Olumiant ® (baricitinib) tabletter

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Olumiant® (baricitinib): Samtidig användning med orala preventivmedel vid klinisk prövning av atopisk dermatit

Ingen undergruppsanalys av effekt och säkerhet har utförts baserat på samtidig användning av orala preventivmedel i de kliniska prövningarna av atopisk dermatit med baricitinib.

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Baricitinib Label Information Related to Pregnancy

Baricitinib is contraindicated during pregnancy. Women of childbearing potential have to use effective contraception during and for at least 1 week after treatment.1

If a patient becomes pregnant while taking baricitinib the parents should be informed of the potential risk to the foetus.1

Overview of the BREEZE-AD Clinical Development Program

The efficacy and safety of BARI has been evaluated in the following placebo-controlled trials in adult patients with moderate to severe AD

  • BREEZE-AD1 (N=624) and BREEZE-AD2 (N=615) compared BARI 1 mg, 2 mg, or 4 mg monotherapy to placebo in adult patients with inadequate response to TCS.2
  • BREEZE-AD4 (N=500) compared BARI 1 mg, 2 mg, or 4 mg in combination with TCS vs placebo with TCS in adult patients who were inadequate responders to, intolerant of, or contraindicated for cyclosporine.3
  • BREEZE-AD5 (N=440) compared BARI 1 mg or 2 mg monotherapy to placebo in adult patients with inadequate response to TCS.4
  • BREEZE-AD7 (N=329) compared BARI 2 mg or 4 mg in combination with TCS vs placebo with TCS in adult patients with inadequate response to topical medications.5

Note: BARI 1 mg was studied in pivotal trials, however it is not approved. Please refer to section 4.2 of the Olumiant Summary of Product Characteristics for approved dosage.

Concomitant Medication Use Criteria in the BREEZE-AD Phase 3 Placebo-Controlled Clinical Studies

Permitted Concomitant Medications

Concomitant treatments for other medical conditions, like oral contraceptives, were permitted during the BREEZE-AD clinical program.

Patients were excluded from participating in BARI clinical studies if they were women of childbearing potential who did not agree to use 2 forms of effective birth control (1 highly effective) when engaging in sexual intercourse while enrolled in the study and for at least 28 days following the last dose of study treatment.6

Efficacy and Safety of Baricitinib in Patients With Concomitant Oral Contraceptive Use

Subgroup analyses of efficacy and safety have not been conducted in patients with concomitant use of oral contraceptives through week 16.6

Summary of Concomitant Oral Contraceptive Use presents the percentages of patients with concomitant use of oral contraceptives in the BREEZE-AD placebo-controlled clinical trials.

At baseline, the percentage of females in each trial were

  • BREEZE-AD1 37.3%
  • BREEZE-AD2 38.0%
  • BREEZE-AD4 35.9%
  • BREEZE-AD5 49.1%, and
  • BREEZE-AD7 34.3%.2
Summary of Concomitant Oral Contraceptive Use6

Categorized by ATC classification, n (%)a

Placebo

BARI 1 mg

BARI 2 mg

BARI 4 mg

Monotherapy Clinical Trials

BREEZE-AD1 N=624
Through Week 16

N=249

N=127

N=123

N=125

Sex Hormones and Modulators of the Genital System

24 (9.6)

10 (7.9)

7 (5.7)

9 (7.2)

Ethinylestradiol; Levonogestrel

11 (4.4)

5 (3.9)

2 (1.6)

2 (1.6)

Dienogest; Ethinylestradiol

3 (1.2) 

1 (0.8)

1 (0.8)

4 (3.2)

Drospirenone; Ethinylestradiol 

5 (2.0)

1 (0.8)

2 (1.6)

1 (0.8)

Desogestrel

2 (0.8)

2 (1.6)

0

0

Estradiol; Nomegestrol

2 (0.8)

0

0

1 (0.8)

Desogestrel; Ethinylestradiol

0

0

1 (0.8)

0

Dydrogesterone; Estradiol

0

0

0

1 (0.8)

Estradiol; Trimegestone

0

0

1 (0.8)

0

Ethinylestradiol; Norelgestromin

1 (0.4)

0

0

0

Medroxyprogesterone

0

1 (0.8)

0

0

Norethisterone

0

0

0

1 (0.8)

BREEZE-AD2 N=615
Through Week 16

N=244

N=125

N=123

N=123

Sex Hormones and Modulators of the Genital System

24 (9.8)

11 (8.8)

21 (17.1)

13 (10.6)

Drospirenone; Ethinylestradiol

9 (3.7)

3 (2.4)

6 (4.9)

5 (4.1)

Ethinylestradiol; Gestodene

3 (1.2)

3 (2.4)

4 (3.3)

0

Ethinylestradiol; Levonorgestrel

2 (0.8)

0

1 (0.8)

2 (1.6)

Chlormadinone; Ethinylestradiol

1 (0.4)

0

3 (2.4)

0

Desogestrel

2 (0.8)

0

1 (0.8)

1 (0.8)

Desogestrel; Ethinylestradiol

1 (0.4)

1 (0.8)

1 (0.8)

1 (0.8)

Cyproterone; Ethinylestradiol

2 (0.8)

1 (0.8)

0

0

Dienogest; Ethinylestradiol

1 (0.4)

0

1 (0.8)

1 (0.8)

Estradiol; Nomegestrol

2 (0.8)

0

0

0

Ethinylestradiol

0

1 (0.8)

1 (0.8)

0

Ethinylestradiol; Norelgestromin

1 (0.4)

0

0

1 (0.8)

Dienogest; Estradiol

0

0

1 (0.8)

0

Drospirenone

0

1 (0.8)

0

0

Estradiol

0

1 (0.8)

0

0

Ethinylestradiol; Lynestrenol

0

1 (0.8)

0

0

Ethinylestradiol; Norgestimate

0

0

0

1 (0.8)

Hormonal Contraceptives for Systemic Use

0

0

1 (0.8)

0

Progesterone

0

0

0

1 (0.8)

Tibolone

0

0

1 (0.8)

0

Levonorgesterel

2 (0.8)

0

0

2 (1.6)

BREEZE-AD5 N=440
Through Week 16b

N=147

N=147

N=146

--

Sex Hormones and Modulators of the Genital System

16 (10.9)

13 (8.8)

20 (13.7)

--

Ethinylestradiol; Norgestimate

3 (2.0)

3 (2.0) 

6 (4.1)

--

Ethinylestradiol; Levonorgesterel

4 (2.7)

3 (2.0) 

1 (0.7)

--

Ethinylestradiol; Iron; Norethisterone

3 (2.0)

2 (1.4)

2 (1.4)

--

Desogestrel; Ethinylestradiol

1 ( 0.7)

4 ( 2.7)

0

--

Etonogestrel

1 ( 0.7)

0

2 (1.4)

--

Medroxyprogesterone

2 (1.4)

0

1 ( 0.7)

--

Estradiol

1 ( 0.7)

0

1 ( 0.7)

--

Ethinylestradiol; Norethisterone 

0

0

2 (1.4)

--

Norethisterone

0

1 ( 0.7)

1 ( 0.7)

--

Testosterone

1 ( 0.7)

1 ( 0.7)

0

--

Estrogen Nos; Medroxyprogesterone

0

0

1 ( 0.7)

--

Estrogen Nos; Progesterone

0

0

1 ( 0.7)

--

Ethinylestradiol; Etynodiol

0

0

1 ( 0.7)

--

Progesterone

0

0

1 ( 0.7)

--

Combination with TCS Clinical Trials

BREEZE-AD4 N=463
Through Week 24c

N=93

N=93

N=185

N=92

Sex Hormones and Modulators of the Genital System

16 (17.2)

11 (11.8) 

13 (7.0) 

9 (9.8)

Desogestrel

4 (4.3)

1 (1.1) 

5 (2.7)

1 (1.1)

Drospirenone; Ethinylestradiol

7 (7.5)

2 (2.2)

2 (1.1)

0

Ethinylestradiol; Levonorgesterel

2 (2.2)

0

4 (2.2) 

4 (4.3)

Desogestrel; Ethinylestradiol

1 (1.1)

4 (4.3)

0

1 (1.1)

Dienogest; Ethinylestradiol

1 (1.1)

1 (1.1)

1 (0.5)

1 (1.1)

Ethinylestradiol; Gestodene

0

2 (2.2)

0

0

Ethinylestradiol; Norelgestromin

0

1 (1.1)

1 (0.5)

0

Chlormadinone; Ethinylestradiol

0

0

0

1 (1.1)

Cyproterone; Ethinylestradiol

1 (1.1)

0

0

0

Dienogest; Estradiol

1 (1.1)

0

0

0

Estriol

1 (1.1)

0

0

0

Medroxyprogesterone

0

0

0

1 (1.1)

BREEZE-AD7 N=329
Through Week 16

N=109

--

N=109

N=111

Sex Hormones and Modulators of the Genital System

10 (9.2)

--

11 (10.1)

10 (9.0)

Drospirenone; Ethinylestradiol

3 (2.8)

--

2 (1.8)

3 (2.7)

Dienogest; Ethinylestradiol

1 (0.9)

--

1 (0.9)

3 (2.7)

Etonogetrel

3 (2.8)

--

0

0

Chlormadinone; Ethinylestradiol

0

--

1 (0.9)

1 (0.9)

Desogestrel

1 (0.9)

--

1 (0.9)

0

Dienogest; Estradiol

0

--

2 (1.8)

0

Estradiol

0

--

1 (0.9)

1 (0.9)

Ethinylestradiol; Levonorgesterel

0

--

1 (0.9)

1 (0.9)

Progesterone

0

--

0

2 (1.8)

Desogestrel; Ethinylestradiol

1 (0.9)

--

0

0

Ethinylestradiol; Norethisterone 

1 (0.9)

--

0

0

Hydroxyprogesterone

0

--

1 (0.9)

0

Levonorgesterel

0

--

0

1 (0.9)

Norethisterone

0

--

1 (0.9)

0

Abbreviations: AD = atopic dermatitis; ATC = Anatomical Therapeutic Chemical classification system; BARI = baricitinib; TCS = topic corticosteroid. 

aTotal n is the number of patients receiving oral contraceptive treatments. Patients could have received multiple agents.

bBREEZE-AD5 is an ongoing study and information provided reflects data through 21 November 2019. 

cBREEZE-AD4 is an ongoing study and information provided reflects data through 28 November 2019. 

Drug – Drug Interactions With Baricitinib and Oral Contraceptives

Potential for Drug-Drug Interactions With Baricitinib Based on PK Studies

Pharmacokinetic Substrate Studies

There were no clinically relevant effects on BARI PK when BARI was coadministered with

  • a CYP3A inhibitor (ketoconazole)
  • a CYP2C19/CYP2C9/CYP3A inhibitor (fluconazole)
  • a CYP3A inducer (rifampicin)
  • a Pgp inhibitor (cyclosporine), or
  • MTX.7

Coadministration with BARI had no clinically relevant effects on the PK of

  • a CYP3A substrate (simvastatin or Microgynon® [(Bayer, United Kingdom; ethiniyl estradiol/levonorgestrel])
  • a OATP1B1 substrate (simvastatin acid)
  • a Pgp substrate (digoxin), or
  • an OAT1, OAT3, and BCRP substrate (MTX).6,7

Metabolism and Elimination

Renal elimination is the principal mechanism for BARI’s clearance through glomerular filtration and active secretion via OAT3, Pgp, BCRP, and MATE2-K.1

In a clinical pharmacology study, BARI was excreted predominately as unchanged drug in urine (69%) and feces (15%). Baricitinib metabolism is mediated by CYP3A4 with approximately 6% of the dose identified as undergoing biotransformation.1

Baricitinib Label Information Related to Drug-Drug Interactions

Potential for Other Medicinal Products to Affect Baricitinib PK

Need for Dose Adjustment in Patients Taking OAT3 Inhibitors

The recommended dose is 2 mg once daily in patients taking Organic Anion Transporter 3 (OAT3) inhibitors with a strong inhibition potential, such as probenecid.1

In vitro, baricitinib is a substrate for1

  • organic anionic transporter (OAT)3,
  • P-glycoprotein (Pgp),
  • breast cancer resistance protein (BCRP) and
  • multidrug and toxic extrusion protein (MATE)2-K.

In a clinical pharmacology study, dosing of probenecid (an OAT3 inhibitor with strong inhibition potential) resulted in approximately

  • a 2-fold increase in AUC(0-∞) with
  • no change in tmax or Cmax of baricitinib.1

Consequently, the recommended dose in patients taking OAT3 inhibitors with a strong inhibition potential, such as probenecid, is 2 mg once daily.1

No clinical pharmacology study has been conducted with OAT3 inhibitors with less inhibition potential.1

  • The prodrug leflunomide rapidly converts to teriflunomide which is a weak OAT3 inhibitor and therefore may lead to an increase in baricitinib exposure.
    Since dedicated interaction studies have not been conducted, caution should be used when leflunomide or teriflunomide are given concomitantly with baricitinib.
  • Concomitant use of the OAT3 inhibitors ibuprofen and diclofenac may lead to increased exposure of baricitinib, however their inhibition potential of OAT3 is less compared to probenecid and thus a clinically relevant interaction is not expected.1

Coadministration of baricitinib with ciclosporin (Pgp/BCRP inhibitor) or methotrexate (substrate of several transporters including OATP1B1, OAT1, OAT3, BCRP, MRP2, MRP3, and MRP4) resulted in no clinically meaningful effects on baricitinib exposure.1

Baricitinib as a Substrate of Cytochrome P450

In vitro, baricitinib is a cytochrome P450 enzyme (CYP)3A4 substrate although less than 10 % of the dose is metabolised via oxidation.1

In clinical pharmacology studies, coadministration of baricitinib with ketoconazole (strong CYP3A inhibitor) resulted in no clinically meaningful effect on the PK of baricitinib.1

Coadministration of baricitinib with fluconazole (moderate CYP3A/CYP2C19/CYP2C9 inhibitor) or rifampicin (strong CYP3A inducer) resulted in no clinically meaningful changes to baricitinib exposure.1

Potential for Baricitinib to Affect PK of Other Medicinal Products

Impact of Baricitinib Transporters

In vitro, baricitinib is not an inhibitor of

  • OAT1,  OAT2, OAT3,
  • organic cationic transporter (OCT) 2,
  • OATP1B1, OATP1B3,
  • BCRP,
  • MATE1 and MATE2-K

at clinically relevant concentrations.1

Baricitinib may be a clinically relevant inhibitor of OCT1, however there are currently no known selective OCT1 substrates for which clinically significant interactions might be predicted.1

In clinical pharmacology studies there were no clinically meaningful effects on exposure when baricitinib was coadministered with digoxin (Pgp substrate) or methotrexate (substrate of several transporters). 1

Impact of Baricitinib on Cytochrome P450

In clinical pharmacology studies, coadministration of baricitinib with the CYP3A substrates simvastatin, ethinyl oestradiol, or levonorgestrel resulted in no clinically meaningful changes in the PK of these medicinal products.1

Clinical Use of Oral Contraceptive Therapy and Baricitinib

The treating physician may use the information provided, the patient’s prior medical history and other concomitant medications, and other individual factors, in formulating an assessment and approach. The treating physician should consider potential risks and benefits of treatment options and monitor appropriately.

References

1Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2Simpson EL, Lacour JP, Spelman L, et al. Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials. Br J Dermatol. 2020;183(2):242-255. http://dx.doi.org/10.1111/bjd.18898

3A long-term study of baricitinib (LY3009104) with topical corticosteroids in adults with moderate to severe atopic dermatitis that are not controlled with cyclosporine or for those who cannot take oral cyclosporine because it is not medically advisable (BREEZE-AD4). ClinicalTrials.gov identifier: NCT03428100. Updated January 3, 2020. Accessed September 16, 2020. https://clinicaltrials.gov/ct2/show/NCT03428100

4Simpson E, Forman S, Silverberg J, et al. Efficacy and safety of baricitinib in moderate-to-severe atopic dermatitis: results from a randomized, double-blinded, placebo-controlled phase 3 clinical trial (BREEZE-AD5). Abstract presented at: Revolutionizing Atopic Dermatitis (RAD) Virtual Symposium; April 5, 2020. Accessed April 5, 2020.

5Reich K, Kabashima K, Peris K, et al. Efficacy and safety of baricitinib in combination with topical corticosteroids in moderate to severe atopic dermatitis: results of a phase 3 randomized, double-blind, placebo-controlled 16-week trial (BREEZE-AD7). Abstract presented at: European Academy of Dermatology and Venereology 28th Congress; October 9-13, 2019; Madrid, Spain.

6Data on file, Eli Lilly and Company and/or one of its subsidiaries.

7Payne C, Zhang X, Shahri N, et al. Evaluation of potential drug-drug interactions with baricitinib. Ann Rheum Dis. 2015;74(suppl 2):1063. European League Against Rheumatism abstract AB0492. https://doi.org/10.1136/annrheumdis-2015-eular.1627

Glossary

AD = atopic dermatitis

BARI = baricitinib

BCRP = breast cancer resistance protein

CYP = cytochrome P450

MTX = methotrexate

OAT = organic anion transporter

Pgp = P-glycoprotein

PK = pharmacokinetic

TCS = topical corticosteroids

Datum fӧr senaste ӧversyn 2020 M04 06


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