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Interactions relevant to tenofovir: Didanosine: Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended (see Precautions and Table 4).
Renally eliminated medicinal products: Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil fumarate with medicinal products that reduce renal function or compete for active tubular secretion via transport proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir and/or the co-administered medicinal products.
Tenofovir disoproxil fumarate should be avoided with concurrent use of a nephrotoxic medicinal product, such as aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see Precautions).
Given that tacrolimus can affect renal function, close monitoring is recommended when it is co-administered with tenofovir disoproxil fumarate.
Other interactions: Interactions between Lamivudine/Tenofovir Disoproxil Fumarate 300mg/300mg and HIV protease inhibitors, as well as antiviral agents other than protease inhibitors, are listed in Table below (increased exposure is indicated as "↑", decreased exposure as "↓", no change as "↔", twice daily as "b.i.d.", and once daily as "q.d."). (See Table 4.)
Click on icon to see table/diagram/imageStudies conducted with other medicinal products: There were no clinically significant pharmacokinetic interactions when Lamivudine/Tenofovir Disoproxil Fumarate 300mg/300mg Tablets is coadministered with indinavir, efavirenz, nelfinavir, saquinavir (ritonavir boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive norgestimate/ethinyl oestradiol.
Food effect: Tenofovir disoproxil fumarate must be taken with food, as food enhances the bioavailability of tenofovir (see Pharmacology: Pharmacodynamics under Actions).
Interactions relevant to dolutegravir: Effect of other agents on the pharmacokinetics of dolutegravir: All factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance.
Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Tables 5a, 5b and 5c).
Co-administration of dolutegravir and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration (see Tables 5a, 5b and 5c). The absorption of dolutegravir is reduced by certain anti-acid agents (see Tables 5an, 5b and 5c).
Effect of dolutegravir on the pharmacokinetics of other agents: In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on in vivo and/or in vitro data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for more information see Pharmacology: Pharmacokinetics under Actions).
In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter (MATE) 1. In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE-1 transport) was observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OCT2 or MATE-1 (e.g. dofetilide, metformin) (see Tables 5a, 5b and 5c, and Contraindications).
In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT1) and OAT3. Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition of OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medical products in which excretion is dependent upon OAT3.
Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Tables 5a, 5b and 5c.
Interaction table dolutegravir: Interactions between dolutegravir and co-administered medicinal products are listed in Tables 5a, 5b and 5c (increase is indicated as "↑", decrease as "↓", no change as "↔", area under the concentration versus time curve as "AUC", maximum observed concentration as "Cmax", concentration at end of dosing interval as "Cτ").
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imagePaediatric population: Interaction studies have only been performed in adults.
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