Coadministration of tenofovir-DF (300 mg once daily) and abacavir (300 mg single dose) had no effect on tenofovir AUC or Cmax, and abacavir AUC; abacavir Cmax increased by 12%. A high rate of virological failure and emergence of resistance have been reported when lamivudine was combined with tenofovir-DF and abacavir as a once daily regimen.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Acamprosate is eliminated unchanged in the urine both via glomerular filtration and active secretion (exact transporter unknown, possibly OATs or OCTs). Given the potential limited role of OCT or OAT in acamprosate’s elimination and considering the therapeutic index of acamprosate, no clinically relevant interaction with tenofovir is anticipated.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as acenocoumarol is mainly metabolized by CYP2C9.

Coadministration has not been studied. Acetazolamide is predominantly excreted unchanged via active renal tubular secretion. In vitro studies have shown acetazolamide may competitively inhibit renal transporters OAT1, OAT3 and OAT4. Tenofovir is mainly eliminated by OAT1 (and to a lesser extent by OAT3) and concentrations of tenofovir may increase. Close monitoring of renal function is recommended.

Coadministration has not been studied but may increase concentrations of both drugs due to reduced renal function or competition for active tubular secretion.

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.

Tenofovir-DF and adefovir dipivoxil should not be coadministered.

Coadministration has not been studied but based on metabolism clearance a clinically significant interaction is unlikely. 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. Tenofovir-DF (the prodrug of tenofovir) is a substrate of P-gp, however, rifampicin (a P-gp inducer) had no significant effect on tenofovir and no interaction is expected with African potato.

Coadministration has not been studied, but based on metabolism and clearance a clinically significant interaction is unlikely. Albendazole is metabolized by CYP3A4 and by the flavine-containing monooxygenase system. There is little potential for an interaction with tenofovir-DF due to competition for renal elimination pathways.

Coadministration has not been studied but based on metabolism and clearance, as well as limited drug-drug interaction data, a clinically significant interaction is unlikely. Tenofovir-DF is eliminated renally. An interaction is unlikely as albuvirtide is a peptide which is eliminated by catabolism to its constituent amino acids.

Coadministration has not been studied. Alcuronium is predominantly excreted unchanged by the kidneys. As there are no available data determining whether excretion is via active tubular secretion or glomerular filtration, there is some potential for competition with tenofovir-DF for active renal transport mechanisms, which may lead to increased levels of either drug.

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

Coadministration has not been studied 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. Amantadine is mainly eliminated in the kidney by glomerular filtration and active secretion via OCT2. Tenofovir is unlikely to interfere with amantadine renal elimination as it is eliminated by different renal transporters.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ambrisentan is mainly glucuronidated by UGT1A9, UGT2B7, UGT1A3 and is metabolized to a lesser extent by CYP3A4. Ambrisentan is also a substrate of P-gp and OATP1B1. Tenofovir-DF does not interfere with ambrisentan metabolism.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely as amikacin is eliminated renally by glomerular filtration. However tenofovir-DF should be avoided with concurrent or recent use of a nephrotoxic agent. If concomitant use of tenofovir-DF and nephrotoxic agents is unavoidable, renal function should be monitored closely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as amiloride is eliminated unchanged by the kidney. In vitro data indicate that amiloride is a substrate of OCT2 and an interaction is unlikely as tenofovir is eliminated by other renal transporters.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amisulpride is weakly metabolized and is primarily eliminated renally (possibly via OCT).

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amoxicillin is mainly eliminated unchanged in the kidney and in vitro data indicate that it is a substrate of OAT3. Tenofovir is mainly eliminated by OAT1 and to a lesser extent by OAT3.

Coadministration has not been studied. Use of tenofovir-DF should be avoided with concurrent or recent use of a nephrotoxic medicinal product (such as amphotericin B). If concomitant use of tenofovir-DF and nephrotoxic agents is unavoidable, renal function should be monitored closely.

Coadministration has not been studied. Renal clearance of ampicillin occurs partly by glomerular filtration and partly by tubular secretion with ~20-40% of an oral dose and ~60-80% of a parenteral dose being excreted in the urine in 6 hours. As tenofovir-DF is eliminated by renal tubular secretion, there is potential for competition with ampicillin for renal transporters, which could lead to increased levels of either drug when ampicillin is administered intravenously. There is little potential for a significant interaction with orally administered ampicillin.

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 but based on metabolism and clearance a clinically significant interaction is unlikely. Apixaban is metabolized by CYP3A4 and to a lesser extent by CYP1A2, CYP2C8, CYP2C9 and CYP2C19.

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.

Coadministration has not been studied. Large doses of ascorbic acid may cause the urine to become acidic causing unexpected renal tubular reabsorption of acidic drugs, thus producing an exaggerated response. Conversely basic drugs may exhibit decreased reabsorption resulting in a decreased therapeutic effect. Tenofovir-DF is predominantly eliminated unchanged via active renal tubular secretion, however unless treatment with ascorbic acid involves large doses of prolonged duration, significant interactions are not expected with vitamin C when given alone or in multivitamins.

Coadministration has not been studied but is unlikely to result in a pharmacokinetic interaction. Aspirin is rapidly deacetylated to form salicylic acid which is further glucuronidated by several UGTs (major UGT1A6). However, coadministration could potentially result in increased risk of nephrotoxicity. The risk is increased if an NSAID is used for a long duration, if the patient has a pre-existing renal dysfunction, has a low body weight, or receives other drugs that may increase tenofovir exposure. Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in patients treated with tenofovir-DF and with risk factors for renal dysfunction. Alternatives to NSAIDs should be considered in patients at risk for renal dysfunction. If tenofovir-DF is co-administered with an NSAID, renal function should be monitored adequately.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aspirin is rapidly deacetylated to form salicylic acid which is further glucuronidated by several UGTs (major UGT1A6). Aspirin used as an antiplatelet agent at 100 mg once daily in chronic use is unlikely to increase the risk of tenofovir-DF nephrotoxicity. 

Coadministration with atazanavir alone is not recommended. Coadministration of tenofovir-DF (300 mg) and atazanavir (400 mg) decreased atazanavir AUC, Cmax and Cmin by 25%, 21% and 40%, respectively, but increased tenofovir AUC, Cmax and Cmin by 24%, 14% and 22%, respectively. If coadministration is necessary, patients should be closely monitored for tenofovir-associated adverse events, including renal disorders.

Coadministration has not been studied. The combination of tenofovir-DF (300 mg) and atazanavir (400 mg) reduced atazanavir AUC, Cmax and Cmin decreased by 25%, 21% and 40%, respectively, but increased tenofovir AUC, Cmax and Cmin by 24%, 14% and 22%, respectively. Atazanavir/cobicistat is also expected to increase tenofovir plasma concentrations. Patients should be closely monitored for tenofovir-associated adverse events, including renal disorders. The European SmPC recommends that atazanavir/cobicistat and tenofovir be given together with food. Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. Atazanavir/cobicistat should not be coadministered with emtricitabine in patients with creatinine clearance less than 70 ml/min.

In a combined analysis of several clinical studies with tenofovir-DF (300 mg) and atazanavir/ritonavir (300/100 mg), atazanavir AUC, Cmax and Cmin decreased by 22%, 16% and 23%, respectively, and tenofovir AUC, Cmax and Cmin increased by 37%, 34% and 29%, respectively. Patients should be closely monitored for tenofovir-associated adverse events, including renal disorders. A dose increase to atazanavir/ritonavir 400/100 mg with TDM may be considered during the second and third trimesters of pregnancy. If atazanavir/ritonavir with tenofovir-DF OR an H2-receptor antagonist are coadministered during the second and third trimesters of pregnancy, a dose increase to atazanavir/ritonavir 400/100 mg is recommended. It is not recommended to use atazanavir with ritonavir for pregnant patients who are receiving both tenofovir-DF AND an H2-receptor antagonist.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Avanafil is primarily metabolized by CYP3A4. 

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bendroflumethiazide is eliminated by hepatic metabolism (70%, exact pathway not known) and excreted unchanged in the urine (30%) via OAT1 and OAT3. In vitro data indicate that bendroflumethiazide inhibits these renal transporters but a clinically relevant drug interaction is unlikely in the range of observed clinical concentrations.

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. A case study of a patient taking an antiretroviral regimen of tenofovir-DF, emtricitabine and raltegravir reported no clinical or laboratory adverse events when the patient received benznidazole 5 mg/kg daily for 90 days. At the end of treatment, the patient’s viral load remained undetectable, and CD4 count was maintained.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as betrixaban is largely eliminated unchanged through biliary secretion via P-gp.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro data suggest that bezafibrate inhibits the renal transporter OAT1 but a clinically relevant drug interaction with tenofovir is unlikely in the observed range of clinical concentrations.

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, Biktarvy contains tenofovir alafenamide and should not be administered with tenofovir-DF. Biktarvy should not be administered concomitantly with medicinal products containing tenofovir used for the treatment of HBV infection.

Coadministration has not been studied but based on limited information concerning the metabolism and clearance of biperiden, there is little potential for clinically significant interaction. Limited human data suggest biperiden undergoes hydroxylation in the liver.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bisoprolol is partly metabolized by CYP3A4 and CYP2D6 and partly eliminated unchanged in the urine. There is no evidence that bisoprolol and tenofovir are eliminated by the same renal transporters.

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

The interaction between buprenorphine and tenofovir-DF was investigated in 10 HIV-negative, buprenorphine/naloxone maintained subjects. When compared to values obtained from control subjects not receiving buprenorphine, no significant changes in buprenorphine pharmacokinetics were observed. When compared to controls, buprenorphine had no statistically significant effect on NRTI concentrations.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Canagliflozin is primarily metabolised by UGT1A9 and UGT2B4 which are not affected by tenofovir-DF. However, since an increased risk for bone fractures has been reported with canagliflozin (particularly in patients with a history of, or at high risk of, cardiovascular disease), caution is recommended when coadministering canagliflozin in the long term with tenofovir-DF due to potential additive bone toxicities.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cannabidiol is mainly metabolized by CYP3A4 and CYP2C19.

Coadministration has not been studied. Capecitabine is activated by sequential enzyme reactions to fluorouracil. Dihydropyrimidine dehydrogenase plays a role in fluorouracil metabolism. Nucleotide analogues such as tenofovir-DF may compete for these metabolic pathways. The clinical relevance of this interaction is unknown.

Coadministration has not been studied. Capreomycin is predominantly excreted in the urine as unchanged drug, and therefore may potentially compete with tenofovir for renal elimination transport mechanisms resulting in increased concentrations of either drug. Renal toxicity has been reported during capreomycin treatment. Tenofovir-DF should be avoided with concurrent or recent use of a nephrotoxic agent. If concomitant use of tenofovir-DF and nephrotoxic agents is unavoidable, renal function should be monitored closely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Captopril is largely excreted in the urine by OAT1 but an interaction with tenofovir via competition for OAT1 is unlikely to be of clinical significance.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carbamazepine is almost completely metabolized in the liver to carbamazepine 10,11 epoxide. Carbamazepine is an inducer of P-gp and therefore could reduce the absorption of tenofovir-DF. However, based on the results of the interaction study between tenofovir-DF and rifampicin, another inducer of P-gp, carbamazepine would be expected to cause only a small decrease in tenofovir-DF.

Coadministration has not been studied. Carboplatin is excreted primarily by renal glomerular filtration and there is little potential for competition for active renal elimination mechanisms by carboplatin and tenofovir-DF. However carboplatin and tenofovir-DF both have nephrotoxic potential and use of tenofovir-DF should be avoided with concurrent or recent use of a nephrotoxic medicinal product. If coadministration is unavoidable, renal function should be monitored closely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and additionally metabolism via CYP2D6 and to a lesser extent by CYPs 2C9 and 1A2.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cat’s claw was demonstrated to strongly inhibit CYP3A4 in vitro, but tenofovir does not undergo CYP3A4 metabolism.

Coadministration has not been studied. Cefalexin is predominantly eliminated unchanged renally by glomerular filtration and tubular secretion via OAT1 and MATE1. Thus, there is potential competition for renal transporters with cefalexin and tenofovir which could lead to increased concentrations of either drug.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefazolin is predominantly excreted unchanged in the urine, mainly by glomerular filtration with some renal tubular secretion via OAT3. OAT3 does not play a major role in tenofovir renal elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefotaxime is partially metabolized by non-specific esterases. Most of a dose of cefotaxime is excreted in the urine - about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime, an active metabolite. In vitro studies indicate that OAT3 participates to the renal elimination of cefotaxime whereas tenofovir is eliminated by other renal transporters.

Coadministration has not been studied. Based on metabolism and clearance a pharmacokinetic interaction is unlikely but coadministration could potentially result in increased risk of nephrotoxicity. The risk is increased if an NSAID is used for a long duration, if the patient has a pre-existing renal dysfunction, has a low body weight, or receives other drugs that may increase tenofovir exposure. Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in patients treated with tenofovir-DF and with risk factors for renal dysfunction. Alternatives to NSAIDs should be considered in patients at risk for renal dysfunction. If tenofovir-DF is co-administered with an NSAID, renal function should be monitored adequately.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as cetirizine is only metabolised to a limited extent and is eliminated unchanged in the urine through both glomerular filtration and tubular secretion. In vitro data indicate that cetirizine inhibits OCT2 but this is not involved in the renal elimination of tenofovir.

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 but based on metabolism and clearance a clinically significant interaction is unlikely. Ciclesonide is a pro-drug activated by esterases in the lungs to des-ciclesonide which then undergoes CYP3A4-mediated metabolism.

Coadministration has not been studied. Since tenofovir-DF is primarily eliminated by the kidneys, coadministration with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenfovir or the coadministered drug. Tenofovir-DF should be avoided with concurrent or recent use of a nephrotoxic agent. If concomitant use of tenofovir-DF and nephrotoxic agents is unavoidable, renal function should be monitored closely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro data indicate that cimetidine inhibits OAT1 and OCT2 at concentrations much higher than the observed clinical concentrations. No interaction is expected with tenofovir.

Coadministration has not been studied. Cisplatin is eliminated renally via OCT2 and MATE1. A pharmacokinetic interaction is unlikely as tenofovir is eliminated by other renal transporters, however, coadministration may increase the risk of nephrotoxicity. Closely monitor renal function.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Citalopram is metabolized by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%).

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clobazam is metabolised by CYP3A4 (major) and CYP2B6 and CYP2C19 (minor) to the active metabolite N-desmethylclobazam, which is metabolised by CYP2C19.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clofibrate is metabolised mainly to an active metabolite, clofibric acid. Excretion of clofibric acid glucuronide is possibly performed via OAT1. No clinically relevant increase in either clofibrate or tenofovir is anticipated as a result of competition for renal secretion via OAT1.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Approximately 70% of administered clonidine is excreted in the urine, mainly in form of the unchanged parent drug (40-60% of the dose). Clonidine is a weak inhibitor of OCT2 but is unlikely to affect tenofovir which is eliminated by different renal transporters.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely 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. There is little potential for interaction with tenofovir-DF via modulation of, or competition for, metabolic pathways.

Coadministration has not been studied. Piperine, a component of Piper cubeba, inhibits intestinal P-gp. Tenofovir-DF is a substrate of P-gp and its absorption could potentially increase, thereby increasing tenofovir systemic concentrations. Monitoring of tenofovir-associated adverse reactions, including frequent renal monitoring, is recommended.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cyproterone acetate is metabolized by CYP3A4.

Coadministration has not been studied. Dacarbazine undergoes activation to MTIC primarily via CYP1A2 and to a lesser extent by CYP2E1, with CYP1A1 having a role in extrahepatic metabolism. In vitro data suggest that dacarbazine is a substrate of the renal transporter OAT1 and concentrations of tenofovir and dacarbazine could be increased due to competition for active tubular secretion. No a priori dosage adjustment is recommended but renal function and haematological parameters should be monitored.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dapagliflozin is primarily metabolised by UGT1A9 which is not affected by tenofovir-DF.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Darifenacin is metabolized by CYP3A4 and CYP2D6.

Coadministration has not been studied but darunavir/cobicistat is expected to increase tenofovir plasma concentrations (inhibition of P-gp). Darunavir/cobicistat and tenofovir disoproxil fumarate can be used without dose adjustments. However, monitoring of renal function may be indicated when darunavir/cobicistat is given in combination with tenofovir disoproxil fumarate, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents. 

Symtuza (darunavir, cobicistat, emtricitabine, tenofovir alafenamide) is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral products. Furthermore, Symtuza contains tenofovir alafenamide and must not be administered with tenofovir-DF.

Note: this interaction was studied using a darunavir/ritonavir dose lower than that licensed. Coadministration of tenofovir-DF (300 mg once daily) and darunavir/ritonavir (300/100 mg twice daily) increased darunavir Cmax (16%), AUC (21%) and Cmin (24%). Tenofovir Cmax, AUC and Cmin increased by 24%, 22% and 37%, respectively. No adjustments to the licensed doses are required. A higher risk of renal impairment has been reported in patients receiving tenofovir-DF and a ritonavir or cobicistat boosted protease inhibitor. Close monitoring of renal function and for tenofovir-associated adverse reactions is required in these patients.

No clinically significant interaction was observed when delamanid and tenofovir-DF were coadministered. Coadministration of delamanid (100 mg twice daily) and tenofovir-DF (300 mg once daily) did not affect delamanid Cmax (16% decrease) or AUC (4% decrease). Tenofovir exposure was unchanged (11% decrease in Cmax, 9% decrease in AUC; n=13).

Coadministration with a desogestrel-containing combined oral contraceptive (COC) has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possible CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. No clinically significant drug interactions were observed when tenofovir-DF was coadministered with a COC containing ethinylestradiol/norgestimate.

Coadministration with a desogestrel-containing progestogen-only pill (POP) has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possible CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4.

Coadministration has not been studied, but could potentially decrease renal elimination of tenofovir-DF (thereby increasing the risk of nephrotoxicity) as diclofenac is a strong inhibitor of MRP4. A retrospective analysis showed that patients treated with diclofenac together with tenofovir-DF containing regimens were at higher risk of developing an acute kidney injury when compared to patients treated with tenofovir-DF-sparing regimens. Since diclofenac can exacerbate tenofovir-DF nephrotoxicity, diclofenac should be used with caution and close monitoring of renal function.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diltiazem is metabolized by CYP3A4 and CYP2D6.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily.

Disopyramide is primarily eliminated by the kidney. Coadministration has not been studied. In vitro data suggest that disopyramide inhibits the renal transporter OCT2 in rats, but no drug interaction is expected as OCT2 does not contribute to tenofovir renal excretion.

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

No clinically significant pharmacokinetic interaction was observed between tenofovir-DF and dolutegravir. Coadministration of tenofovir-DF (300 mg once daily) and dolutegravir (50 mg once daily) decreased dolutegravir Cmax and Ctrough by 3% and 8%, and increased AUC by 1%. Tenofovir Cmax, AUC and Ctrough increased by 9%, 12% and 19%, respectively. No dosage adjustment is necessary.

Triumeq (dolutegravir, abacavir, lamivudine) can be used as a complete regimen for the treatment of HIV-1 infection. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration with tenofovir-DF would be possible from a pharmacokinetic standpoint. No clinically significant pharmacokinetic interaction was observed between tenofovir-DF and dolutegravir, abacavir or lamivudine. Coadministration of tenofovir-DF (300 mg once daily) and dolutegravir (50 mg once daily) decreased dolutegravir Cmax and Ctrough by 3% and 8%, and increased AUC by 1%. Tenofovir Cmax, AUC and Ctrough increased by 9%, 12% and 19%, respectively. No significant pharmacokinetic interaction was observed when tenofovir-DF (300 mg once daily) and lamivudine (150 mg twice daily for 7 days) were coadministered. There was no change in AUC, Cmax or Cmin of tenofovir. Lamivudine AUC and Cmin were unaltered, and there was a 24% decrease in Cmax. Coadministration of tenofovir-DF (300 mg once daily) and abacavir (300 mg single dose) had no effect on tenofovir AUC or Cmax, and abacavir AUC; abacavir Cmax increased by 12%.

Dovato (dolutegravir/lamivudine) is indicated for use as a complete regimen for the treatment of HIV 1 infection. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration with tenofovir-DF would be possible from a pharmacokinetic standpoint. The European product label for Dovato advises that no dose adjustment is necessary with tenofovir. No clinically significant pharmacokinetic interaction was observed between tenofovir-DF and dolutegravir or lamivudine. Coadministration of tenofovir-DF (300 mg once daily) and dolutegravir (50 mg once daily) decreased dolutegravir Cmax and Ctrough by 3% and 8%, and increased AUC by 1%. Tenofovir Cmax, AUC and Ctrough increased by 9%, 12% and 19%, respectively. Coadministration of tenofovir-DF (300 mg once daily) and lamivudine (150 mg twice daily for 7 days) had no effect on AUC, Cmax or Cmin of tenofovir. Lamivudine AUC and Cmin were unaltered, and there was a 24% decrease in Cmax.

Juluca (dolutegravir/rilpivirine) is indicated for use as a complete regimen for the treatment of HIV-1 infection. However, in specific clinical situations where an intensification of HIV treatment is needed, coadministration with tenofovir-DF would be possible from a pharmacokinetic standpoint. Coadministration of tenofovir-DF (300 mg once daily) and dolutegravir (50 mg once daily) decreased dolutegravir Cmax and Ctrough by 3% and 8%, and increased AUC by 1%. Tenofovir Cmax, AUC and Ctrough increased by 9%, 12% and 19%, respectively. Coadministration of rilpivirine (150 mg once daily) and tenofovir-DF (300 mg once daily) decreased rilpivirine Cmax and Cmin by 4% and 1%, and increased AUC by 1%. Tenofovir Cmax, AUC and Cmin increased by 19%, 23% and 24%. [Note: this interaction study has been performed with a dose higher than the licensed dose for rilpivirine assessing the maximal effect on the co-administered drug. The dosing recommendation is applicable to the licensed dose of rilpivirine 25 mg once daily.]

Coadministration has no significant effect on the pharmacokinetics of doravirine or tenofovir. Coadministration of doravirine (100 mg single dose) and tenofovir-DF (300 mg once daily) decreased doravirine AUC, Cmax and C24 by 3%, 18% and 5%, respectively (n=8).

Delstrigo (doravirine, lamivudine, tenofovir-DF) is indicated for use as a complete regimen for the treatment of HIV 1 infection and must not be administered with other antiretroviral products or with additional tenofovir-DF.

Coadministration with a drospirenone-containing combined oral contraceptive (COC) has not been studied. Drospirenone is metabolized to a minor extent via CYP3A4. Ethinylestradiol is mainly metabolized by hydroxylation. Tenofovir-DF does not interact with these metabolic pathways. No clinically significant drug interactions were observed when tenofovir-DF was coadministered with a COC containing ethinylestradiol/norgestimate.

Coadministration with drospirenone as hormone replacement therapy (HRT) has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Drospirenone is metabolized to a minor extent via CYP3A4. Tenofovir-DF does not interact with this metabolic pathway. In addition, no interaction is expected with estradiol or estrogens administered as part of HRT.

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

Coadministration with dydrogesterone as hormone replacement therapy (HRT) has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dydrogesterone is metabolized to dihydrodydrogesterone (possibly via CYP3A4). Tenofovir-DF does not interact with this metabolic pathway. In addition, no interaction is expected with estradiol or estrogens administered as part of HRT.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Edoxaban is minimally metabolised by hydrolysis (mediated by carboxylesterase 1), conjugation, or oxidation by CYP3A4/5 (<10%). Edoxaban is eliminated primarily as unchanged drug in urine.

Coadministration of tenofovir-DF (300 mg once daily) and efavirenz (600 mg once daily) had no effect on the Cmax, AUC or Cmin of either tenofovir or efavirenz.

Coadministration has not been studied. Approximately 80% of oral/intravenous doses of eflornithine are excreted unchanged via the kidneys. As there are no available data determining whether excretion is via active tubular secretion or glomerular filtration, there is potential for competition with tenofovir for active renal transport mechanisms, which may lead to increased levels of either drug. A clinically significant interaction is not expected with topical preparations as less than 1% of topically applied eflornithine is systemically absorbed.

The interaction between elbasvir/grazoprevir and tenofovir-DF was evaluated in clinical studies, and no dose adjustments are required. There was no clinically significant effect on tenofovir pharmacokinetics when administered with elbasvir (tenofovir AUC, Cmax, Ctrough increased by 34%, 47%, 29%),  grazoprevir (tenofovir AUC, Cmax, Ctrough increased by 18%, 14%, 24%) or elbasvir/grazoprevir (tenofovir AUC, Cmax and Ctrough increased by 27%, 14% and ~20%). Tenofovir-DF had no clinically significant effect on elbasvir (AUC, Cmax, C24 decreased by 7%, 12%,8%) or grazoprevir (AUC, Cmax, C24 decreased by 14%, 22%, 11%).

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. Furthermore, Genvoya contains tenofovir alafenamide and should not be administered with tenofovir-DF. 

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. Furthermore, Stribild contains tenofovir-DF and should not be administered with additional tenofovir-DF. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Empagliflozin is mainly glucuronidated by UGTs 1A3, 1A8, 1A9 and 2B7. It is a substrate of P-gp and BCRP, and also a substrate of the renal transporter OAT3 and the hepatic transporters OATP1B1 and OATP1B3, but there is little potential for an interaction via competition for these transporters.

No significant interactions were observed between emtricitabine and tenofovir-DF. Coadministration of tenofovir-DF (300 mg once daily) and emtricitabine (200 mg once daily for 7 days) had no effect on tenofovir AUC, Cmax or Cmin. Emtricitabine AUC and Cmax were unaltered and there was a 20% increase in Cmin.

Descovy contains tenofovir alafenamide and therefore should not be administered with tenofovir-DF.

Emtricitabine/tenofovir-DF should not be administered with additional tenofovir-DF. Coadministration of tenofovir-DF (300 mg once daily) and emtricitabine (200 mg once daily for 7 days) had no effect on tenofovir AUC, Cmax or Cmin; emtricitabine AUC and Cmax were unaltered and there was a 20% increase in Cmin (n=17).

No significant pharmacokinetic interactions were observed when tenofovir-DF (300 mg once daily) was coadministered with entecavir (1 mg once daily). There was no change in tenofovir AUC, Cmax or Cmin and no change in entecavir Cmax or Cmin; however, entecavir AUC increased by 13%.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Ephedrine is predominantly eliminated unchanged via the kidneys possibly via the renal transporter OCT2. Tenofovir is not a substrate of OCTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as eplerenone is mainly metabolized by CYP3A4.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Erythromycin is extensively metabolized in the liver.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Eslicarbazepine is partly eliminated unchanged renally and partly glucuronidated by UGT2B4.

Coadministration with estradiol as hormone replacement therapy (HRT) has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Estradiol is metabolized by CYP3A4, CYP1A2 and is glucuronidated. Tenofovir-DF does not interact with these metabolic pathways. When estradiol was administered as part of feminizing hormone therapy to 20 HIV-infected transgender women receiving efavirenz and emtricitabine/tenofovir-DF, estradiol AUC, Cmax and C24 decreased by 28%, 19% and 36%, respectively, likely due to enzyme induction by efavirenz. There was no significant change in tenofovir pharmacokinetics.

Coadministration of tenofovir-DF and ethambutol alone has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%). Coadministration of TB treatment containing ethambutol (with rifampicin, isoniazid and pyrazinamide) and tenofovir-DF (with emtricitabine and efavirenz) increased tenofovir AUC and Cmin by 13% and 9% and decreased Cmax by 2%; there was no effect on ethambutol concentrations.

No clinically significant drug interactions were observed when tenofovir-DF was coadminstered with oral contraceptives (ethinylestradiol/norgestimate). Note, use of ethinylestradiol as part of gender affirming treatment is not recommended due to thrombotic risks.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as etidocaine is metabolized by CYP3A4.

Coadministration with an etonogestrel-containing progestogen-only implant has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Etonogestrel is metabolized by CYP3A4. Tenofovir-DF does not interact with this metabolic pathway.

Coadministration with etonogestrel as a combined vaginal ring (CVR) has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Etonogestrel is metabolized by CYP3A4. Tenofovir-DF does not interact with this metabolic pathway. No clinically significant drug interactions were observed when tenofovir-DF was coadministered with a COC containing ethinylestradiol/norgestimate.

No dose adjustment needed for either drug. Coadministration with tenofovir-DF (300 mg once daily) decreased etravirine Cmax and AUC (both by 19%) and Cmin by 18%. Tenofovir Cmax and AUC both increased by 15% and Cmin increased by 19%.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. There is no evidence to suggest that eucalyptus impacts UGTs or P-gp.

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 may increase concentrations of famciclovir and tenofovir due to competition for active tubular secretion. No a priori dosage adjustment is recommended, but renal function should be monitored.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Felodipine is metabolized by CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fenofibrate is metabolised to an active metabolite, fenofibric acid: in vitro data suggest that fenofibric acid inhibits OAT3. A clinically relevant drug interaction is unlikely as tenofovir is mainly excreted via OAT1.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fesoterodine is rapidly hydrolysed to its active metabolite which is subsequently metabolized by CYP2D6 and CYP3A4.

Coadministration has not been studied. Flucloxacillin is mainly eliminated renally partly by glomerular filtration and partly by active secretion via OAT1. Use with caution as flucloxacillin and tenofovir can compete at the level of OAT1-mediated renal secretion which can potentially decrease their renal elimination.

Coadministration has not been studied. Fluconazole is mainly eliminated renally by glomerular filtration and is an inhibitor of CYP3A4 and P-gp. Fluconazole could potentially increase the absorption of tenofovir-DF (inhibition of P-gp), thereby increasing the systemic concentration of tenofovir. No dose adjustment is required, but monitoring of tenofovir-associated adverse reactions, including frequent renal monitoring, is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flunisolide undergoes CYP3A4-mediated metabolism.

Coadministration has not been studied. Fluorouracil is metabolised via the same mechanisms as endogenous uracil, including via dihydropyrimidine dehydrogenase. Nucleotide analogues such as tenofovir-DF may compete for this metabolic pathway. The clinical relevance of this interaction is unknown.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluoxetine is metabolized by CYPs 2D6 and 2C9 and to a lesser extent by CYPs 2C19 and 3A4 to form norfluoxetine.

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

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

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

Coadministration has not been studied. Tenofovir-DF should be avoided with concurrent or recent use of a nephrotoxic agent. If concomitant use of tenofovir-DF and nephrotoxic agents is unavoidable, renal function should be monitored closely.

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

Coadministration has not been studied. Furosemide is glucuronidated mainly in the kidney (UGT1A9) and to a lesser extent in the liver (UGT1A1). A large proportion of furosemide is also eliminated unchanged renally (via OATs). In vitro data indicate that furosemide is a weak inhibitor of the renal transporters OAT1/OAT3 and therefore is predicted to have a limited effect on tenofovir renal elimination. No a priori dosage adjustment is recommended.

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

Coadministration has not been studied. Since tenofovir-DF is primarily eliminated by the kidneys, coadministration with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir or the coadministered drug. Tenofovir-DF should be avoided with concurrent or recent use of a nephrotoxic agent. If concomitant use of tenofovir-DF and nephrotoxic agents is unavoidable, renal function should be monitored closely.

Coadministration has not been studied. Garlic supplements have been shown to decrease unboosted saquinavir AUC by 50% in a clinical trial likely due to induction of intestinal CYP3A4 and/or P-gp by garlic. Based on the drug interaction study with rifampicin (another inducer of P-gp), no significant effect is expected on tenofovir-DF.

Coadministration has not been studied. As gentamicin is eliminated unchanged predominantly via renal glomerular filtration, there is little potential for interaction with tenofovir-DF via competition for active renal transport mechanisms. However, both gentamicin and tenofovir-DF are potentially nephrotoxic and tenofovir-DF should be avoided with concurrent or recent use of a nephrotoxic agent. If concomitant use of tenofovir-DF and nephrotoxic agents is unavoidable, renal function should be monitored closely.

Coadministration with a gestodene-containing combined oral contraceptive (COC) has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gestodene is metabolized by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Ethinylestradiol is mainly metabolized by hydroxylation. Tenofovir-DF does not interact with these metabolic pathways. No clinically significant drug interactions were observed when tenofovir-DF was coadministered with a COC containing ethinylestradiol/norgestimate.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. No effect on absorption of tenofovir-DF is expected as gingerols are unlikely to cause clinically significant inhibition of P-gp.

Coadministration with tenofovir-DF alone has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. No clinically significant interactions were observed when tenofovir-DF (with efavirenz and emtricitabine) and glecaprevir/pibrentasvir were coadministered. No dose adjustment is required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glyceryl trinitrate is metabolised by aldehyde dehydrogenase-2. 

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro data indicate that extracts of hop activate PXR and induce expression of MDR1 gene to a degree similar to that of St John’s wort. However, based on the drug interaction study with the potent inducer rifampicin, hops are unlikely to significantly alter tenofovir-DF exposure.

Coadministration has not been studied. A pharmacokinetic interaction is unlikely as there is little potential for competition of hydralazine and tenofovir-DF for active renal elimination mechanisms. However hydralazine has some nephrotoxic potential and use of tenofovir-DF should be avoided with concurrent or recent use of a nephrotoxic medicinal product. If coadministration is unavoidable, renal function should be monitored closely.

Coadministration has not been studied. Hydrochlorothiazide is not metabolised and is cleared by the kidneys via OAT1. In vitro data indicate that hydrochlorothiazide is unlikely to inhibit OAT1 in the range of clinically relevant drug concentrations and therefore is unlikely to affect the renal elimination of tenofovir.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. However, hydroxyurea is not licensed for use in combination with stavudine and didanosine as toxicities including pancreatitis and hepatitis (in some cases fatal) in HIV patients have been reported via post marketing surveillance. Thus, caution and monitoring for side effects is recommended if coadministered with other NRTIs such as tenofovir-DF

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. No drug interaction studies have been conducted with ibalizumab: based on ibalizumab’s mechanism of action and target-mediated drug disposition, drug-drug interactions are not expected. Tenofovir-DF is eliminated renally whereas ibalizumab, a monoclonal antibody binding to the CD4 receptor, is likely to be eliminated via intracellular catabolism similarly to other monoclonal antibodies. Dose modifications of ibalizumab are not required when administered with any other antiretroviral.

Ibandronic acid should be taken after an overnight fast (at least 6 hours) and before the first food or drink of the day. Medicinal products and supplements should be similarly avoided prior to taking ibandronic acid. Fasting should be continued for at least 30 minutes after taking ibandronic acid.