Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on doravirine
Doravirine is primarily metabolised by CYP3A, and medicinal products that induce or inhibit CYP3A are expected to affect the clearance of doravirine (see section 5.2). Doravirine should not be co- administered with medicinal products that are strong CYP3A enzyme inducers as significant decreases in doravirine plasma concentrations are expected to occur, which may decrease the effectiveness of doravirine (see sections 4.3 and 5.2).

Co-administration with the moderate CYP3A inducer rifabutin decreased doravirine concentrations (see Table 1). When doravirine is co-administered with rifabutin, the doravirine dose should be increased to 100 mg twice daily (the doses should be taken approximately 12 hours apart) (see section 4.2).

Co-administration of doravirine with other moderate CYP3A inducers has not been evaluated, but decreased doravirine concentrations are expected. If co-administration with other moderate CYP3A inducers (e.g., dabrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl) cannot be avoided, the doravirine dose should be increased to 100 mg twice daily (the doses should be taken approximately 12 hours apart) (see section 4.2).

Co-administration of doravirine and medicinal products that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine. However, no dose adjustment is needed when doravirine is co-administered with CYP3A inhibitors.

Effects of doravirine on other medicinal products
Doravirine at a dose of 100 mg once daily is not likely to have a clinically relevant effect on the plasma concentrations of medicinal products that are dependent on transport proteins for absorption and/or elimination or that are metabolised by CYP enzymes.

However, co-administration of doravirine and the sensitive CYP3A substrate midazolam resulted in a 18 % decrease in midazolam exposure, suggesting that doravirine may be a weak CYP3A inducer.
Therefore caution should be used when co-administering doravirine with medicinal products that are sensitive CYP3A substrates that also have a narrow therapeutic window (e.g., tacrolimus and sirolimus).

Interactions table
Table 1 shows the established and other potential medicinal product interactions with doravirine but is not all inclusive (increase is indicated as ↑, decrease is indicated as ↓, and no change as ↔).


Table 1: Interactions of doravirine with other medicinal products

Medicinal product by          Effects on medicinal product          Recommendation concerning therapeutic area              levels geometric mean ratio            co-administration with (90 % CI)*                        doravirine
Acid-reducing agents antacid (aluminium and          ↔ doravirine magnesium hydroxide oral        AUC 1.01 (0.92, 1.11) suspension)                     Cmax 0.86 (0.74, 1.01)                No dose adjustment is required.
(20 mL SD,                      C24 1.03 (0.94, 1.12) doravirine 100 mg SD)
↓ doravirine pantoprazole
AUC 0.83 (0.76, 0.91)
(40 mg QD,                                                            No dose adjustment is required.
Cmax 0.88 (0.76, 1.01) doravirine 100 mg SD)
C24 0.84 (0.77, 0.92)
Interaction not studied.
omeprazole                                                         No dose adjustment is required.
Expected:
↔ doravirine
Angiotensin converting enzyme inhibitors
Interaction not studied.
lisinopril                                                            No dose adjustment is required.
Expected:
↔ lisinopril
Antiandrogens
Interaction not studied.
Co-administration is enzalutamide                    Expected: contraindicated.
↓ doravirine
(Induction of CYP3A)
Antibiotics
Interaction not studied.              Co-administration should be avoided. If co-administration
Expected:                             cannot be avoided, one tablet of nafcillin
↓ doravirine                          doravirine should be taken twice (Induction of CYP3A)                  daily (approximately 12 hours apart).



Medicinal product by      Effects on medicinal product       Recommendation concerning therapeutic area          levels geometric mean ratio         co-administration with (90 % CI)*                      doravirine
Anticonvulsants carbamazepine              Interaction not studied.
oxcarbazepine
Co-administration is phenobarbital              Expected: contraindicated.
phenytoin                  ↓ doravirine
(Induction of CYP3A)
Antidiabetics metformin                  ↔ metformin
(1 000 mg SD,              AUC 0.94 (0.88, 1.00)               No dose adjustment is required.
doravirine 100 mg QD)      Cmax 0.94 (0.86, 1.03)
Interaction not studied.
canagliflozin
Expected: liraglutide                                                    No dose adjustment is required.
↔ canagliflozin sitagliptin
↔ liraglutide
↔ sitagliptin
Antidiarrhoeals
Interaction not studied.            Co-administration should be avoided. If co-administration
Expected:                           cannot be avoided, one tablet of telotristat ethyl
↓ doravirine                        doravirine should be taken twice (Induction of CYP3A)                daily (approximately 12 hours apart).
Antigout and uricosuric agents
Interaction not studied.            Co-administration should be avoided. If co-administration
Expected:                           cannot be avoided, one tablet of lesinurad
↓ doravirine                        doravirine should be taken twice (Induction of CYP3A)                daily (approximately 12 hours apart).
Antimycobacterials
Single dose rifampicin     ↔ doravirine
(600 mg SD,                AUC 0.91 (0.78, 1.06) doravirine 100 mg SD)      Cmax 1.40 (1.21, 1.63)
C24 0.90 (0.80, 1.01)
Co-administration is
Multiple dose rifampicin   ↓ doravirine                        contraindicated.
(600 mg QD,                AUC 0.12 (0.10, 0.15) doravirine 100 mg SD)      Cmax 0.43 (0.35, 0.52)
C24 0.03 (0.02, 0.04)
(Induction of CYP3A)
Interaction not studied.
Co-administration is rifapentine                Expected: contraindicated.
↓ doravirine
(Induction of CYP3A)
↓ doravirine                        If doravirine is co-administered rifabutin                  AUC 0.50 (0.45, 0.55)               with rifabutin, the doravirine dose (300 mg QD,                Cmax 0.99 (0.85, 1.15)              should be increased to 100 mg doravirine 100 mg SD)      C24 0.32 (0.28, 0.35)               twice daily (approximately (Induction of CYP3A)                12 hours apart).


Medicinal product by     Effects on medicinal product       Recommendation concerning therapeutic area         levels geometric mean ratio         co-administration with (90 % CI)*                      doravirine
Antineoplastics
Interaction not studied.
Co-administration is mitotane                  Expected: contraindicated.
↓ doravirine
(Induction of CYP3A)
Antipsychotics
Interaction not studied.            Co-administration should be avoided. If co-administration
Expected:                           cannot be avoided, one tablet of thioridazine
↓ doravirine                        doravirine should be taken twice (Induction of CYP3A)                daily (approximately 12 hours apart).
Azole antifungal agents
↑ doravirine ketoconazole              AUC 3.06 (2.85, 3.29)
(400 mg QD,               Cmax 1.25 (1.05, 1.49)              No dose adjustment is required.
doravirine 100 mg SD)     C24 2.75 (2.54, 2.98)
(Inhibition of CYP3A)
Interaction not studied.
fluconazole itraconazole
Expected:                           No dose adjustment is required.
posaconazole
↑ doravirine voriconazole
(Inhibition of CYP3A4)
Calcium channel blockers
Interaction not studied.
diltiazem
Expected:                           No dose adjustment is required.
verapamil
↑ doravirine
(CYP3A inhibition)
Cystic fibrosis treatment
Interaction not studied.
Co-administration is lumacaftor                Expected: contraindicated.
↓ doravirine
(Induction of CYP3A)
Endothelin receptor antagonists
Interaction not studied.            Co-administration should be avoided. If co-administration
Expected:                           cannot be avoided, one tablet of bosentan
↓ doravirine                        doravirine should be taken twice (Induction of CYP3A)                daily (approximately 12 hours apart).



Medicinal product by        Effects on medicinal product        Recommendation concerning therapeutic area            levels geometric mean ratio          co-administration with (90 % CI)*                       doravirine
Hepatitis C antiviral agents
↑ doravirine
AUC 1.56 (1.45, 1.68)
Cmax 1.41 (1.25, 1.58)
C24 1.61 (1.45, 1.79)
(Inhibition of CYP3A) elbasvir + grazoprevir
↔ elbasvir
(50 mg elbasvir QD +
AUC 0.96 (0.90, 1.02)                No dose adjustment is required.
200 mg grazoprevir QD,
Cmax 0.96 (0.91, 1.01) doravirine 100 mg QD)
C24 0.96 (0.89, 1.04)

↔ grazoprevir
AUC 1.07 (0.94, 1.23)
Cmax 1.22 (1.01, 1.47)
C24 0.90 (0.83, 0.96)
↑ doravirine
AUC 1.15 (1.07, 1.24)
Cmax 1.11 (0.97, 1.27)
C24 1.24 (1.13, 1.36)

↔ ledipasvir ledipasvir + sofosbuvir      AUC 0.92 (0.80, 1.06)
(90 mg ledipasvir SD +       Cmax 0.91 (0.80, 1.02)
No dose adjustment is required.
400 mg sofosbuvir SD,
doravirine 100 mg SD)        ↔ sofosbuvir
AUC 1.04 (0.91, 1.18)
Cmax 0.89 (0.79, 1.00)
↔ GS-331007
AUC 1.03 (0.98, 1.09)
Cmax 1.03 (0.97, 1.09)
Interaction not studied.
sofosbuvir/velpatasvir                                            No dose adjustment is required.
Expected:
↔ doravirine
Interaction not studied.
sofosbuvir                                                        No dose adjustment is required.
Expected:
↔ doravirine
Interaction not studied.
daclatasvir
No dose adjustment is required.
Expected:
↔ doravirine
Interaction not studied.
ombitasvir/
Expected: paritaprevir/ritonavir and                                        No dose adjustment is required.
↑ doravirine dasabuvir+/-ritonavir
(Inhibition of CYP3A due to ritonavir)



Medicinal product by       Effects on medicinal product       Recommendation concerning therapeutic area           levels geometric mean ratio         co-administration with (90 % CI)*                      doravirine
Interaction not studied.
dasabuvir                   Expected:                           No dose adjustment is required.
↔ doravirine
Interaction not studied.
 glecaprevir, pibrentasvir   Expected:                           No dose adjustment is required.
↑ doravirine
(inhibition of CYP3A)
Interaction not studied.
ribavirin                                                       No dose adjustment is required.
Expected:
↔ doravirine
Herbal supplements
Interaction not studied.
St. John’s wort
Co-administration is
(Hypericum perforatum)      Expected: contraindicated.
↓ doravirine
(Induction of CYP3A)
HIV antiviral agents
Fusion and entry inhibitors
Interaction not studied.
 enfuvirtide                 Expected:                           No dose adjustment is required.
↔ doravirine
↔ enfuviritide
Interaction not studied.
maraviroc                   Expected:                           No dose adjustment is required.
↔ doravirine
↔ maraviroc
Protease inhibitors
Interaction not studied.
ritonavir†- boosted PIs
(atazanavir, darunavir,     Expected: fosamprenavir, indinavir,   ↑ doravirine                        No dose adjustment is required.
lopinavir, saquinavir,      (Inhibition of CYP3A) tipranavir)
↔ boosted PIs
Interaction not studied.

Expected: cobicistat-boosted PIs
↑ doravirine                        No dose adjustment is required.
(darunavir, atazanavir)
(Inhibition of CYP3A)

↔ boosted PIs


Medicinal product by         Effects on medicinal product          Recommendation concerning therapeutic area             levels geometric mean ratio            co-administration with (90 % CI)*                        doravirine
Integrase strand transfer inhibitors
↔ doravirine
AUC 1.00 (0.89, 1.12)
Cmax 1.06 (0.88, 1.28)
C24 0.98 (0.88, 1.09) dolutegravir
(50 mg QD,                                                           No dose adjustment is required.
↑ dolutegravir doravirine 200 mg QD)
AUC 1.36 (1.15, 1.62)
Cmax 1.43 (1.20, 1.71)
C24 1.27 (1.06, 1.53)
(Inhibition of BCRP)
Interaction not studied.
 raltegravir                    Expected:                             No dose adjustment is required.
↔ doravirine
↔ raltegravir
Interaction not studied.

Expected: ritonavir†-boosted
↑ doravirine                          No dose adjustment is required.
elvitegravir
(CYP3A inhibition)
↔ elvitegravir
Interaction not studied.
 cobicistat-boosted             Expected:
No dose adjustment is required.
elvitegravir                   ↑ doravirine
(CYP3A inhibition)
↔ elvitegravir
Nucleoside reverse transcriptase inhibitors (NRTI)
↔ doravirine tenofovir disoproxil
AUC 0.95 (0.80, 1.12)
(245 mg QD,                                                           No dose adjustment is required.
Cmax 0.80 (0.64, 1.01) doravirine 100 mg SD)
C24 0.94 (0.78, 1.12)
↔ doravirine
AUC 0.96 (0.87, 1.06)
Cmax 0.97 (0.88, 1.07) lamivudine + tenofovir         C24 0.94 (0.83, 1.06) disoproxil
(300 mg lamivudine SD +        ↔ lamivudine
No dose adjustment is required.
245 mg tenofovir disoproxil    AUC 0.94 (0.88, 1.00)
SD,                            Cmax 0.92 (0.81, 1.05) doravirine 100 mg SD)
↔ tenofovir
AUC 1.11 (0.97, 1.28)
Cmax 1.17 (0.96, 1.42) abacavir                       Interaction not studied.              No dose adjustment is required.

Expected:
↔ doravirine
↔ abacavir


Medicinal product by     Effects on medicinal product    Recommendation concerning therapeutic area         levels geometric mean ratio      co-administration with (90 % CI)*                   doravirine
Interaction not studied.
 emtricitabine             Expected:                        No dose adjustment is required.
↔ doravirine
↔ emtricitabine
Interaction not studied.
 tenofovir alafenamide     Expected:                        No dose adjustment is required.
↔ doravirine
↔ tenofovir alafenamide
Immunosuppressants
Interaction not studied.
Monitor blood concentrations of tacrolimus and sirolimus as the tacrolimus                Expected: dose of these agents may need to sirolimus                 ↔ doravirine be adjusted.
↓ tacrolimus, sirolimus
(Induction of CYP3A)
Kinase inhibitors
Interaction not studied.         Co-administration should be avoided. If co-administration
Expected:                        cannot be avoided, one tablet of dabrafenib
↓ doravirine                     doravirine should be taken twice
(Induction of CYP3A)             daily (approximately 12 hours apart).
Opioid analgesics
↓ doravirine
AUC 0.74 (0.61, 0.90)
Cmax 0.76 (0.63, 0.91)
C24 0.80 (0.63, 1.03) methadone                 ↔ R-methadone
20-200 mg QD              AUC 0.95 (0.90, 1.01)
No dose adjustment is required.
individualised dose,      Cmax 0.98 (0.93, 1.03) doravirine 100 mg QD      C24 0.95 (0.88, 1.03)

↔ S-methadone
AUC 0.98 (0.90, 1.06)
Cmax 0.97 (0.91, 1.04)
C24 0.97 (0.86, 1.10)
Interaction not studied.
buprenorphine
Expected:                        No dose adjustment is required.
naloxone
↔ buprenorphine
↔ naloxone



Medicinal product by              Effects on medicinal product                 Recommendation concerning therapeutic area                  levels geometric mean ratio                   co-administration with (90 % CI)*                                doravirine
Oral contraceptives
0.03 mg ethinyl oestradiol/         ↔ ethinyl oestradiol
0.15 mg levonorgestrel SD,          AUC 0.98 (0.94, 1.03) doravirine 100 mg QD                Cmax 0.83 (0.80, 0.87)
No dose adjustment is required.
↑ levonorgestrel
AUC 1.21 (1.14, 1.28)
Cmax 0.96 (0.88, 1.05)
Interaction not studied.
norgestimate/ethinyl
No dose adjustment is required.
oestradiol                          Expected:
↔ norgestimate/ethinyl oestradiol
Pharmacokinetic enhancers
↑ doravirine ritonavir                           AUC 3.54 (3.04, 4.11)
(100 mg BID,                        Cmax 1.31 (1.17, 1.46)                       No dose adjustment is required.
doravirine 50 mg SD)                C24 2.91 (2.33, 3.62)
(Inhibition of CYP3A)
Interaction not studied.
 cobicistat                          Expected:                                    No dose adjustment is required.
↑ doravirine
(Inhibition of CYP3A)
Psychostimulants
Interaction not studied.                     Co-administration should be avoided. If co-administration
Expected:                                    cannot be avoided, one tablet of modafinil
↓doravirine                                  doravirine should be taken twice (Induction of CYP3A)                         daily (approximately 12 hours apart).
Sedatives/hypnotics midazolam                           ↓ midazolam
(2 mg SD,                           AUC 0.82 (0.70, 0.97)                        No dose adjustment is required.
doravirine 120 mg QD)               Cmax 1.02 (0.81, 1.28)
Statins atorvastatin                        ↔ atorvastatin
(20 mg SD,                          AUC 0.98 (0.90, 1.06)                        No dose adjustment is required.
doravirine 100 mg QD)               Cmax 0.67 (0.52, 0.85)
Interaction not studied.
rosuvastatin                        Expected:
No dose adjustment is required.
simvastatin                         ↔ rosuvastatin
↔ simvastatin
↑ = increase, ↓ = decrease, ↔ = no change
CI = Confidence Interval; SD = Single Dose; QD = Once Daily; BID = Twice Daily *AUC0-∞ for single dose, AUC0-24 for once daily.
†The interaction was evaluated with ritonavir only.