Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Delstrigo is a complete regimen for the treatment of HIV-1 infection; therefore, Delstrigo should not be administered with other antiretroviral medicinal products. Information regarding potential medicinal product interactions with other antiretroviral medicinal products is not provided.
Interaction studies have only been performed in adults.

Delstrigo contains doravirine, lamivudine, and tenofovir disoproxil, therefore any interactions identified for these individually are relevant to Delstrigo and are presented in Table 1.

Effects of other medicinal products on doravirine, lamivudine, and tenofovir disoproxil 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/lamivudine/tenofovir disoproxil 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/lamivudine/tenofovir disoproxil (see sections 4.3 and 5.2).

Co-administration with the moderate CYP3A inducer rifabutin decreased doravirine concentrations (see Table 1). When Delstrigo is co-administered with rifabutin, a 100 mg dose of doravirine should be given daily, approximately 12 hours after doravirine/lamivudine/tenofovir disoproxil dose (see section 4.2).

Co-administration of doravirine/lamivudine/tenofovir disoproxil 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., debrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl) cannot be avoided, a 100 mg dose of doravirine should be administered daily, approximately 12 hours after the administration of doravirine/lamivudine/tenofovir disoproxil dose (see section 4.2).

Co-administration of doravirine/lamivudine/tenofovir disproxil 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.

Lamivudine
Because lamivudine is primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion (see section 5.2), co-administration of doravirine/lamivudine/tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion may increase serum concentrations of lamivudine.

Tenofovir disoproxil
Because tenofovir is primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion (see section 5.2), co-administration of doravirine/lamivudine/tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion via OAT1, OAT3 or MRP4 may increase serum concentrations of tenofovir.

Due to the tenofovir disoproxil component of doravirine/lamivudine/tenofovir disoproxil, use of the product should be avoided with concurrent or recent use of nephrotoxic medicinal products. Some examples include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs (see section 4.4).

Effects of doravirine, lamivudine, and tenofovir disoproxil on other medicinal products Doravirine
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).

Lamivudine
Lamivudine does not inhibit or induce CYP enzymes.

Tenofovir
Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP-mediated interactions involving tenofovir with other medicinal products is low.

Interaction table
Table 1 shows the established and other potential medicinal product interactions with the individual components of Delstrigo but is not all inclusive (increase is indicated as ↑, decrease is indicated as ↓, and no change as ↔). For potential medicinal product interactions with tenofovir disoproxil or lamivudine, (see sections 4.4 and 5.2).

Table 1: Interactions between the individual components of Delstrigo and other medicinal products

Recommendation concerning
Effects on medicinal product
Medicinal product by                                                      co-administration with levels therapeutic area                                                          doravirine/lamivudine/tenofovir geometric mean ratio (90 % CI)* disoproxil
Acid-reducing agents antacid (aluminium and
↔ doravirine magnesium hydroxide oral
AUC 1.01 (0.92, 1.11) suspension)                                                                 No dose adjustment is required.
Cmax 0.86 (0.74, 1.01)
(20 mL SD,
doravirine 100 mg SD)           C24 1.03 (0.94, 1.12)
↓ 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 with doravirine or doravirine/lamivudine/tenofovir omeprazole                      disoproxil.                                 No dose adjustment is required.

Expected:
↔ doravirine



Recommendation concerning co-
Effects on medicinal product           administration with
Medicinal product by levels                                 doravirine/lamivudine/tenofovir therapeutic area geometric mean ratio (90 % CI)*        disoproxil
Angiotensin converting enzyme inhibitors
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir lisinopril              disoproxil.                             No dose adjustment is required.

Expected:
↔ lisinopril
Antiandrogens
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.                            Co-administration is enzalutamide contraindicated.
Expected:
↓ doravirine
(Induction of CYP3A)
Antibiotics
Interaction not studied with           Co-administration should be doravirine or                          avoided. If co-administration doravirine/lamivudine/tenofovir        cannot be avoided, a 100 mg dose disoproxil.                            of doravirine should be taken nafcillin daily, approximately 12 h after
Expected:                              the dose of
↓ doravirine                           doravirine/lamivudine/tenofovir (Induction of CYP3A)                   disoproxil.
Anticonvulsants
Interaction not studied with carbamazepine           doravirine or oxcarbazepine           doravirine/lamivudine/tenofovir phenobarbital           disoproxil.                            Co-administration is phenytoin                                                      contraindicated.
Expected:
↓ doravirine
(Induction of CYP3A)
Antidiabetics
Metformin               ↔ metformin
(1 000 mg               AUC 0.94 (0.88, 1.00)                   No dose adjustment is required.
SD,                     Cmax 0.94 (0.86, 1.03) doravirine 100 mg QD)
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir canagliflozin           disoproxil.
liraglutide                                                     No dose adjustment is required.
sitagliptin             Expected:
↔ canagliflozin
↔ liraglutide
↔ sitagliptin



Recommendation concerning co-
Effects on medicinal product            administration with
Medicinal product by levels                                  doravirine/lamivudine/tenofovir therapeutic area geometric mean ratio (90 % CI)*         disoproxil
Antidiarrhoeals
Interaction not studied with            Co-administration should be telotristat ethyl          doravirine or                           avoided. If co-administration doravirine/lamivudine/tenofovir         cannot be avoided, a 100 mg dose disoproxil.                             of doravirine should be taken daily, 12 h after the dose of
Expected:                               doravirine/lamivudine/tenofovir ↓ doravirine                            disoproxil.
(Induction of CYP3A)
Antigout and uricosuric agents
Interaction not studied with            Co-administration should be doravirine or                           avoided. If co-administration doravirine/lamivudine/tenofovir         cannot be avoided, a 100 mg dose lesinurad                  disoproxil.                             of doravirine should be taken daily, approximately 12 h after
Expected:                               the dose of
↓ doravirine                            doravirine/lamivudine/tenofovir (Induction of CYP3A)                    disoproxil.
Antimycobacterials
↔ doravirine
AUC 0.91 (0.78, 1.06)
Single dose rifampicin
Cmax 1.40 (1.21, 1.63)
(600 mg SD,
C24 0.90 (0.80, 1.01) doravirine 100 mg SD)
Co-administration is
↓ doravirine                            contraindicated.
Multiple dose rifampicin
AUC 0.12 (0.10, 0.15)
(600 mg QD,
Cmax 0.43 (0.35, 0.52) doravirine 100 mg SD)
C24 0.03 (0.02, 0.04)
(Induction of CYP3A)
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.                             Co-administration is rifapentine contraindicated.
Expected:
↓ doravirine
(Induction of CYP3A)
If doravirine/ lamivudine/
↓ doravirine tenofovir disoproxil is co-
AUC 0.50 (0.45, 0.55) rifabutin                                                          administered with rifabutin, a Cmax 0.99 (0.85, 1.15)
(300 mg QD,                                                        100 mg dose of doravirine C24 0.32 (0.28, 0.35) doravirine 100 mg SD)                                              should be taken daily, (Induction of CYP3A) approximately 12 h after dose of doravirine/lamivudine/tenofovir disoproxil.



Recommendation concerning co-
Effects on medicinal product         administration with
Medicinal product by levels                               doravirine/lamivudine/tenofovir therapeutic area geometric mean ratio (90 % CI)*      disoproxil
Antineoplastics
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.                          Co-administration is mitotane contraindicated.
Expected:
↓ doravirine
(Induction of CYP3A)
Antipsychotics
Interaction not studied with         Co-administration should be doravirine or                        avoided. If co-administration doravirine/lamivudine/tenofovir      cannot be avoided, a 100 mg dose disoproxil.                          of doravirine should be taken thioridazine                                                 daily, approximately 12 h after the Expected:                            dose of
↓ doravirine                         doravirine/lamivudine/tenofovir (Induction of CYP3A)                 disoproxil.
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 with doravirine or fluconazole             doravirine/lamivudine/tenofovir itraconazole            disoproxil.
No dose adjustment is required.
posaconazole voriconazole            Expected:
↑ doravirine
(Inhibition of CYP3A)
Calcium channel blockers
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir diltiazem               disoproxil.
No dose adjustment is required.
verapamil
Expected:
↑ doravirine
(Inhibition of CYP3A)



Recommendation concerning co-
Effects on medicinal product            administration with
Medicinal product by levels                                  doravirine/lamivudine/tenofovir therapeutic area geometric mean ratio (90 % CI)*         disoproxil
Cystic fibrosis treatment
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir lumacaftor               disoproxil.                             Co-administration is contraindicated.
Expected:
↓ doravirine
(Induction of CYP3A)
Endothelin receptor antagonists
Interaction not studied with            Co-administration should be doravirine or                           avoided. If co-administration doravirine/lamivudine/tenofovir         cannot be avoided, a 100 mg dose disoproxil.                             of doravirine should be taken bosentan                                                         daily, approximately 12 h after Expected:                               the dose of
↓ doravirine                            doravirine/lamivudine/tenofovir (Induction of CYP3A)                    disoproxil.
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)



Recommendation concerning co-
Effects on medicinal product      administration with
Medicinal product by levels                            doravirine/lamivudine/tenofovir therapeutic area geometric mean ratio (90 % CI)*   disoproxil
↑ doravirine
AUC 1.15 (1.07, 1.24)
Cmax 1.11 (0.97, 1.27)
C24 1.24 (1.13, 1.36)
↔ ledipasvir
AUC 0.92 (0.80, 1.06)             Patients receiving ledipasvir + sofosbuvir       Cmax 0.91 (0.80, 1.02)            doravirine/lamivudine/tenofovir (90 mg ledipasvir SD +                                          disoproxil concomitantly with 400 mg sofosbuvir SD,         ↔ sofosbuvir                      ledipasvir/sofosbuvir doravirine 100 mg SD)         AUC 1.04 (0.91, 1.18)             should be monitored for Cmax 0.89 (0.79, 1.00)            adverse reactions associated with tenofovir disoproxil.
↔ GS-331007
AUC 1.03 (0.98, 1.09)
Cmax 1.03 (0.97, 1.09)

Expected:
↑ tenofovir
Interaction not studied with
Patients receiving doravirine or doravirine/lamivudine/tenofovir doravirine/lamivudine/tenofovir disoproxil concomitantly with disoproxil.
sofosbuvir/velpatasvir                                          sofosbuvir/velpatasvir should be monitored for adverse reactions
Expected: associated with tenofovir
↔ doravirine disoproxil.
↑ tenofovir
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir sofosbuvir                    disoproxil.                       No dose adjustment is required.

Expected:
↔ doravirine
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir daclatasvir disoproxil.                       No dose adjustment is required.

Expected:
↔ doravirine
Interaction not studied with doravirine or ombitasvir/paritaprevir/      doravirine/lamivudine/tenofovir ritonavir and dasabuvir +/-   disoproxil.
ritonavir                                                       No dose adjustment is required.
Expected:
↑ doravirine
(Inhibition of CYP3A due to ritonavir)


Recommendation concerning co-
Effects on medicinal product        administration with
Medicinal product by levels                              doravirine/lamivudine/tenofovir therapeutic area geometric mean ratio (90 % CI)*     disoproxil
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir dasabuvir                     disoproxil.                          No dose adjustment is required.

Expected:
↔ doravirine
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir disoproxil.
glecaprevir, pibrentasvir                                          No dose adjustment is required.
Expected:
↑ doravirine
(inhibition of CYP3A)
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir ribavirin                     disoproxil.                          No dose adjustment is required.

Expected:
↔ doravirine
Herbal supplements
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir
St. John’s wort disoproxil.                         Co-administration is
(Hypericum perforatum) contraindicated.
Expected:
↓ doravirine
(Induction of CYP3A)
HIV antiviral agents
↔ doravirine tenofovir disoproxil
AUC 0.95 (0.80, 1.12)
(300 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)


Recommendation concerning co-
Effects on medicinal product           administration with
Medicinal product by levels                                 doravirine/lamivudine/tenofovir therapeutic area geometric mean ratio (90 % CI)*        disoproxil
Immunosuppressants
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir
Monitor blood concentrations of tacrolimus                   disoproxil.
tacrolimus and sirolimus as the sirolimus dose of these agents may need to
Expected: be adjusted.
↔ doravirine
↓ tacrolimus, sirolimus
(Induction of CYP3A)
Kinase inhibitors
Interaction not studied with           Co-administration should be doravirine or                          avoided. If co-administration doravirine/lamivudine/tenofovir        cannot be avoided, a 100 mg dose disoproxil.                            of doravirine should be taken dabrafenib                                                          daily, approximately 12 h after the Expected:                              dose of
↓ doravirine                           doravirine/lamivudine/tenofovir (Induction of CYP3A)                   disoproxil.
Miscellaneous
Single dose lamivudine oral solution   When possible, avoid chronic co- 300 mg                                 administration of doravirine/lamivudine/tenofovir lamivudine                             disoproxil with medicinal sorbitol solution (3.2 g,    AUC ↓ 14 %; 32 %; 35 %                 products containing sorbitol or 10.2 g, 13.4 g)/lamivudine   Cmax ↓ 28 %; 52 %; 55 %                other osmotic acting poly- alcohols (e.g., xylitol, mannitol,
lactitol, maltitol). Consider more frequent monitoring of HIV-1 viral load when chronic co- administration cannot be avoided.



Recommendation concerning co-
Effects on medicinal product        administration with
Medicinal product by levels                              doravirine/lamivudine/tenofovir therapeutic area geometric mean ratio (90 % CI)*     disoproxil
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 with doravirine or doravirine/lamivudine/tenofovir buprenorphine                 disoproxil.
No dose adjustment is required.
naloxone
Expected:
↔ buprenorphine
↔ naloxone
Oral contraceptives
↔ ethinyl oestradiol
AUC 0.98 (0.94, 1.03)
0.03 mg ethinyl oestradiol/   Cmax 0.83 (0.80, 0.87)
0.15 mg levonorgestrel SD,                                         No dose adjustment is required.
doravirine 100 mg QD          ↑ levonorgestrel
AUC 1.21 (1.14, 1.28)
Cmax 0.96 (0.88, 1.05)
Interaction not studied with doravirine or doravirine/lamivudine/tenofovir norgestimate/ethinyl disoproxil.                          No dose adjustment is required.
oestradiol
Expected:
↔ norgestimate/ethinyl oestradiol
Psychostimulants
Interaction not studied with        Co-administration should be doravirine or                       avoided. If co-administration doravirine/lamivudine/tenofovir     cannot be avoided, a 100 mg dose disoproxil.                         of doravirine should be taken modafinil                                                         daily, approximately 12 h after the Expected:                           dose of
↓ doravirine                        doravirine/lamivudine/tenofovir (Induction of CYP3A)                disoproxil.
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)

Recommendation concerning co-
Effects on medicinal product                   administration with
Medicinal product by levels                                         doravirine/lamivudine/tenofovir therapeutic area geometric mean rratio (90 % CI)*               disoproxil
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 with doravirine or doravirine/lamivudine/tenofovir rosuvastatin                      disoproxil.
No dose adjustment is required.
simvastatin
Expected:
↔ 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.