Chemical formula: C₁₆H₁₇N₇O₂S Molecular mass: 371.42 g/mol PubChem compound: 44205240
Baricitinib interacts in the following cases:
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 treatment, it is recommended that all patients, and particularly paediatric patients, be brought up to date with all immunisations in agreement with current immunisation guidelines.
In patients taking strong Organic Anion Transporter 3 (OAT3) inhibitors such as probenecid, or with creatinine clearance between 30 and 60 mL/min the recommended dose should be reduced by half for paediatric patients and the recommended dose is 2 mg for adult patients.
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, in patients taking OAT3 inhibitors with a strong inhibition potential, such as probenecid, the recommended dose of baricitinib should be reduced by half.
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 biological DMARDs, biological immunomodulators or other Janus kinase (JAK) inhibitors is not recommended, as a risk of additive immunosuppression cannot be excluded.
In rheumatoid arthritis and juvenile idiopathic arthritis, data concerning use of baricitinib with potent immunosuppressive medicinal products other than methotrexate (e.g., azathioprine, tacrolimus, ciclosporin) are limited. Caution should be exercised when using such combinations.
In atopic dermatitis and alopecia areata, combination with ciclosporin or other potent immunosuppressants has not been studied and is not recommended.
The recommended dose is 2 mg once daily in adult patients with creatinine clearance between 30 and 60 mL/min. In paediatric patients with creatinine clearance between 30 and 60 mL/min, the recommended dose of baricitinib should be reduced by half.
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.
Baricitinib should only be used if no suitable treatment alternatives are available in patients:
Baricitinib should be used with caution in patients with diverticular disease and especially in patients chronically treated with concomitant medicinal products associated with an increased risk of diverticulitis: nonsteroidal anti-inflammatory drugs, corticosteroids, and opioids. Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis or gastrointestinal perforation.
The risks and benefits of treatment should be carefully considered prior to initiating baricitinib in patients with active, chronic or recurrent infections.
Patients should be screened for tuberculosis (TB) before starting therapy. Baricitinib should not be given to patients with active TB. Anti-TB therapy should be considered prior to initiation of treatment in patients with previously untreated latent TB.
There have been reports of hypoglycaemia following initiation of JAK inhibitors, including baricitinib, in patients receiving medication for diabetes. Dose adjustment of anti-diabetic medication may be necessary in the event that hypoglycaemia occurs.
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 doses.
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 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.
Baricitinib has no or negligible influence on the ability to drive and use machines.
The most commonly reported adverse reactions with baricitinib are increased LDL cholesterol (26.0%), upper respiratory tract infections (16.9%), headache (5.2%), herpes simplex (3.2%), and urinary tract infections (2.9%). Serious pneumonia and serious herpes zoster occurred uncommonly in patients with rheumatoid arthritis.
Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000). The frequencies in the table below are based on integrated data from clinical trials in adults and/or postmarketing setting across rheumatoid arthritis, atopic dermatitis, and alopecia areata indications unless stated otherwise; where notable differences in frequency between indications are observed, these are presented in the footnotes below the table.
Adverse reactions:
| System organ class | Very common | Common | Uncommon |
|---|---|---|---|
| Infections and infestations | Upper respiratory tract infections | Herpes zosterb Herpes simplex Gastroenteritis Urinary tract infections Pneumoniad Folliculitisg | |
| Blood and lymphatic system disorders | Thrombocytosis >600 × 109 cells/La,d | Neutropaenia <1 × 109 cells/La | |
| Immune system disorders | Swelling of the face, Urticaria | ||
| Metabolism and nutrition disorders | Hypercholesterolaemiaa | Hypertriglyceridaemiaa | |
| Nervous system disorders | Headache | ||
| Vascular disorders | Deep vein thrombosisb | ||
| Respiratory, thoracic, mediastinal disorders | Pulmonary embolismf | ||
| Gastrointestinal disorders | Nausead Abdominal paind | Diverticulitis | |
| Hepatobiliary disorders | ALT increased ≥3 x ULNa,d | AST increased ≥3 x ULNa,e | |
| Skin and subcutaneous tissue disorders | Rash Acnec | ||
| Investigations | Creatine phosphokinase increased >5 x ULNa,c | Weight increased |
a Includes changes detected during laboratory monitoring (see text below).
b Frequency for herpes zoster and deep vein thrombosis is based on rheumatoid arthritis clinical trials.
c In rheumatoid arthritis clinical trials, the frequency of acne and creatine phosphokinase increased >5 x ULN was uncommon.
d In atopic dermatitis clinical trials, the frequency of nausea, and ALT ≥3 x ULN was uncommon. In alopecia areata clinical trials, the frequency of abdominal pain was uncommon. In atopic dermatitis and alopecia areata clinical trials, the frequency of pneumonia and thrombocytosis >600 × 109 cells/L was uncommon.
e In alopecia areata clinical trials, the frequency of AST ≥3 x ULN was common.
f Frequency for pulmonary embolism is based on rheumatoid arthritis and atopic dermatitis clinical trials.
g Folliculitis was observed in alopecia areata clinical trials. It was usually localized in the scalp region associated with hair regrowth.
In rheumatoid arthritis clinical studies, 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%). In the integrated data from rheumatoid arthritis, atopic dermatitis and alopecia areata clinical trials, nausea was most frequent during the first 2 weeks of treatment.
Cases of abdominal pain were usually mild, transient, not associated with infectious or inflammatory gastrointestinal disorders, and did not lead to treatment interruption.
In the integrated data from rheumatoid arthritis, atopic dermatitis and alopecia areata clinical trials, most infections were mild to moderate in severity. In studies which included both doses, infections were reported in 31.0%, 25.7% and 26.7% of patients in the 4 mg, 2 mg and placebo groups, respectively. In rheumatoid arthritis clinical studies, combination with methotrexate resulted in increased frequency of infections compared to baricitinib monotherapy. Frequency of herpes zoster was common in rheumatoid arthritis, very rare in atopic dermatitis and uncommon in alopecia areata. In atopic dermatitis clinical trials, there were less skin infections requiring antibiotic treatment with baricitinib than with placebo.
The incidence of serious infections with baricitinib was similar to placebo. The incidence 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 rheumatoid arthritis, 2.1 in atopic dermatitis and 0.8 in alopecia areata. Serious pneumonia and serious herpes zoster occurred uncommonly in patients with rheumatoid arthritis.
Dose dependent increases in blood ALT and AST activity were reported in studies extended over week 16. Elevations in mean ALT/AST remained stable over time. Most cases of hepatic transaminase elevations ≥3 x ULN were asymptomatic and transient.
In patients with rheumatoid arthritis, the combination of baricitinib with potentially hepatotoxic medicinal products, such as methotrexate, resulted in increased frequency of these elevations.
In the integrated data from rheumatoid arthritis, atopic dermatitis and alopecia areata clinical trials, baricitinib treatment was associated with dose-dependent increases in lipid parameters including total cholesterol, LDL cholesterol, and high density lipoprotein (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 rheumatoid arthritis. Mean total and LDL cholesterol increased through week 52 in patients with atopic dermatitis and alopecia areata. In rheumatoid arthritis clinical trials, baricitinib treatment was associated with dose-dependent increases in triglycerides. There was no increase in triglycerides levels in atopic dermatitis and alopecia areata clinical trials.
Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy.
Baricitinib treatment was associated with dose-dependent increases in CPK. Mean CPK was increased at week 4 and remained at a higher value than baseline thereafter. Across indications, most cases of CPK elevations >5 x ULN were transient and did not require treatment discontinuation.
In clinical trials, there were no confirmed cases of rhabdomyolysis.
Mean neutrophil counts decreased at 4 weeks and remained stable at a lower value than baseline over time. There was no clear relationship between neutropaenia and the occurrence of serious infections. However, in clinical studies, treatment was interrupted in response to ANC <1 × 109 cells/L.
Dose-dependent increases in mean platelet counts were observed and remained stable at a higher value than baseline over time.
A total of 220 patients from 2 to less than 18 years of age were exposed to any dose of baricitinib in the juvenile idiopathic arthritis clinical trial programme, representing 326 patient years' exposure.
In paediatric patients treated with baricitinib in the placebo-controlled double-blind randomised withdrawal period of the juvenile idiopathic arthritis clinical trial (n=82), headache was very common (11%), neutropenia <1 000 cells/mm³ was common (2.4%, one patient) and pulmonary embolism was common (1.2%, one patient).
The safety assessment in children and adolescents is based on the safety data of the phase III trial BREEZE-AD-PEDS in which 466 patients between 2 and 18 years of age received any dose of baricitinib. Overall, the safety profile in these patients was comparable to that observed in the adult population. Neutropaenia (<1 × 109 cells/L) was more common (1.7%) compared to adults.
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