XELJANZ / XELJANZ XR (tofacitinib) Drug Interactions

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Overview

In vitro studies indicate that tofacitinib does not significantly inhibit the activity of the major human drug metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations exceeding 80 times the steady state Cmax of a 5 and 10 mg BID dose in patients treated with tofacitinib. In vitro studies also indicated a low risk of induction of CYP3A4 (2-fold mRNA at 6.25 µM), CYP2B6 (2-fold mRNA at 12.5 µM), and CYP1A2 (no enzyme changes) at clinically relevant concentrations (total Cmax of 0.186 µM).

In vitro, tofacitinib is a substrate for multidrug resistance (MDR) 1, but not for breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1/1B3, or organic cationic transporter (OCT) 1/2. In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, MDR1, organic anion transporter (OAT) P1B1/1B3, OCT2, OAT1/3, cationic transporters or multidrug resistance‑associated protein (MRP) at therapeutic concentrations is also low.

Tofacitinib exposure is increased when XELJANZ is coadministered with potent CYP3A4 inhibitors (e.g., ketoconazole) or when administration of one or more concomitant medications results in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). Tofacitinib exposure is decreased when XELJANZ is coadministered with potent CYP3A4 inducers (e.g. rifampin). Inhibitors of CYP2C19 or P-glycoprotein are unlikely to alter the PK of tofacitinib.

The in vitro results were confirmed by a human drug interaction study showing no changes in the PK of midazolam, a highly sensitive CYP3A4 substrate, when coadministered with XELJANZ.

In vitro studies indicate that tofacitinib does not significantly inhibit the activity of the major human drug-metabolizing uridine 5'-diphospho-glucuronosyltransferases (UGTs) [UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7] at concentrations exceeding 250 times the steady state Cmax of a 5 and 10 mg twice daily dose in RA, PsA and UC patients.

The oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in patients. Therefore, coadministration with XELJANZ/XELJANZ XR is not expected to result in clinically relevant increases in the metabolism of CYP substrates.

Drug-Drug Interactions

Table 4: Summary of Drug-Drug Interactions
 
Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Drug

Reference

Effect

Clinical Comment

Methotrexate

CT

Coadministration with methotrexate (15-25 mg MTX once weekly) had no effect on the PK of tofacitinib and decreased methotrexate AUC (area under the curve) and Cmax by 10% and 13% respectively.

No dose adjustment is required for either drug.

Ketoconazole

CT

Coadministration of ketoconazole, a strong CYP3A4 inhibitor, with a single dose of XELJANZ increased the AUC and Cmax of tofacitinib by 103% and 16%, respectively

XELJANZ XR is not recommended in patients coadministered with strong inhibitors of CYP3A4.

The recommended dose is half the daily dose indicated for patients not receiving strong CYP3A4 inhibitors concomitantly, i.e., in patients already taking:

XELJANZ 10 mg twice daily, reduce the dose to XELJANZ 5 mg twice daily or

XELJANZ 5 mg twice daily, reduce the dose to XELJANZ 5 mg once daily.

Fluconazole

CT

Coadministration of fluconazole, a moderate inhibitor of CYP3A4 and a strong inhibitor of CYP2C19, increased the AUC and Cmax of tofacitinib by 79% and 27%, respectively

XELJANZ XR is not recommended in patients coadministered with medications that result in moderate inhibition of CYP3A4 and potent inhibition of CYP2C19.

The recommended dose is half the daily dose indicated for patients not receiving concomitant medications that result in moderate inhibition of CYP3A4 and potent inhibition of CYP2C19, i.e., in patients already taking:

XELJANZ 10 mg twice daily, reduce the dose to XELJANZ 5 mg twice daily or

XELJANZ 5 mg twice daily, reduce the dose to XELJANZ 5 mg once daily.

Tacrolimus and Cyclosporine

CT

Coadministration of tacrolimus, a mild inhibitor of CYP3A4, increased the AUC of tofacitinib by 21% and decreased the Cmax of tofacitinib by 9%.


Coadministration of cyclosporine, a moderate inhibitor of CYP3A4, increased the AUC of tofacitinib by 73% and decreased Cmax of tofacitinib by 17%.

There is a risk of added immunosuppression when XELJANZ/XELJANZ XR is co-administered with potent immunosuppressive drugs (e.g: tacrolimus, cyclosporine, azathioprine). The combined use with these potent immunosuppressives has not been studied in patients and is not recommended.

Rifampin

CT

Coadministration of rifampin, a strong CYP3A4 inducer, decreased the AUC and Cmax of tofacitinib by 84% and 74%, respectively

Coadministration of XELJANZ/XELJANZ XR with potent inducers of CYP3A4 may result in loss of or reduced clinical response /efficacy.

Midazolam

CT

Coadministration of XELJANZ with midazolam, a highly sensitive CYP3A4 substrate, had no effect on midazolam PK

No dosage adjustment is required for CYP3A4 substrates such as midazolam.

Oral contraceptives (Ethinyl Estradiol and Levonorgestrel)

CT

Coadministration of XELJANZ with oral contraceptives had no effect on the PK of either oral contraceptive in healthy females

No dose adjustment is required for either oral contraceptives ethinyl estradiol and levonorgestrel.

Metformin

CT

Coadministration of XELJANZ with metformin, a substrate of Organic Cationic Transporter and Multidrug and Toxic Compound Extrusion, had no effect on the PK of metformin

No dosage adjustment is required for metformin.

The impact of extrinsic factors on tofacitinib pharmacokinetics is summarized in Figure 1 and 2 with dosage adjustment recommendations.

Figure 1: Impact of Co-administered drugs on Pharmacokinetics of Tofacitinib

 
Note: Reference group is administration of tofacitinib alone; PK=Pharmacokinetics; CI=Confidence Interval
a In RA patients the recommended dose is XELJANZ 5 mg once daily. In UC patients receiving 10 mg twice daily, XELJANZ dosage should be reduced to 5 mg twice daily, and in UC patients receiving 5 mg twice daily, XELJANZ dosage should be reduced to 5 mg once daily

Figure 2: Impact of Tofacitinib on Pharmacokinetics of Co-administered Drugs

 
Note: Reference group is administration of concomitant medication alone; OCT = Organic Cationic Transporter; MATE = Multidrug and Toxic Compound Extrusion; PK=Pharmacokinetics; CI=Confidence Interval

Drugs that Decrease Heart Rate and/or Prolong the PR Interval: XELJANZ resulted in a decrease in heart rate and an increase in the PR interval (see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS). Caution should be observed if XELJANZ/XELJANZ XR is used concomitantly with other drugs that lower heart rate and/or prolong the PR interval, such as antiarrhythmics, beta blockers, alpha2 adrenoceptor agonists, non-dihydropyridine calcium channel blockers, digitalis glycosides, cholinesterase inhibitors, sphingosine-1 phosphate receptor modulators, and some HIV protease inhibitors.

Combination with other therapies

XELJANZ/XELJANZ XR has not been studied and is not indicated to be used in combination with biologics such as TNF antagonists, interleukin (IL)-1R antagonists, IL-6R antagonists, IL‑17 antagonists, IL-12/IL-23 antagonists, anti‑CD20 monoclonal antibodies, anti-integrins, selective co-stimulation modulators, and potent immunosuppressants such as azathioprine, 6-mercaptopurine, cyclosporine, and tacrolimus because of the possibility of increased immunosuppression and increased risk of infection.

The use of XELJANZ/XELJANZ XR in combination with phosphodiesterase 4 inhibitors has not been studied in XELJANZ clinical trials.

Drug-Food Interactions

Grapefruit juice affects CYP450 3A-mediated metabolism and concomitant administration with XELJANZ/XELJANZ XR should be avoided.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Drug-Herb Interactions

St John’s Wort is a CYP3A4 inducer and co-administration with XELJANZ/XELJANZ XR may result in loss of or reduced clinical response.

Drug-Lifestyle Interactions

No formal studies have been conducted on the effects on the ability to drive and use machines.