Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Eli Lilly Nederland B.V., Papendorpseweg 83, 3528BJ Utrecht, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Pregnancy (see section 4.6).
Baricitinib is associated with an increased rate of infections such as upper respiratory tract infections compared to placebo (see section 4.8). In treatment naïve patients, combination with methotrexate resulted in increased frequency of infections compared to baricitinib monotherapy. The risks and benefits of treatment with Olumiant should be carefully considered prior to initiating therapy in patients with active, chronic or recurrent infections (see section 4.2). If an infection develops, the patient should be monitored carefully and Olumiant therapy should be temporarily interrupted if the patient is not responding to standard therapy. Olumiant treatment should not be resumed until the infection resolves.
Patients should be screened for tuberculosis (TB) before starting Olumiant therapy. Olumiant should not be given to patients with active TB. Anti-TB therapy should be considered prior to initiation of Olumiant in patients with previously untreated latent TB.
Absolute Neutrophil Count (ANC) <1 × 109 cells/L, Absolute Lymphocyte Count (ALC) <0.5 × 109 cells/L and haemoglobin <8 g/dL were reported in less than 1% of patients in clinical trials. Treatment should not be initiated, or should be temporarily interrupted, in patients with an ANC <1 × 109 cells/L, ALC <0.5 × 109 cells/L or haemoglobin <8 g/dL observed during routine patient management (see section 4.2).
The risk of lymphocytosis is increased in elderly patients with rheumatoid arthritis. Rare cases of lymphoproliferative disorders have been reported.
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster, herpes simplex), were reported in clinical studies (see section 4.8). Herpes zoster was reported more commonly in patients ≥65 years of age who had previously been treated with both biologic and conventional DMARDs. If a patient develops herpes zoster, Olumiant treatment should be temporarily interrupted until the episode resolves.
Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with Olumiant. Patients with evidence of active hepatitis B or C infection were excluded from clinical trials. Patients, who were positive for hepatitis C antibody but negative for hepatitis C virus RNA, were allowed to participate. Patients with hepatitis B surface antibody and hepatitis B core antibody, without hepatitis B surface antigen, were also allowed to participate; such patients should be monitored for expression of hepatitis B virus (HBV) DNA. If HBV DNA is detected, a liver specialist should be consulted to determine if treatment interruption is warranted.
No data are available on the response to vaccination with live vaccines in patients receiving baricitinib. Use with live, attenuated vaccines during, or immediately prior to, Olumiant therapy is not recommended. Prior to initiating Olumiant, it is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines.
Dose dependent increases in blood lipid parameters were reported in patients treated with baricitinib compared to placebo (see section 4.8). Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy. Lipid parameters should be assessed approximately 12 weeks following initiation of Olumiant therapy and thereafter patients should be managed according to international clinical guidelines for hyperlipidaemia. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.
Increases in alanine transaminase (ALT) and aspartate transaminase (AST) to ≥5 and ≥10 x upper limit of normal (ULN) were reported in less than 1% of patients in clinical trials. In treatment-naïve patients, combination with methotrexate resulted in increased frequency of hepatic transaminase elevations compared with baricitinib monotherapy (see section 4.8). If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, Olumiant should be temporarily interrupted until this diagnosis is excluded.
The risk of malignancies including lymphoma is increased in patients with rheumatoid arthritis. Immunomodulatory medicinal products may increase the risk of malignancies including lymphoma.
The clinical data are insufficient to assess the potential incidence of malignancies following exposure to baricitinib. Long-term safety evaluations are ongoing.
Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving baricitinib. Olumiant should be used with caution in patients with risk factors for DVT/PE, such as older age, obesity, a medical history of DVT/PE, or patients undergoing surgery and immobilisation. If clinical features of DVT/PE occur, Olumiant treatment should be temporarily interrupted and patients should be evaluated promptly, followed by appropriate treatment.
Table 1. Laboratory measures and monitoring guidance:
| Laboratory Measure | Action | Monitoring Guidance |
|---|---|---|
| Lipid parameters | Patients should be managed according to international clinical guidelines for hyperlipidaemia | 12 weeks after initiation of treatment and thereafter according to international clinical guidelines for hyperlipidaemia |
| Absolute Neutrophil Count (ANC) | Treatment should be interrupted if ANC <1 × 109 cells/L and may be restarted once ANC return above this value | Before treatment initiation and thereafter according to routine patient management |
| Absolute Lymphocyte Count (ALC) | Treatment should be interrupted if ALC <0.5 × 109 cells/L and may be restarted once ALC return above this value | |
| Haemoglobin (Hb) | Treatment should be interrupted if Hb <8 g/dL and may be restarted once Hb return above this value | |
| Hepatic transaminases | Treatment should be temporarily interrupted if drug-induced liver injury is suspected |
Combination with biologic DMARDs or other Janus kinase (JAK) inhibitors is not recommended, as a risk of additive immunosuppression cannot be excluded. Data concerning use of baricitinib with potent immunosuppressive medicinal products (e.g., azathioprine, tacrolimus, ciclosporin) are limited and caution should be exercised when using such combinations (see section 4.5).
Combination with biologic DMARDs or other JAK inhibitors has not been studied. Use of baricitinib with potent immunosuppressive medicinal products such as azathioprine, tacrolimus, or ciclosporin was limited in clinical studies of baricitinib, and a risk of additive immunosuppression cannot be excluded (see section 4.4).
In vitro, baricitinib is a substrate for 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. Consequently, the recommended dose in patients taking OAT3 inhibitors with a strong inhibition potential, such as probenecid, is 2 mg once daily (see section 4.2). No clinical pharmacology study has been conducted with OAT3 inhibitors with less inhibition potential. 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. 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.
In vitro, baricitinib is a cytochrome P450 enzyme (CYP)3A4 substrate although less than 10% of the dose is metabolised via oxidation. In clinical pharmacology studies, coadministration of baricitinib with ketoconazole (strong CYP3A inhibitor) resulted in no clinically meaningful effect on the PK of baricitinib. Coadministration of baricitinib with fluconazole (moderate CYP3A/CYP2C19/CYP2C9 inhibitor) or rifampicin (strong CYP3A inducer) resulted in no clinically meaningful changes to baricitinib exposure.
Elevating gastric pH with omeprazole had no clinically significant effect on baricitinib exposure.
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. 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. 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).
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.
The JAK/STAT pathway has been shown to be involved in cell adhesion and cell polarity which can affect early embryonic development. There are no adequate data from the use of baricitinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Baricitinib was teratogenic in rats and rabbits. Animal studies indicate that baricitinib may have an adverse effect on bone development in utero at higher dosages.
Olumiant is contraindicated during pregnancy (see section 4.3). Women of childbearing potential have to use effective contraception during and for at least 1 week after treatment. If a patient becomes pregnant while taking Olumiant the parents should be informed of the potential risk to the foetus.
It is unknown whether baricitinib/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of baricitinib in milk (see section 5.3).
A risk to newborns/infants cannot be excluded and Olumiant should not be used during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue Olumiant therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Studies in animals suggest that treatment with baricitinib has the potential to decrease female fertility while on treatment, but there was no effect on male spermatogenesis (see section 5.3).
Olumiant has no or negligible influence on the ability to drive and use machines.
The most commonly reported adverse drug reactions (ADRs) occurring in ≥ 2% of patients treated with Olumiant monotherapy or in combination with conventional synthetic DMARDs were increased LDL cholesterol (33.6%), upper respiratory tract infections (14.7%) and nausea (2.8%). Infections reported with Olumiant treatment included Herpes zoster.
A total of 3,464 patients were treated with Olumiant in clinical studies in rheumatoid arthritis representing 4214 patient-years of exposure. Of these, 2166 rheumatoid arthritis patients were exposed to Olumiant for at least one year. Six placebo-controlled studies were integrated (997 patients on 4 mg once daily and 1070 patients on placebo) to evaluate the safety of Olumiant in comparison to placebo for up to 16 weeks after treatment initiation.
Table 2. Adverse Reactions Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100):
Very common: Upper respiratory tract infectionsa
Common: Herpes zoster, Herpes simplexb, Gastroenteritis, Urinary tract infections, Pneumonia
Common: Thrombocytosis >600 × 109 cells/Lc
Uncommon: Neutropaenia <1 × 109 cells/Lc
Very common: Hypercholesterolaemiac
Uncommon: Hypertriglyceridaemiac
Common: Nausea
Common: ALT increased ≥3 x ULNc
Uncommon: AST increased ≥3 x ULNc
Uncommon: Acne
Uncommon: Weight increased Creatine phosphokinase increased >5 x ULNc
a Combined term (acute sinusitis, epiglottitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, tonsillitis, tracheitis, upper respiratory tract infection).
b Combined term (eczema herpeticum, herpes simplex, ophthalmic herpes simplex, oral herpes).
c Includes changes detected during laboratory monitoring (see text below).
In treatment-naïve patients, through 52 weeks, the frequency of nausea was greater for the combination treatment of methotrexate and Olumiant (9.3%) compared to methotrexate alone (6.2%) or Olumiant alone (4.4%). Nausea was most frequent during the first 2 weeks of treatment.
In controlled studies, for up to 16 weeks, the incidence rate of all infections (rate of patients with ≥1 event per 100 patient-years of exposure) was 101 with Olumiant compared to 83 in the placebo group. Most infections were mild to moderate in severity. In studies which included both doses, infections were reported in 31.9%, 28.8% and 24.1% of patients up to 16 weeks in the 4 mg, 2 mg and placebo groups, respectively. Reporting rates for Olumiant compared to placebo for the infection-related ADRs were: Upper respiratory tract infections (14.7% vs. 11.7%), urinary tract infections (3.4% vs. 2.7%), gastroenteritis (1.6% vs. 0.8%), herpes simplex (1.8% vs. 0.7%), and herpes zoster (1.4% vs. 0.4%). In treatment-naïve patients, for up to 52 weeks, the frequency of upper respiratory tract infections was greater for the combination treatment of methotrexate and Olumiant (26.0%) compared to methotrexate alone (22.9%) or Olumiant alone (22.0%). The rate of serious infections with Olumiant (1.1%) was similar to placebo (1.2%). For Olumiant, the most common serious infections were herpes zoster, and cellulitis. The rate of serious infections remained stable during long term exposure. The overall incidence rate of serious infections in the clinical trial programme was 3.2 per 100 patient-years.
In controlled studies, for up to 16 weeks, alanine transaminase (ALT) and aspartate transaminase (AST) elevations ≥3 x upper limit of normal (ULN) were observed in 1.4% and 0.8% of patients treated with Olumiant, compared to 1.0% and 0.8% respectively of patients treated with placebo. Most cases of hepatic transaminase elevations were asymptomatic and transient.
In treatment-naïve patients, the combination of Olumiant with potentially hepatotoxic medicinal products, such as methotrexate, resulted in increased frequency of these elevations. For up to 52 weeks, the frequency of ALT and AST elevations ≥3 x ULN were greater for the combination treatment of methotrexate and Olumiant (7.5% and 3.8%) compared to methotrexate alone (2.9% and 0.5%) or Olumiant alone (1.9% and 1.3%).
The pattern and incidence of elevation in ALT/AST remained stable over time including in the longterm extension study.
Baricitinib treatment was associated with dose-dependent increases in lipid parameters including total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol. There was no change in the LDL/HDL ratio. Elevations were observed at 12 weeks and remained stable thereafter at a higher value than baseline including in the long-term extension study. In controlled studies, for up to 16 weeks, the following rates were observed for Olumiant vs. placebo:
In studies which included both doses, a dose-relationship was observed with increased total cholesterol ≥5.17 mmol/L reported in 48.8%, 34.7% and 17.8% of patients up to 16 weeks in the 4 mg, 2 mg and placebo groups, respectively.
Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy.
In controlled studies, for up to 16 weeks, increases in CPK values were common. Significant increases (>5 x ULN) occurred in 0.8% of patients treated with Olumiant and 0.3% of patients treated with placebo. A dose relationship was observed with CPK elevations ≥5 x ULN of normal reported in 1.5%, 0.8% and 0.6% of patients at 16 weeks in the 4 mg, 2 mg and placebo groups, respectively. Most cases were transient and did not require treatment discontinuation. In clinical trials, there were no confirmed cases of rhabdomyolysis. Elevations of CPK were observed at 4 weeks and remained stable at a higher value than baseline thereafter including in the long-term extension study.
In controlled studies, for up to 16 weeks, decreases in neutrophil counts below 1 × 109 cells/L occurred in 0.3% of patients treated with Olumiant compared to 0% of patients treated with placebo. There was no clear relationship between decreases in neutrophil counts and the occurrence of serious infections. However, in clinical studies, treatment was interrupted in response to ANC <1 × 109 cells/L. The pattern and incidence of decreases in neutrophil counts remained stable at a lower value than baseline over time including in the long-term extension study.
In controlled studies, for up to 16 weeks, increases in platelet counts above 600 × 109 cells/L occurred in 2.0% of patients treated with Olumiant 4 mg and 1.1% of patients treated with placebo. No association was observed between increased platelet counts and adverse events of a thrombotic nature. The pattern and incidence of increases in platelet counts remained stable at a higher value than baseline over time including in the long term extension study.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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