does not appear to markedly inhibit CYP2D6. However, as a modest increase in chlorprothixene concentrations may prolong QT, caution is advised. [Note, ECG monitoring is mandatory prior to treatment with chlorprothixene.]

Ciclosporin is a substrate of CYP3A4. Ciclosporin AUC and Ctrough increases by 5.8-fold and 15.8-fold respectively when coadministered with ombitasvir/paritaprevir/ritonavir + dasabuvir. Give one-fifth of the total daily dose of ciclosporin once daily when coadministered. Monitor ciclosporin levels and adjust dose and/or dosing frequency as needed.

Coadministration has not been studied but cilazapril can be administered with ombitasvir/paritaprevir/ritonavir + dasabuvir and no dose alteration is required. Cilazapril is metabolised by esterases to the active cilazaprilat which is excreted unchanged in urine. [Note, in patients with cirrhosis, a maximum dose of 0.5 mg/day is recommended as significant hypotension may occur.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cisatracurium undergoes mainly (80% of overall elimination) spontaneous degradation in plasma and tissues at physiological pH and temperature (Hofmann elimination).

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cisplatin is eliminated renally via OCT2 and MATE-1. Ombitasvir/Paritaprevir/r + dasabuvir does not inhibit MATE-1 at clinically relevant concentrations.

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug interaction is unlikely. Clavulanic acid is extensively metabolized (likely by a non-CYP mediated pathway) and excreted in the urine by glomerular filtration.  

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clevidipine is rapidly metabolised by hydrolysis of the ester linkage and does not undergo CYP metabolism.

Coadministration has not been studied. Clindamycin is a substrate of CYP3A4 and its exposure may increase due to CYP3A4 inhibition by ritonavir. Use with caution and with close monitoring. A decrease in clindamycin dose may be needed.

Coadministration has not been studied. Clobazam is a substrate of CYP3A4 and to a lesser extent CYP2C19 but its exposure may increase due to CYP3A4 inhibition by ritonavir. Consider starting patient on the recommended dose with close clinical monitoring for side effects associated with clobazam and decrease dose if necessary.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clodronate is not metabolised and is primarily excreted unchanged by the kidney. However, if administered orally, clodronate should be taken more than two hours after and one hour before any other oral drugs. [Note: this interaction is not specific for ombitasvir/paritaprevir/ritonavir + dasabuvir, but for any oral medication taken with clodronate.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clofazimine is a moderate inhibitor of CYP3A4 and may increase paritaprevir and dasabuvir concentrations to a modest extent. This is unlikely to be relevant in the context of ritonavir, a potent CYP3A4 inhibitor. [Note, the US Prescribing Information for clofazimine recommends to avoid clofazimine in patients with hepatic impairment (Child-Pugh Class A, B, and C) unless the benefit outweighs the risk.]

Coadministration has not been studied. Studies suggest that clomifene is metabolised by CYP2D6 (major) and CYP3A4 and UGTs. It is possible that concentrations may increase due to inhibition of CYP3A4 by ritonavir. Monitoring may be required as clinically indicated.

Coadministration has not been studied. Clomipramine is a substrate of CYPs 2C19, 3A4 and 1A2. Clomipramine exposure may increase due to CYP3A4 inhibition by ritonavir. Use the lowest possible dose of clomipramine. A potential increase in clomipramine concentration may increase the risk of QTc prolongation. Close monitoring is recommended, using ECG if appropriate.

Coadministration has not been studied. Clonidine is substantially renally eliminated, but is also a substrate of CYP2D6 and CYP3A4. At 100 mg dose, ritonavir does not inhibit CYP2D6, but potentially clonidine exposure may increase due to CYP3A4 inhibition by ritonavir. Monitoring may be required as clinically indicated.

Coadministration of clopidogrel and ritonavir-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. The interaction between clopidogrel (300 mg loading dose followed by 75 mg once daily) and ritonavir (100 mg twice daily) was investigated in 12 HCV-negative subjects in the presence of dasabuvir (250 mg single dose). Dasabuvir AUC increased by 289% and Cmax increased by 82% in the presence of clopidogrel and ritonavir when compared to ritonavir alone. The AUC and Cmax of clopidogrel’s active metabolite decreased by 51% and 48% in the presence of ritonavir, with the average inhibition of platelet aggregation decreasing from 51% in the clopidogrel/dasabuvir phase to 31% in the clopidogrel/dasabuvir/ritonavir phase. 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). Subjects showed a comparable decrease in prasugrel’s active metabolite AUC (52% decrease), however this decrease did not impair prasugrel’s antiplatelet effect. Given the risk of diminished clopidogrel response, prasugrel should be preferred in presence of ritonavir-boosted regimens, unless the patient has a clinical condition which contraindicates its use in which case an alternative antiplatelet agent should be considered. [Note, the European SmPC for clopidogrel contraindicates its use in severe hepatic impairment but the US Prescribing Information states no dose alteration.]

Coadministration has not been studied. Clorazepate is a substrate of CYP3A4 and its exposure may increase due to CYP3A4 inhibition by ritonavir causing CNS depression, sedation. Close monitoring is recommended. A decrease in clorazepate dose may be needed.

Coadministration has not been studied. The metabolism of clotiapine has not been well characterised but is likely to involve CYP450 enzymes. Ritonavir is a potent CYP3A4 inhibitor and may increase clotiapine exposure. In the absence of further data, use with caution. If coadministration is unavoidable, monitoring for side effects associated with increased concentrations of clotiapine is recommended. A clinically significant effect on ombitasvir, paritaprevir, ritonavir or dasabuvir is unlikely.

Coadministration has not been studied. Clozapine is a substrate of CYPs 1A2, 2D6 and 3A4, and its exposure may increase due to CYP3A4 inhibition by ritonavir. Close monitoring is recommended. A decrease in clozapine dose may be needed.

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 in vitro data suggest that ritonavir is an inhibitor of CYP2D6. Ritonavir could potentially reduce the analgesic efficacy.

Coadministration has not been studied. Colchicine is a substrate of CYP3A4 and P-gp. Colchicine exposure may increase due to CYP3A4 inhibition by ritonavir. Fatal colchicine toxicity has been reported with clarithromycin, a strong CYP3A4 inhibitor. Close monitoring is recommended. A decrease in colchicine dose may be needed. Patients with renal or hepatic impairment should not be given colchicine with ritonavir. Refer to the ritonavir product label.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metabolism of colecalciferol 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 colecalciferol and introduction of 6',7'-dihydroxybergamottin (a CYP3A4 inhibitor in grapefruit juice) reversed the effects of rifampicin on colecalciferol clearance. Inhibition of CYP3A by ombitasvir/paritaprevir/r + dasabuvir is not expected to reduce the effect of colecalciferol, but the consequence of CYP3A inhibition on the clinical effect of colecalciferol is not known. However, no effect of antiretroviral therapy (including ritonavir) on the response to colecalciferol supplementation was found in a PK modelling study. Multiple CYP enzymes and drug transporters, including P-gp, BCRP, and OATP1B are involved in the metabolism and elimination of ombitasvir/paritaprevir/ritonavir + dasabuvir. Colecalciferol does not interact with these pathways.

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 ombitasvir/paritaprevir/ritonavir + dasabuvir, but for any medication taken with colestyramine.]

Coadministration has not been studied. The metabolism of conjugated estrogens is complex and involves CYP3A4 isoenzymes and glucuronidation in the liver. Coadministration could potentially increase exposure of medroxyprogesterone and estrogens due to potent CYP3A4 inhibition by ritonavir. Further impact on estrogen exposure may be seen due to UGT inhibition of paritaprevir/ritonavir/ombitasvir + dasabuvir. Close monitoring is recommended as the overall effect and clinical significance is difficult to predict. 

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.

Co-administration has not been studied but based on limited data for the metabolism and clearance of cyclizine, a clinically significant interaction is unlikely. Cyclizine undergoes hepatic metabolism which may include CYP2D6.

Coadministration has not been studied. Cyclobenzaprine undergoes a complex metabolic process involving glucuronidation and several CYP enzymes including CYPs 3A4 and 1A2. Coadministration may increase cyclobenzaprine concentrations due to inhibition of CYP3A4 by ritonavir, though the clinical significance of this is unknown. Monitoring may be required for signs and symptoms of toxicity.

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. Ritonavir is a potent CYP3A4 inhibitor and in vivo data suggest that it induces CYP2B6. The net impact of coadministration is difficult to predict as 2B6 induction may increase conversion of cyclophosphamide to the active metabolite, whereas CYP3A4 inhibition would block this pathway. Additionally, in theory, ritonavir could potentially reduce the risk of neurotoxicity and increase the amount of drug available for the activation pathway. If coadministration is necessary, careful monitoring of cyclophosphamide related side effects and therapeutic effectiveness is recommended.

Coadministration has not been studied. Dabigatran exposure may theoretically increase due to P-gp inhibition by ombitasvir/paritaprevir/ritonavir + dasabuvir. Dabigatran is metabolised by hydrolysis and is a substrate of UGT and P-gp. Ombitasvir/paritaprevir/ritonavir + dasabuvir increased exposure of raltegravir (a UGT substrate) by up to 2-fold and a similar interaction is possible with other UGT substrates. Use with caution and with close monitoring. A reduction in dabigatran dose may be needed or start with the lowest possible dose.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Danaparoid is renally excreted and no hepatic involvement was shown in animal studies.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dantron is absorbed from the small intestine and acts at the large intestine. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dapagliflozin is primarily metabolised by UGT1A9. Coadministration of dapagliflozin with rifampicin (an inducer of several UGT enzymes decreases dapagliflozin systemic exposure by 22% but with no clinically meaningful effect on 24-hour urinary glucose excretion. Similarly, ritonavir may affect dapagliflozin via UGT induction but a clinically relevant effect is not expected. No interaction is anticipated with ombitasvir, paritaprevir and dasabuvir. No dose adjustment is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Like other protein therapeutics, daratumumab is expected to be degraded into small peptides and amino acids via catabolic pathways and is not anticipated to alter drug-metabolising enzymes.

Coadministration with ombitasvir/paritaprevir/ritonavir + dasabuvir decreased darunavir Ctrough by ~50%, although Cmax and AUC did not show a clinically significant change. Coadministration of darunavir with ombitasvir/paritaprevir/ritonavir + dasabuvir is not recommended in the US product label for ombitasvir/paritaprevir/ritonavir + dasabuvir. The European product label for ombitasvir/paritaprevir/ritonavir + dasabuvir states that coadministration is not recommended in patients with extensive HIV PI resistance but advises that darunavir (dosed at 800 mg once daily and administered at the same time as ombitasvir/paritaprevir/ritonavir + dasabuvir) can be used in the absence of extensive HIV PI resistance and should be taken without additional ritonavir, since ritonavir 100 mg once daily is provided as part of the ombitasvir/paritaprevir/ritonavir fixed dose combination. Exercise caution with use dependent on knowledge of the patient.

Symtuza should not be administered concomitantly with medicinal products requiring pharmacokinetic enhancement with ritonavir. Coadministration may increase concentrations of ombitasvir and paritaprevir due to inhibition of CYP3A4 by cobicistat.

Coadministration of ombitasvir/paritaprevir/ritonavir + dasabuvir with an additional pharmacokinetic booster, such as cobicistat, is contraindicated. Coadministration may increase concentrations of ombitasvir, paritaprevir and dasabuvir due to inhibition of CYP3A4 by cobicistat. Coadministration of unboosted darunavir decreased darunavir Ctrough by 41%.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Deferiprone is glucuronidated by UGT1A6 which is not affected by ombitasvir/paritaprevir/ritonavir + dasabuvir.

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. Coadministration 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 with ombitasvir, paritaprevir and dasabuvir 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). [Note, delamanid is not recommended in patients with moderate to severe hepatic impairment.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Denosumab is not eliminated via hepatic metabolism but follows the immunoglobulin clearance pathway resulting in degradation to small peptides and individual amino acids.

Coadministration 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 may increase the conversion to the active metabolite etonogestrel due to inhibition of CYP3A4 by ritonavir. Although no dose adjustment is necessary for norethindrone (a progestogen) when coadministered with ombitasvir/paritaprevir/ritonavir in the absence of an estrogen, it is unclear if this will apply to other orally administered progestogen only contraceptives.

There is a potential for ALT elevations in patients using ethinylestradiol-containing medications such as combined oral contraceptives, contraceptive patches or contraceptive vaginal rings. Ethinylestradiol-containing medications must be discontinued prior to starting therapy with ombitasvir/paritaprevir/ritonavir + dasabuvir. Alternative methods of contraception (e.g., progestin only contraception or non-hormonal methods) are recommended. Ethinylestradiol-containing medications can be restarted approximately 2 weeks following completion of HCV treatment.

There is a potential for ALT elevations in patients using ethinylestradiol-containing medications such as combined oral contraceptives, contraceptive patches or contraceptive vaginal rings. Ethinylestradiol-containing medications must be discontinued prior to starting therapy with ombitasvir/paritaprevir/ritonavir + dasabuvir. Alternative methods of contraception (e.g., progestin only contraception or non-hormonal methods) are recommended. Ethinylestradiol-containing medications can be restarted approximately 2 weeks following completion of HCV treatment.

Coadministration has not been studied. Desvenlafaxine is a substrate of CYP2D6, CYP3A4 and P-gp. Ketoconazole, an inhibitor of CYP3A4/P-gp, increased exposure of venlafaxine and its metabolite by 20-141%. A similar magnitude of increase may be seen due to CYP3A4 inhibition by ritonavir when administered with ombitasvir/paritaprevir/ritonavir + dasabuvir. Monitoring may be required as clinically indicated. A decrease in dose may be needed.

Coadministration has not been studied. Dexamethasone is a substrate of CYP3A4 and P-gp. Dexamethasone exposure (after IV and oral administration) increased by 3.3- to 3.7-fold when administered with itraconazole, a CYP3A4 inhibitor. A similar magnitude of increase may be seen with ombitasvir/paritaprevir/ritonavir + dasabuvir due to CYP3A4 inhibition by ritonavir. A decrease in dexamethasone dose is recommended and close monitoring for side effects due to adrenal suppression. Additionally, dexamethasone is a moderate CYP3A4 inducer of CYP3A4 at doses above 16mg. Chronic or high dose dexamethasone may decrease ombitasvir/paritaprevir/ritonavir + dasabuvir concentrations which may lead to reduced therapeutic effect.

Coadministration has not been studied. The role of CYP450 in the metabolism of dexamfetamine has not been fully described and potent inhibitors of CYP3A4, such as ritonavir, should be used with caution.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Dexketoprofen is mainly glucuronidated, with CYP mediated metabolism (CYP2C8/9) playing only a minor role. It is likely that multiple UGTs are involved in the metabolism of dexketoprofen and so no interaction is expected via this pathway. There was no interaction between ombitasvir/paritaprevir/ritonavir + dasabuvir and warfarin, a CYP2C9 substrate, so no effect on dexketoprofen is likely. Ritonavir is a weak inducer of CYP2C8, but no clinically relevant effect is expected as CYP2C8 metabolism of dexketoprofen is minimal. [Note, use in patients with severe hepatic impairment (Child Pugh class C) is contraindicated in the European product label for dexketoprofen.]

Coadministration has not been studied. Diamorphine is metabolised by hydrolysis to its metabolite morphine. Morphine is metabolized by UGT2B7, UGT1A3 with a minor contribution from CYP2D6 and CYP3A4. No a priori dose adjustment is required, however, close monitoring for side effects is recommended and decrease the dose if clinically indicated.

Coadministration of diazepam (2 mg single dose) and ombitasvir/paritaprevir/ritonavir plus dasabuvir increased diazepam Cmax by 18%, but decreased AUC by 22%. Nordiazepam Cmax increased by 10%, but AUC decreased by 40%. There was no clinically significant effect on exposures of ombitasvir, paritaprevir, ritonavir or dasabuvir. No a priori dose modification is recommended, but close monitoring is recommended and adjust the dose if clinically indicated.

Coadministration has not been studied. Dihydroartemisinin (the active metabolite of artesunate) induces CYP3A4 and there is the possibility of a decrease in exposure of ombitasvir/paritaprevir/ritonavir + dasabuvir although it is difficult to judge the clinical relevance. Close monitoring is recommended for therapeutic effect.

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 has not been studied. Diltiazem is a substrate of CYP3A4 and its exposure may increase due to CYP3A4 inhibition by ritonavir. Concentrations of paritaprevir may increase, but the efffect on dasabuvir is unclear (no change or concentrations may increase). Use with caution due to the expected increase in paritaprevir exposures. Close monitoring is recommended. Start with the lowest possible dose. Clinical monitoring of calcium channel blockers is recommended when co-administered.

Coadministration has not been studied. Diosmin is a naturally occurring flavonoid. Diosmin-containing products are available as dietary supplements or on prescription (in certain countries). Interaction studies suggest that diosmin may be a weak inhibitor of CYP3A4 and P-gp but any effect on ombitasvir/paritaprevir/ritonavir is unlikely to be clinically relevant. However, dasabuvir is metabolised by CY2C8 and is contraindicated with strong CYP2C8 inhibitors. Limited in vitro data suggest that diosmin may inhibit CYP2C8 and, in the absence of further data, coadministration is not recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diphenhydramine is a substrate of CYP2D6. Ritonavir inhibits CYP2D6 at higher doses but at the 100 mg dose ritonavir does not appear to markedly inhibit CYP2D6. [Note, diphenhydramine should be used with caution in patients with moderate to severe hepatic impairment.]

Coadministration has not been studied. Dipyridamole is glucuronidated but the UGTs involved have not been well described. Dipyridamole exposure may increase due to UGT inhibition by ombitasvir/paritaprevir/ritonavir + dasabuvir but the magnitude of the interaction is difficult to predict. No a priori dose adjustment is recommended but monitoring may be required for increased side effects and toxicities of dipyridamole.

Coadministration has not been studied. Disopyramide is a substrate of CYP3A4 and CYP1A2 and concentrations may increase due to CYP3A4 inhibition by ritonavir causing cardiotoxicity. Coadministration is contraindicated in the European product label for ombitasvir/paritaprevir/ritonavir, but the US product label advises caution and therapeutic concentration monitoring of disopyramide if available.

Coadministration has not been studied and is not recommended due to the increased risk of QT prolongation. Although dofetilide is only metabolised to a small extent by CYP3A4, use with concominant CYP3A4 inhibitors, such as ritonavir may increase dofetilide concentrations, increasing the risk of QT prolongation.

Coadministration of ombitasvir/paritaprevir/ritonavir + dasabuvir and dolutegravir (50 mg once daily) was studied in 12 HIV/HCV-negative subjects and had no clinically significant effect on the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, dasabuvir or dolutegravir. No dose adjustment is required for ombitasvir/paritaprevir/ritonavir + dasabuvir or dolutegravir during coadministration.

Coadministration with dolutegravir/lamivudine alone has not been studied. Coadministration of ombitasvir/paritaprevir/ritonavir + dasabuvir and dolutegravir (50 mg once daily) with abacavir/lamivudine (600/300 mg once daily) was studied in 12 HIV/HCV-negative subjects and had no clinically significant effect on the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, dasabuvir, dolutegravir or lamivudine. No dose adjustment is required for ombitasvir/paritaprevir/ritonavir or dolutegravir/lamivudine during coadministration.

Coadministration with dolutegravir/rilpivirine has not been studied. Coadministration of ombitasvir/paritaprevir/ritonavir + dasabuvir and dolutegravir (50 mg once daily) was studied in 12 HIV/HCV-negative subjects and had no clinically significant effect on the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, dasabuvir or dolutegravir. Coadministration of rilpivirine and ombitasvir/paritaprevir/ritonavir + dasabuvir is not recommended unless the benefit outweighs the risk due to the potential for QT interval prolongation with higher concentrations of rilpivirine. Rilpivirine Cmax, AUC and Cmin increased by 2.55-, 3.25- and 3.62-fold when administered with ombitasvir/paritaprevir/ritonavir + dasabuvir. Coadministration should only be considered in patients without known QT-prolongation and without other QT-prolongation co-medications. If treatment is warranted, use with caution and with repeated ECG monitoring.

Coadministration has not been studied. Donepezil is metabolised by CYP3A4 and CYP2D6 (minor). Concentrations may increase due to inhibition of CYP3A4 by ritonavir. No a priori dose modification is required but monitoring for increased side effects is recommended.

Coadministration has not been studied. Coadministration with ritonavir alone 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 good tolerability of doravirine with up to a 3-4 fold increase in exposure.

Coadministration with Delstrigo has not been studied. Coadministration of doravirine 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 good tolerability of doravirine with up to a 3-4 fold increase in exposure. Coadministration of lamivudine (in combination with abacavir) and ombitasvir, paritaprevir/r and dasabuvir had no effect on the pharmacokinetic parameters of lamivudine, ombitasvir, paritaprevir/r and dasabuvir. Tenofovir-DF can be administered with ombitasvir/paritaprevir/ritonavir + dasabuvir and no dose alteration is required. No significant interactions were seen in clinical studies. Coadministration with emtricitabine/tenofovir-DF (200/300 mg once daily) increased tenofovir Cmax, AUC and Cmin by 7%, 13% and 24%, respectively. Ombitasvir Cmax, AUC and Cmin decreased by 11%, 1% and 3%, respectively. Paritaprevir Cmax and AUC decreased by 32% and 16%, but Cmin increased by 6%. Dasabuvir Cmax, AUC and Cmin all decreased by 15%. Similarly, coadministration of lamivudine (in combination with abacavir) and ombitasvir, paritaprevir/r and dasabuvir had no effect on the pharmacokinetic parameters of lamivudine, ombitasvir, paritaprevir/r and dasabuvir.

Coadministration has not been studied. Dosulepin is extensively metabolised in the liver, likely by CYP2D6 (major) and CYP3A4. Dosulepin concentrations may increase due to inhibition of CYP2D6 and CYP3A4 inhibition by ritonavir, but as metabolism is via multiple CYP pathways the clinical significance of this is unknown. Close monitoring for increased side effects and QT prolongation is recommended. [Note: Dosulepin should be used with caution in mild to moderate hepatic impairment and avoided in severe hepatic impairment.]

Coadministration has not been studied. Doxazosin is a substrate of CYP3A4 and its exposure may increase due to CYP3A4 inhibition by ritonavir. Close monitoring is recommended. Start with the lowest possible dose of doxazosin. [Note, the European SmPC does not recommend doxazosin in severe hepatic impairment; the US Prescribing Information has a caution for use in hepatic impairment.]

Coadministration has not been studied but doxepin can be administered with ombitasvir/paritaprevir/ritonavir + dasabuvir and no dose alteration is required. Doxepin is metabolised by CYP2D6 and CYP2C9. Ritonavir inhibits CYP2D6 at higher doses but at the 100 mg dose, ritonavir does not appear to markedly inhibit CYP2D6. Ombitasvir/paritaprevir/ritonavir at steady-state did not affect the plasma exposures of the anticoagulant warfarin which is metabolised by CYP2C9. [Note, the European and US product labels for doxepin advise caution and monitoring in patients with hepatic impairment as a dosage reduction may be required.]

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

Coadministration has not been studied. Ritonavir is a weak inhibitor of CYP2D6 at a dose of 100 mg. In vitro data indicate that ritonavir induces CYP1A2 and in vivo data indicate that ritonavir is a weak inducer of CYP2C9. Coadministration may inhibit CYP2D6 but induce CYP1A2 and CYP2C9. The net effect on doxylamine concentrations is not known. No a priori dosage adjustment is recommended, but use with caution and be aware of the possibility of lack of therapeutic effect or increased side effects.

Coadministration has not been studied but droperidol can be administered with ombitasvir/paritaprevir/ritonavir + dasabuvir and no dose alternation is required. However, droperidol has a QT risk and concentrations may alter due to induction of CYP1A2 and inhibition of CYP3A4 by ritonavir. If coadministration is deemed necessary, caution is warranted and close monitoring for increased side effects should be performed including ECG monitoring.

Coadministration has not been studied. Estradiol is metabolized to estriol by CYP3A4 and CYP1A2 and is glucuronidated. Drospirenone is metabolised in part by CYP3A4. Coadministration could increase drospirenone due to potent CYP3A4 inhibition by ritonavir. Estradiol concentrations could potentially increase due to inhibition of CYP3A4, or decrease due to induction of CYP1A2. Estriol concentrations could increase due to inhibition of UGT1A1. Close monitoring is recommended as the overall effect and clinical significance is difficult to predict.

There is a potential for ALT elevations in patients using ethinylestradiol-containing medications such as combined oral contraceptives, contraceptive patches or contraceptive vaginal rings. Ethinylestradiol-containing medications must be discontinued prior to starting therapy with ombitasvir/paritaprevir/ritonavir + dasabuvir. Alternative methods of contraception (e.g., progestin only contraception or non-hormonal methods) are recommended. Ethinylestradiol-containing medications can be restarted approximately 2 weeks following completion of HCV treatment.

There is a potential for ALT elevations in patients using ethinylestradiol-containing medications such as combined oral contraceptives, contraceptive patches or contraceptive vaginal rings. Ethinylestradiol-containing medications must be discontinued prior to starting therapy with ombitasvir/paritaprevir/ritonavir + dasabuvir. Alternative methods of contraception (e.g., progestin only contraception or non-hormonal methods) are recommended. Ethinylestradiol-containing medications can be restarted approximately 2 weeks following completion of HCV treatment.

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 but interaction studies showed no clinically significant effect on the absorption of concomitantly administered oral medicinal products and no dose adjustment of comedications is recommended.

Duloxetine can be administered with ombitasvir/paritaprevir/ritonavir + dasabuvir and no dose alteration is required. Duloxetine is metabolized by CYP2D6 and CYP1A2. There was no interaction between duloxetine and ombitasvir/paritaprevir/ritonavir + dasabuvir. Coadministration with duloxetine (60 mg single dose) decreased duloxetine Cmax and AUC by 21% and 25%. Ombitasvir Cmax decreased by 2%, there was no change in AUC and Cmin increased by 1%. Paritaprevir Cmax, AUC and Cmin decreased by 21%, 17% and 23%, respectively. Dasabuvir Cmax, AUC and Cmin decreased by 6%, 8% and 12%, respectively. [Note, duloxetine is contraindicated in patients with hepatic impairment as concentrations may increase due to decreased clearance of duloxetine.]

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dupilimab is a protein and degrades to small peptides and individual amino acids. 

Coadministration has not been studied. Dutasteride is a substrate of CYP3A4 and its exposure may increase in the presence of ritonavir, a CYP3A4 inhibitor. Close monitoring is recommended. A reduction of the dutasteride dosing frequency can be considered if side effects are noted. [Note, the European SmPC (but not the US Prescribing Information) cautions against dutasteride use in mild to moderate hepatic impairment and contraindicates it in severe hepatic impairment.]

Coadministration has not been studied. Estradiol is metabolized to estriol by CYP3A4 and CYP1A2 and is glucuronidated. Dydrogesterone is metabolized to dihydrodydrogesterone (possibly via CYP3A4). Coadministration could increase dydrogesterone exposure due to potent CYP3A4 inhibition by ritonavir. Estradiol concentrations could potentially increase due to inhibition of CYP3A4, or decrease due to induction of CYP1A2. Estriol concentrations could increase due to inhibition of UGT1A1. Close monitoring is recommended as the overall effect and clinical significance is difficult to predict.

Coadministration has not been studied. Ebastine is metabolised by CYP450 and concentrations may be increased due to CYP3A4 inhibition by ritonavir. Use with caution as increased concentrations of ebastine may prolong QT interval. Consider ECG monitoring.

Coadministration has not been studied but may increase edoxaban concentrations due to inhibition of P-gp by ritonavir. 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. Close monitoring is recommended with dose modification as clinically indicated. [Note: product labels state that edoxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. It is not recommended in severe hepatic impairment and should be used with caution in patients with mild or moderate hepatic impairment.]

Coadministration has not been studied. Eliglustat is metabolised primarily by CYP2D6 and to a lesser extent by CYP3A4. Concentrations of eliglustat may increase due to CYP3A4 inhibition by ritonavir. In the absence of knowledge of CYP2D6 genotyping (i.e., whether the patient is a CYP2D6 poor metabolizer), coadministration is contraindicated.

Coadministration has not been studied but based on metabolism and clearance an interaction is unlikely. Eltrombopag is metabolised by cleavage, conjugation and to a minor extent by CYP1A2 and CYP2C8. No interaction is expected with ombitasvir/paritaprevir/ritonavir + dasabuvir.

Coadministration has not been studied but is contraindicated as both fixed dose combinations contain a pharmacokinetic booster. Coadministration may increase concentrations of ombitasvir, paritaprevir and dasabuvir due to inhibition of CYP3A4 by cobicistat. 

Coadministration has not been studied. Both regimens contain a pharmacokinetic booster and coadministration may increase concentrations of ombitasvir, paritaprevir and dasabuvir due to inhibition of CYP3A4 by cobicistat. 

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 ombitasvir/paritaprevir/ritonavir + dasabuvir inhibits UGT, P-gp and OATP, data with probenecid (a UGT inhibitor), verapamil (a P-gp inhibitor) and rifampicin (a OATP1B1/1B3 inhibitor) suggest a clinically relevant effect on empagliflozin is unlikely.

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 systemic concentrations. Descovy should be used at a dose of 200/10 mg once daily (where available).

Coadministration of emtricitabine/tenofovir-DF (200/300 mg once daily) and ombitasvir/paritaprevir/ritonavir + dasabuvir increased emtricitabine AUC, Cmax and Cmin by 5%, 7% and 9%, respectively and tenofovir Cmax, AUC and Cmin by 7%, 13% and 24%, respectively. Ombitasvir Cmax, AUC and Cmin decreased by 11%, 1% and 3%, respectively. Paritaprevir Cmax and AUC decreased by 32% and 16%, but Cmin increased by 6%. Dasabuvir Cmax, AUC and Cmin all decreased by 15%.  Emtricitabine/tenofovir-DF can be administered with ombitasvir/paritaprevir/ritonavir + dasabuvir and no dose alteration is required.

Coadministration has not been studied. Enalapril is a substrate of OATP1B1 and its exposure may increase due to OATP1B1 inhibition by paritaprevir. Rosuvastatin (OATP1B1 substrate) shows 160% increase when administered with ombitasvir/paritaprevir/ritonavir + dasabuvir and a similar increase in enalapril exposure may be expected. Close monitoring is recommended. A decrease in enalapril dose may be needed.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. CYP3A4/5, CYP2D6 and CYP2C8 are involved in the metabolism of ombitasvir, paritaprevir, ritonavir and dasabuvir. Entecavir is not hepatically metabolised and the potential for interactions via this route is low. Entecavir is eliminated primarily in the urine by glomerular filtration and tubular secretion by OAT1.