Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Based on exposure and indicated doses, the interaction profile is considered to be the same for all strengths.

Lumacaftor is a strong inducer of CYP3A and ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. There is potential for other medicinal products to affect lumacaftor/ivacaftor when administered concomitantly, and also for lumacaftor/ivacaftor to affect other medicinal products.

Potential for other medicinal products to affect lumacaftor/ivacaftor 
Inhibitors of CYP3A
Co-administration of lumacaftor/ivacaftor with itraconazole, a strong CYP3A inhibitor, did not impact the exposure of lumacaftor, but increased ivacaftor exposure by 4.3-fold. Due to the induction effect of lumacaftor on CYP3A, at steady-state, the net exposure of ivacaftor when co-administered with a CYP3A inhibitor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg every 12 hours, the approved dose of ivacaftor monotherapy.

No dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking lumacaftor/ivacaftor. However, when initiating lumacaftor/ivacaftor in patients taking strong CYP3A inhibitors, the dose should be adjusted (see sections 4.2 and 4.4).

No dose adjustment is recommended when used with moderate or weak CYP3A inhibitors.

Inducers of CYP3A
Co-administration of lumacaftor/ivacaftor with rifampicin, a strong CYP3A inducer, had minimal effect on the exposure of lumacaftor, but decreased ivacaftor exposure (AUC) by 57%. Therefore, co-administration of lumacaftor/ivacaftor is not recommended with strong CYP3A inducers (see sections 4.2 and 4.4).

No dose adjustment is recommended when used with moderate or weak CYP3A inducers.

Potential for lumacaftor/ivacaftor to affect other medicinal products 
CYP3A substrates
Lumacaftor is a strong inducer of CYP3A. Ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. The net effect of lumacaftor/ivacaftor therapy is expected to be strong CYP3A induction.
Therefore, concomitant use of lumacaftor/ivacaftor with CYP3A substrates may decrease the exposure of these substrates (see section 4.4).

ORKA_100_125-200_125-SPC-0121-V1                   Page 6 of 31
P-gp substrates
In vitro studies indicated that lumacaftor has the potential to both inhibit and induce P-gp. Additionally, a clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of lumacaftor/ivacaftor with P-gp substrates (e.g., digoxin) may alter the exposure of these substrates.

CYP2B6 and CYP2C substrates
Interaction with CYP2B6 and CYP2C substrates has not been investigated in vivo. In vitro studies suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; however, inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in vitro studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of lumacaftor/ivacaftor may alter (i.e., either increase or decrease) the exposure of CYP2C8 and CYP2C9 substrates, decrease the exposure of CYP2C19 substrates, and substantially decrease the exposure of CYP2B6 substrates.

Potential for lumacaftor/ivacaftor to interact with transporters

In vitro experiments show that lumacaftor is a substrate for Breast Cancer Resistance Protein (BCRP).
Co-administration of Orkambi with medicinal products that inhibit BCRP may increase plasma lumacaftor concentration. Lumacaftor inhibits the organic anion transporter (OAT) 1 and 3. Lumacaftor and ivacaftor are inhibitors of BCRP. Co-administration of Orkambi with medicinal products that are substrates for OAT1/3 and BCRP transport may increase plasma concentrations of such medicinal products. Lumacaftor and ivacaftor are not inhibitors of OATP1B1, OATP1B3, and organic cation transporter (OCT) 1 and 2. Ivacaftor is not an inhibitor of OAT1 and OAT3.

Established and other potentially significant interactions

Table 3 provides the established or predicted effect of lumacaftor/ivacaftor on other medicinal products or the effect of other medicinal products on lumacaftor/ivacaftor. The information reported in Table 3 mostly derives from in vitro studies. The recommendations provided under “Clinical comment” in Table 3 are based on interaction studies, clinical relevance, or predicted interactions due to elimination pathways. Interactions that have the most clinical relevance are listed first.

Table 3: Established and other potentially significant interactions - dose recommendations for use of lumacaftor/ivacaftor with other medicinal products
Concomitant medicinal product class:
Active substance name Effect                     Clinical comment
Concomitant medicinal products of most clinical relevance


ORKA_100_125-200_125-SPC-0121-V1                    Page 7 of 31
Anti-allergics: montelukast           ↔ LUM, IVA


↓ montelukast              No dose adjustment for montelukast is
Due to the induction of    recommended. Appropriate clinical
CYP3A/2C8/2C9 by           monitoring should be employed, as is
LUM                        reasonable, when co-administered with lumacaftor/ivacaftor. Lumacaftor/ivacaftor may decrease the exposure of montelukast,
which may reduce its efficacy.
fexofenadine          ↔ LUM, IVA
↑ or ↓ fexofenadine        Dose adjustment of fexofenadine may be Due to potential           required to obtain the desired clinical effect.
induction or inhibition    Lumacaftor/ivacaftor may alter the exposure of P-gp                    of fexofenadine.
Antibiotics: clarithromycin,       ↔ LUM                      No dose adjustment of lumacaftor/ivacaftor telithromycin         ↑ IVA                      is recommended when clarithromycin or Due to inhibition of       telithromycin are initiated in patients
CYP3A by                   currently taking lumacaftor/ivacaftor.
clarithromycin,
telithromycin

↓ clarithromycin,          The dose of lumacaftor/ivacaftor should be telithromycin              reduced to one tablet daily for the first week Due to induction of        of treatment when initiating lumacaftor/
CYP3A by LUM               ivacaftor in patients currently taking clarithromycin or telithromycin.

An alternative to these antibiotics, such as azithromycin, should be considered.
Lumacaftor/ivacaftor may decrease the exposures of clarithromycin and telithromycin, which may reduce their efficacy.
 erythromycin          ↔ LUM                      No dose adjustment of lumacaftor/ivacaftor ↑ IVA                      is recommended when co-administered with Due to inhibition of       erythromycin.
CYP3A by erythromycin

↓ erythromycin             An alternative to erythromycin, such as
Due to induction of        azithromycin, should be considered.
CYP3A by LUM               Lumacaftor/ivacaftor may decrease the exposure of erythromycin, which may reduce its efficacy.

ORKA_100_125-200_125-SPC-0121-V1              Page 8 of 31
Anticonvulsants: carbamazepine,        ↔ LUM phenobarbital,        ↓ IVA phenytoin             Due to induction of
CYP3A by these anticonvulsants

↓ carbamazepine,           Concomitant use of lumacaftor/ivacaftor phenobarbital,             with these anticonvulsants is not phenytoin                  recommended. The exposures of ivacaftor
Due to induction of        and the anticonvulsant may be significantly CYP3A by LUM               decreased, which may reduce the efficacy of both active substances.
Antifungals: itraconazole*,        ↔ LUM                      No dose adjustment of lumacaftor/ivacaftor ketoconazole,         ↑ IVA                      is recommended when these antifungals are posaconazole,         Due to inhibition of       initiated in patients currently taking voriconazole          CYP3A by these             lumacaftor/ivacaftor.
antifungals

↓ itraconazole,            The dose of lumacaftor/ivacaftor should be ketoconazole,              reduced to one tablet daily for the first week voriconazole               of treatment when initiating lumacaftor/
Due to induction of        ivacaftor in patients currently taking these CYP3A by LUM               antifungals.


↓ posaconazole             Concomitant use of lumacaftor/ivacaftor
Due to induction of        with these antifungals is not recommended.
UGT by LUM                 Patients should be monitored closely for breakthrough fungal infections if such medicinal products are necessary.
Lumacaftor/ivacaftor may decrease the exposures of these antifungals, which may reduce their efficacy.

ORKA_100_125-200_125-SPC-0121-V1              Page 9 of 31
fluconazole               ↔ LUM                      No dose adjustment of lumacaftor/ivacaftor ↑ IVA                      is recommended when co-administered with Due to inhibition of       fluconazole.
CYP3A by fluconazole

↓ fluconazole              A higher dose of fluconazole may be
Due to induction by        required to obtain the desired clinical effect.
LUM; fluconazole is        Lumacaftor/ivacaftor may decrease the cleared primarily by       exposure of fluconazole, which may reduce renal excretion as         its efficacy.
unchanged drug;
however, modest reduction in fluconazole exposure has been observed with strong inducers
Anti-inflammatories: ibuprofen                 ↔ LUM, IVA

↓ ibuprofen                A higher dose of ibuprofen may be required Due to induction of        to obtain the desired clinical effect.
CYP3A/2C8/2C9 by           Lumacaftor/ivacaftor may decrease the
LUM                        exposure of ibuprofen, which may reduce its efficacy.
Anti-mycobacterials: rifabutin, rifampicin*,   ↔ LUM rifapentine               ↓ IVA
Due to induction of
CYP3A by anti- mycobacterials

↓ rifabutin                Concomitant use of lumacaftor/ivacaftor
Due to induction of        with these anti-mycobacterials is not
CYP3A by LUM               recommended. The exposure of ivacaftor will be decreased, which may reduce the efficacy of lumacaftor/ivacaftor.

A higher dose of rifabutin may be required to obtain the desired clinical effect.
Lumacaftor/ivacaftor may decrease the exposure of rifabutin, which may reduce its efficacy.
↔ rifampicin,
rifapentine

ORKA_100_125-200_125-SPC-0121-V1                  Page 10 of 31
Benzodiazepines: midazolam, triazolam       ↔ LUM, IVA

↓ midazolam,              Concomitant use of lumacaftor/ivacaftor triazolam                 with these benzodiazepines is not
Due to induction of       recommended. Lumacaftor/ivacaftor will
CYP3A by LUM              decrease the exposures of midazolam and triazolam, which will reduce their efficacy.
Hormonal contraceptives:            ↓ ethinyl estradiol,      Hormonal contraceptives, including oral, ethinyl estradiol,         norethindrone, and        injectable, transdermal, and implantable, norethindrone, and other   other progestogens        should not be relied upon as an effective progestogens               Due to induction of       method of contraception when CYP3A/UGT by LUM          co-administered with lumacaftor/ivacaftor.
Lumacaftor/ivacaftor may decrease the exposure of hormonal contraceptives, which may reduce their efficacy.
Immunosuppressants: ciclosporin, everolimus,   ↔ LUM, IVA sirolimus, tacrolimus
(used after organ          ↓ ciclosporin,            Concomitant use of lumacaftor/ivacaftor transplant)                everolimus, sirolimus,    with these immunosuppressants is not tacrolimus                recommended. Lumacaftor/ivacaftor will
Due to induction of       decrease the exposure of these
CYP3A by LUM              immunosuppressants, which may reduce the efficacy of these immunosuppressants. The use of lumacaftor/ivacaftor in organ transplant patients has not been studied.
Proton pump inhibitors:                ↔ LUM, IVA esomeprazole,
lansoprazole,              ↓ esomeprazole,           A higher dose of these proton pump omeprazole                 lansoprazole,             inhibitors may be required to obtain the omeprazole                desired clinical effect.
Due to induction of       Lumacaftor/ivacaftor may decrease the
CYP3A/2C19 by             exposures of these proton pump inhibitors,
LUM                       which may reduce their efficacy.


ORKA_100_125-200_125-SPC-0121-V1                  Page 11 of 31
Herbals:
St. John’s wort         ↔ LUM                    Concomitant use of lumacaftor/ivacaftor (Hypericum perforatum)  ↓ IVA                    with St. John’s wort is not recommended.
Due to induction of      The exposure of ivacaftor will be decreased, CYP3A by St. John’s      which may reduce the efficacy of wort                     lumacaftor/ivacaftor.
Other concomitant medicinal products of clinical relevance
Antiarrhythmics: digoxin                 ↔ LUM, IVA

↑ or ↓ digoxin            The serum concentration of digoxin should Due to potential          be monitored and the dose should be titrated induction or              to obtain the desired clinical effect.
inhibition of P-gp        Lumacaftor/ivacaftor may alter the exposure of digoxin.
Anticoagulants: dabigatran                 ↔ LUM, IVA

↑ or ↓ dabigatran         Appropriate clinical monitoring should be Due to potential          employed when co-administered with induction or              lumacaftor/ivacaftor. Dose adjustment of inhibition of P-gp        dabigatran may be required to obtain the desired clinical effect.
Lumacaftor/ivacaftor may alter the exposure of dabigatran.
warfarin
↔ LUM, IVA

↑ or ↓ warfarin           The international normalised ratio (INR) Due to potential          should be monitored when warfarin induction or              co-administration with lumacaftor/ivacaftor inhibition of CYP2C9      is required.
by LUM                    Lumacaftor/ivacaftor may alter the exposure of warfarin.
Antidepressants: citalopram,                ↔ LUM, IVA escitalopram, sertraline
↓ citalopram,             A higher dose of these antidepressants may escitalopram,             be required to obtain the desired clinical sertraline                effect. Lumacaftor/ivacaftor may decrease
Due to induction of       the exposures of these antidepressants,
CYP3A/2C19 by             which may reduce their efficacy.
LUM bupropion                  ↔ LUM, IVA

↓ bupropion               A higher dose of bupropion may be required Due to induction of       to obtain the desired clinical effect.
CYP2B6 by LUM             Lumacaftor/ivacaftor may decrease the exposure of bupropion, which may reduce its efficacy.
ORKA_100_125-200_125-SPC-0121-V1                  Page 12 of 31
Corticosteroids,
systemic:                   ↔ LUM, IVA methylprednisolone,
prednisone                  ↓ methylprednisolone,
prednisone                  A higher dose of these systemic
Due to induction of         corticosteroids may be required to obtain CYP3A by LUM                the desired clinical effect.
Lumacaftor/ivacaftor may decrease the exposures of methylprednisolone and prednisone, which may reduce their efficacy.
H2 blockers: ranitidine                  ↔ LUM, IVA

↑ or ↓ ranitidine           Dose adjustment of ranitidine may be
Due to potential            required to obtain the desired clinical effect.
induction or inhibition     Lumacaftor/ivacaftor may alter the of P-gp                     exposure of ranitidine.
Oral hypoglycemics: repaglinide                 ↔ LUM, IVA

↓ repaglinide              A higher dose of repaglinide may be
Due to induction of        required to obtain the desired clinical effect.
CYP3A/2C8 by LUM           Lumacaftor/ivacaftor may decrease the exposure of repaglinide, which may reduce its efficacy.
Note: ↑ = increase, ↓ = decrease, ↔ = no change; LUM = lumacaftor; IVA = ivacaftor.
* Based on clinical interaction studies. All other drug interactions shown are predicted.
False positive urine tests for THC
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving Orkambi. An alternative confirmatory method should be considered to verify results.

Paediatric population

Interaction studies have only been performed in adults.