Baricitinib

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, baricitinib therapy is not recommended. Prior to initiating baricitinib, it is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines.

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.

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

Combination with biologic DMARDs or other Janus kinase (JAK) inhibitors is not recommended, as a risk of additive immunosuppression cannot be excluded.

The recommended dose is 2 mg once daily in patients with creatinine clearance between 30 and 60 mL/min.

Baricitinib is not recommended for use in patients with creatinine clearance <30 mL/min.

Baricitinib is not recommended for use in patients with severe hepatic impairment.

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.

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.

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. Baricitinib 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, baricitinib treatment should be temporarily interrupted and patients should be evaluated promptly, followed by appropriate treatment.

Baricitinib is associated with an increased rate of infections such as upper respiratory tract infections compared to placebo.

In treatment naïve patients, combination with methotrexate resulted in increased frequency of infections compared to baricitinib monotherapy. The risks and benefits of treatment with baricitinib should be carefully considered prior to initiating therapy in patients with active, chronic or recurrent infections. If an infection develops, the patient should be monitored carefully and baricitinib therapy should be temporarily interrupted if the patient is not responding to standard therapy. Baricitinib treatment should not be resumed until the infection resolves.

Patients should be screened for tuberculosis (TB) before starting baricitinib therapy. Baricitinib should not be given to patients with active TB. Anti-TB therapy should be considered prior to initiation of baricitinib in patients with previously untreated latent TB.

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. 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.

Baricitinib is contraindicated during pregnancy. 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 baricitinib 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.

A risk to newborns/infants cannot be excluded and baricitinib should not be used during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue baricitinib therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

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.

Baricitinib has no or negligible influence on the ability to drive and use machines.

Summary of safety profile

The most commonly reported adverse drug reactions (ADRs) occurring in ≥ 2% of patients treated with baricitinib 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 baricitinib treatment included Herpes zoster.

Tabulated list of adverse reactions

A total of 3,464 patients were treated with baricitinib in clinical studies in rheumatoid arthritis representing 4214 patient-years of exposure. Of these, 2166 rheumatoid arthritis patients were exposed to baricitinib 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 baricitinib 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):

Infections and infestations

Very common: Upper respiratory tract infectionsa

Common: Herpes zoster, Herpes simplex^b, Gastroenteritis, Urinary tract infections, Pneumonia

Blood and lymphatic system disorders

Common: Thrombocytosis >600 × 10⁹ cells/L^c

Uncommon: Neutropaenia <1 × 10⁹ cells/L^c

Metabolism and nutrition disorders

Very common: Hypercholesterolaemia^c

Uncommon: Hypertriglyceridaemia^c

Gastrointestinal disorders

Common: Nausea

Hepatobiliary disorders

Common: ALT increased ≥3 x ULN^c

Uncommon: AST increased ≥3 x ULN^c

Skin and subcutaneous tissue disorders

Uncommon: Acne

Investigations

Uncommon: Weight increased Creatine phosphokinase increased >5 x ULN^c

^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).

Description of selected adverse reactions

Nausea

In treatment-naïve patients, through 52 weeks, the frequency of nausea was greater for the combination treatment of methotrexate and baricitinib (9.3%) compared to methotrexate alone (6.2%) or baricitinib alone (4.4%). Nausea was most frequent during the first 2 weeks of treatment.

Infections

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 baricitinib 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 baricitinib 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 baricitinib (26.0%) compared to methotrexate alone (22.9%) or baricitinib alone (22.0%). The rate of serious infections with baricitinib (1.1%) was similar to placebo (1.2%). For baricitinib, 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.

Hepatic transaminase elevations

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 baricitinib, 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 baricitinib 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 baricitinib (7.5% and 3.8%) compared to methotrexate alone (2.9% and 0.5%) or baricitinib 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.

Lipid elevations

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 baricitinib vs. placebo:

• Increased total cholesterol ≥5.17 mmol/L: 49.1% vs.15.8%, respectively
• Increased LDL cholesterol ≥3.36 mmol/L: 33.6% vs. 10.3%, respectively
• Increased HDL cholesterol ≥1.55 mmol/L: 42.7% vs. 13.8%, respectively
• Increased triglycerides ≥5.65 mmol/L: 0.4% vs. 0.5%, respectively

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.

Creatine phosphokinase (CPK)

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 baricitinib 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.

Neutropaenia

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 baricitinib 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.

Thrombocytosis

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 baricitinib 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.