Interactions : אינטראקציות

4.5     Interaction with other medicinal products and other forms of interaction
Nevirapine is an inducer of CYP3A and potentially CYP2B6, with maximal induction occurring within 2-4 weeks of initiating multiple-dose therapy.
Compounds using this metabolic pathway may have decreased plasma concentrations when co-administered with nevirapine. Careful monitoring of the therapeutic effectiveness of P450 metabolised medicinal products is recommended when taken in combination with nevirapine.
The absorption of nevirapine is not affected by food, antacids or medicinal products which are formulated with an alkaline buffering agent.

The interaction data is presented as geometric mean value with 90% confidence interval (90% CI) whenever these data were available. ND = Not Determined, ↑ = Increased, ↓ = Decreased, ↔ = No Effect.


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Medicinal            Interaction                            Recommendations concerning products by                                                 co-administration therapeutic areas
ANTI-INFECTIVES
Antiretrovirals
NRTIs
Didanosine          Didanosine AUC ↔ 1.08 (0.92-            Didanosine and VIRAMUNE can 100-150 mg BID      1.27)                                   be co-administered without dose Didanosine Cmin ND                      adjustments.
Didanosine Cmax ↔ 0.98 (0.79-1.21)

Emtricitabine       Emtricitabine is not an inhibitor of    Viramune and emtricitabine may be human CYP 450 enzymes.                  coadministered without dose adjustments.

Abacavir            In human liver microsomes, abacavir     Viramune and abacavir may be did not inhibit cytochrome P450         coadministered without dose isoforms.                               adjustments.

Lamivudine          No changes to lamivudine apparent       Lamivudine and Viramune can be 150 mg BID          clearance and volume of                 co-administered without dose distribution, suggesting no induction   adjustments.
effect of nevirapine on lamivudine clearance.

Stavudine:          Stavudine AUC ↔ 0.96 (0.89-1.03)        Stavudine and Viramune can be 30/40 mg BID        Stavudine Cmin ND                       co-administered without dose Stavudine Cmax ↔ 0.94 (0.86-1.03)       adjustments.

Nevirapine: compared to historical controls, levels appeared to be unchanged.

Tenofovir           Tenofovir plasma levels remain          Tenofovir and Viramune can be 300 mg QD           unchanged when co-administered          co-administered without dose with Nevirapine.                        adjustments.

Nevirapine plasma levels were not altered by co-administration of tenofovir.

Zidovudine          Zidovudine AUC ↓ 0.72 (0.60-0.96)       Zidovudine and Viramune can be 100-200 mg TID      Zidovudine Cmin ND                      co-administered without dose Zidovudine Cmax ↓ 0.70 (0.49-1.04)      adjustments

Nevirapine: Zidovudine had no           Granulocytopenia is commonly effect on its pharmacokinetics.         associated with zidovudine.
Therefore, patients who receive nevirapine and zidovudine concomitantly and especially paediatric patients and patients who receive higher zidovudine doses or patients with poor bone marrow reserve, in particular those with advanced HIV disease,
have an increased risk of granulocytopenia. In such patients

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haematological parameters should be carefully monitored.


NNRTIs
Efavirenz           Efavirenz AUC ↓ 0.72 (0.66-0.86)               It is not recommended to co- 600 mg QD           Efavirenz Cmin ↓ 0.68 (0.65-0.81)              administer efavirenz and Efavirenz Cmax ↓ 0.88 (0.77-1.01)              Viramune (see section 4.4), because of additive toxicity and no benefit in terms of efficacy over either NNRTI alone (for results of 2NN study, see section
5.1).

Delavirdine         Interaction has not been studied.              The concomitant administration of Viramune with NNRTIs is not recommended (see section 4.4).

Etravirine          Concomitant use of etravirine with             The concomitant administration nevirapine may cause a significant             of Viramune with NNRTIs is not decrease in the plasma concentrations of       recommended (see section 4.4).
etravirine and loss of therapeutic effect of etravirine.

Rilpivirine         Interaction has not been studied.              The concomitant administration of Viramune with NNRTIs is not recommended (see section 4.4).



PIs
Atazanavir/ritona   Atazanavir/r 300/100mg:                        It is not recommended to co- vir 300/100 mg      Atazanavir/r AUC ↓ 0.58 (0.48-0.71)            administer atazanavir/ritonavir QD                  Atazanavir/r Cmin ↓ 0.28 (0.20-0.40)           and Viramune (see section 4.4)..
400/100 mg QD       Atazanavir/r Cmax ↓ 0.72 (0.60-0.86)


Atazanavir/r 400/100mg:
Atazanavir/r AUC ↓ 0.81 (0.65-1.02)
Atazanavir/r Cmin ↓ 0.41 (0.27-0.60)
Atazanavir/r Cmax ↔ 1.02 (0.85–
1.24)
(compared to 300/100mg without nevirapine)

Nevirapine AUC ↑ 1.25 (1.17-1.34)
Nevirapine Cmin ↑ 1.32 (1.22–1.43)
Nevirapine Cmax ↑ 1.17 (1.09-1.25)

Darunavir/ritonav   Darunavir AUC ↑ 1.24 (0.97-1.57)               Darunavir and Viramune can be ir 400/100 mg       Darunavir Cmin ↔ 1.02 (0.79-1.32)              co-administered without dose BID                 Darunavir Cmax ↑ 1.40 (1.14-1.73)              adjustments.


Nevirapine AUC ↑ 1.27 (1.12-1.44)
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Nevirapine Cmin ↑ 1.47 (1.20-1.82)
Nevirapine Cmax ↑ 1.18 (1.02-1.37)


Fosamprenavir        Amprenavir AUC ↓ 0.67 (0.55-0.80)     It is not recommended to co-administer 1,400 mg BID         Amprenavir Cmin ↓ 0.65 (0.49-0.85)    fosamprenavir and Viramune if Amprenavir Cmax ↓ 0.75 (0.63-0.89)    fosamprenavir is not co-administered with ritonavir (see section 4.4).
Nevirapine AUC ↑ 1.29 (1.19-1.40)     .
Nevirapine Cmin ↑ 1.34 (1.21-1.49)
Nevirapine Cmax ↑ 1.25 (1.14-1.37)

Fosamprenavir/rit    Amprenavir AUC ↔ 0.89 (0.77-          Fosamprenavir/ritonavir and onavir 700/100       1.03)                                 Viramune can be co-administered mg BID               Amprenavir Cmin ↓ 0.81 (0.69-0.96)    without dose adjustments Amprenavir Cmax ↔ 0.97 (0.85-1.10)

Nevirapine AUC ↑ 1.14 (1.05-1.24)
Nevirapine Cmin ↑ 1.22 (1.10-1.35)
Nevirapine Cmax ↑ 1.13 (1.03-1.24)

Lopinavir/ritonav    Adult patients:                       An increase in the dose of ir (capsules)        Lopinavir AUC ↓ 0.73 (0.53-0.98)      lopinavir/ritonavir to 533/133 mg    400/100 mg BID       Lopinavir Cmin ↓ 0.54 (0.28-0.74)     (4 capsules) or 500/125 mg (5
Lopinavir Cmax ↓ 0.81 (0.62-0.95)     tablets with 100/25 mg each) twice daily with food is recommended in combination with Viramune. Dose adjustment of Viramune is not required when co-administered with lopinavir.

Lopinavir/ritonav    Paediatric patients:                  For children, increase of the dose ir (oral solution)   Lopinavir AUC ↓ 0.78 (0.56-1.09)      of lopinavir/ritonavir to 300/75 300/75 mg/m2         Lopinavir Cmin ↓ 0.45 (0.25-0.82)     mg/m2 twice daily with food BID                  Lopinavir Cmax ↓ 0.86 (0.64-1.16)     should be considered when used in combination with Viramune,
particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected.


Ritonavir            Ritonavir AUC↔ 0.92 (0.79-1.07)       Ritonavir and Viramune can be 600 mg BID           Ritonavir Cmin ↔ 0.93 (0.76-1.14)     co-administered without dose Ritonavir Cmax ↔ 0.93 (0.78-1.07)     adjustments.

Nevirapine: Co-administration of ritonavir does not lead to any clinically relevant change in nevirapine plasma levels.
Saquinavir/ritona    The limited data available with       Saquinavir/ritonavir and vir                  saquinavir soft gel capsule boosted   Viramune can be co-administered with ritonavir do not suggest any     without dose adjustments.
clinically relevant interaction between saquinavir boosted with ritonavir and nevirapine


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Tipranavir/ritona   No specific drug-drug interaction          Tipranavir and Viramune can be vir 500/200 mg      study has been performed.                  co-administered without dose BID                 The limited data available from a          adjustments.
phase IIa study in HIV-infected patients have shown a clinically non significant 20% decrease of TPV
Cmin.

Entry Inhibitors
Enfuvirtide         Due to the metabolic pathway no            Enfuvirtide and Viramune can be clinically significant                     co-administered without dose pharmacokinetic interactions are           adjustments.
expected between enfuvirtide and nevirapine.
Maraviroc           Maraviroc AUC ↔ 1.01 (0.6 -1.55)           Maraviroc and Viramune can be 300 mg QD           Maraviroc Cmin ND                          co-administered without dose Maraviroc Cmax ↔ 1.54 (0.94-2.52)          adjustments.
compared to historical controls

Nevirapine concentrations not measured, no effect is expected.

Integrase
Inhibitors
Elvitegravir/       Interaction has not been studied.          Coadministration of Viramune with cobicistat          Cobicistat, a cytochrome P450 3A           elvitegravir in combination with inhibitor significantly inhibits hepatic   cobicistat is not recommended (see enzymes, as well as other metabolic        section 4.4).
pathways. Therefore coadministration would likely result in altered plasma levels of cobicistat and Viramune.

Raltegravir         No clinical data available. Due to the     Raltegravir and Viramune can be    400 mg BID          metabolic pathway of raltegravir no        co-administered without dose interaction is expected.                   adjustments.

Antibiotics
Clarithromycin      Clarithromycin AUC ↓ 0.69 (0.62-           Clarithromycin exposure was 500 mg BID          0.76)                                      significantly decreased, 14-OH Clarithromycin Cmin ↓ 0.44 (0.30-          metabolite exposure increased.
0.64)                                      Because the clarithromycin active Clarithromycin Cmax ↓ 0.77 (0.69-          metabolite has reduced activity 0.86)                                      against Mycobacterium avium- intracellulare complex overall activity against the pathogen may
Metabolite 14-OH clarithromycin            be altered. Alternatives to AUC ↑ 1.42 (1.16-1.73)                     clarithromycin, such as
Metabolite 14-OH clarithromycin            azithromycin should be
Cmin ↔ 0 (0.68-1.49)                       considered. Close monitoring for Metabolite 14-OH clarithromycin            hepatic abnormalities is
Cmax ↑ 1.47 (1.21-1.80)                    recommended

Nevirapine AUC ↑ 1.26
Nevirapine Cmin ↑ 1.28
Nevirapine Cmax ↑ 1.24 compared to historical controls.


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Rifabutin             Rifabutin AUC ↑ 1.17 (0.98-1.40)          No significant effect on rifabutin 150 or 300 mg         Rifabutin Cmin ↔ 1.07 (0.84-1.37)         and Viramune mean PK QD                    Rifabutin Cmax ↑ 1.28 (1.09-1.51)         parameters is seen. Rifabutin and Viramune can be co-administered
Metabolite 25-O-desacetylrifabutin        without dose adjustments.
AUC ↑ 1.24 (0.84-1.84)                    However, due to the high
Metabolite 25-O-desacetylrifabutin        interpatient variability some Cmin ↑ 1.22 (0.86-1.74)                   patients may experience large Metabolite 25-O-desacetylrifabutin        increases in rifabutin exposure Cmax ↑ 1.29 (0.98-1.68)                   and may be at higher risk for rifabutin toxicity. Therefore,
A clinically not relevant increase in     caution should be used in the apparent clearance of nevirapine      concomitant administration.
(by 9%) compared to historical data was reported.

Rifampicin            Rifampicin AUC ↔ 1.11 (0.96-1.28)         It is not recommended to co- 600 mg QD             Rifampicin Cmin ND                        administer rifampicin and Rifampicin Cmax ↔ 1.06 (0.91-1.22)        Viramune (see section 4.4).
Physicians needing to treat
Nevirapine AUC ↓ 0.42                     patients co-infected with Nevirapine Cmin ↓ 0.32                    tuberculosis and using a
Nevirapine Cmax ↓ 0.50                    Viramune containing regimen compared to historical controls.          may consider co-administration of rifabutin instead.



Antifungals
Fluconazole             Fluconazole AUC ↔ 0.94 (0.88-1.01)           Because of the risk of    200 mg QD               Fluconazole Cmin ↔ 0.93 (0.86-1.01)          increased exposure to
Fluconazole Cmax ↔ 0.92 (0.85-0.99)          Viramune, caution should be exercised if the medicinal
Nevirapine: exposure: ↑100% compared         products are given with historical data where nevirapine        concomitantly and patients was administered alone.                      should be monitored closely.
Itraconazole            Itraconazole AUC ↓ 0.39                      A dose increase for    200 mg QD               Itraconazole Cmin ↓ 0.13                     itraconazole should be
Itraconazole Cmax ↓ 0.62                     considered when these two agents are administered
Nevirapine: there was no significant         concomitantly.
difference in nevirapine pharmacokinetic parameters.
Ketoconazole            Ketoconazole AUC ↓ 0.28 (0.20-0.40)          It is not recommended to co-    400 mg QD               Ketoconazole Cmin ND                         administer ketoconazole and
Ketoconazole Cmax ↓ 0.56 (0.42-0.73)         Viramune (see section 4.4).
.
Nevirapine: plasma levels: ↑ 1.15-1.28 compared to historical controls.
ANTIVIRALS FOR CHRONIC HEPATITIS B AND C
Adefovir          Results of in vitro studies showed a weak          Adefovir and Viramune antagonism of nevirapine by adefovir (see          may be coadministered section 5.1), this has not been confirmed in       without dose adjustments.
clinical trials and reduced efficacy is not expected. Adefovir did not influence any of the common CYP isoforms known to be
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involved in human drug metabolism and is excreted renally. No clinically relevant drug- drug interaction is expected.

Boceprevir            Boceprevir is partly metabolized by           It is not recommended to CYP3A4/5. Co-administration of boceprevir     coadminister boceprevir and with medicines that induce or inhibit         Viramune (see section 4.4).
CYP3A4/5 could increase or decrease exposure. Plasma trough concentrations of boceprevir were decreased when administered with an NNRTI with a similar metabolic pathway as nevirapine. The clinical outcome of this observed reduction of boceprevir trough concentrations has not been directly assessed.

Entecavir              Entecavir is not a substrate, inducer or an     Entecavir and Viramune inhibitor of cytochrome P450 (CYP450)            may be coadministered enzymes. Due to the metabolic pathway of         without dose adjustments.
entecavir, no clinically relevant drug-drug interaction is expected.

Interferons           Interferons have no known effect on CYP      Interferons and Viramune (pegylated            3A4 or 2B6. No clinically relevant drug-drug may be coadministered interferons alfa 2a   interaction is expected.                     without dose adjustments.
and alfa 2b)
Ribavirin             Results of in vitro studies showed a weak        Ribavirin and Viramune antagonism of nevirapine by ribavirin (see       may be coadministered section 5.1), this has not been confirmed in     without dose adjustments.
clinical trials and reduced efficacy is not expected. Ribavirin does not inhibit cytochrome P450 enzymes, and there is no evidence from toxicity studies that ribavirin induces liver enzymes. No clinically relevant drug-drug interaction is expected.

Telaprevir            Telaprevir is metabolised in the liver by        Caution should be exercised CYP3A and is a P-glycoprotein substrate.         when co-administering telaprevir Other enzymes may be involved in the             with nevirapine.
metabolism. Co-administration of telaprevir      If co-administered with and medicinal products that induce CYP3A         Viramune, an adjustment in the and/or P-gp may decrease telaprevir plasma       telaprevir dose should be concentrations. No drug-drug interaction         considered.
study of telaprevir with nevirapine has been conducted, however, interaction studies of telaprevir with an NNRTI with a similar metabolic pathway as nevirapine demonstrated reduced levels of both. Results of DDI studies of telaprevir with efavirenz indicate that caution should be exercised when co-administering telaprevir with P450 inducers.
Telbivudine           Telbivudine is not a substrate, inducer or       Telbivudine and Viramune inhibitor of the cytochrome P450 (CYP450)        may be coadministered enzyme system. Due to the metabolic              without dose adjustments.
pathway of telbivudine, no clinically relevant drug-drug interaction is expected.


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ANTACIDS
Cimetidine            Cimetidine: no significant effect on         Cimetidine and Viramune cimetidine PK parameters is seen.            can be co-administered without dose adjustments.
Nevirapine Cmin ↑ 1.07
ANTITHROMBO
TICS
Warfarin              The interaction between nevirapine and       Close monitoring of the antithrombotic agent warfarin is         anticoagulation levels is complex, with the potential for both         warranted.
increases and decreases in coagulation time when used concomitantly.
CONTRACEPTIVES
Depo-                  DMPA AUC ↔                                    Viramune co- medroxyprogesteron     DMPA Cmin ↔                                   administration did not e acetate (DMPA)       DMPA Cmax ↔                                   alter the ovulation 150 mg every 3                                                       suppression effects of months                 Nevirapine AUC ↑ 1.20                         DMPA. DMPA and Nevirapine Cmax ↑ 1.20                        Viramune can be co- administered without dose adjustments.
Ethinyl estradiol      EE AUC ↓ 0.80 (0.67 - 0.97)                   Oral hormonal (EE) 0.035 mg          EE Cmin ND                                    contraceptives should not EE Cmax ↔ 0.94 (0.79 - 1.12)                  be used as the sole method of contraception
Norethindrone          NET AUC ↓ 0.81 (0.70 - 0.93)                  in women taking (NET) 1.0 mg QD        NET Cmin ND                                   Viramune (see section NET Cmax ↓ 0.84 (0.73 - 0.97)                 4.4). Appropriate doses for hormonal contraceptives (oral or other forms of application) other than
DMPA in combination with Viramune have not been established with respect to safety and efficacy.



ANALGESICS/OPIOIDS
Methadone          Methadone AUC ↓ 0.40 (0.31 - 0.51)                Methadone-maintained Individual         Methadone Cmin ND                                 patients beginning Patient Dosing     Methadone Cmax ↓ 0.58 (0.50 - 0.67)               Viramune therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.

HERBAL PRODUCTS
St. John's Wort        Serum levels of nevirapine can be reduced     Herbal preparations by concomitant use of the herbal              containing St. John‘s preparation St. John's Wort (Hypericum        Wort and Viramune must perforatum). This is due to induction of      not be co-administered medicinal product metabolism enzymes          (see section 4.3). If a and/or transport proteins by St. John’s       patient is already taking Wort.                                         St. John‘s Wort check nevirapine and if possible
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viral levels and stop St
John‘s Wort. Nevirapine levels may increase on stopping St John‘s Wort.
The dose of Viramune may need adjusting. The inducing effect may persist for at least
2 weeks after cessation of treatment with St. John‘s
Wort.


Other information:
Nevirapine metabolites: Studies using human liver microsomes indicated that the formation of nevirapine hydroxylated metabolites was not affected by the presence of dapsone, rifabutin, rifampicin, and trimethoprim/sulfamethoxazole. Ketoconazole and erythromycin significantly inhibited the formation of nevirapine hydroxylated metabolites.