Baricitinib 4 mg Tablet: Information for Healthcare Professionals

BARICITINIB 4 MG TABLET (OLUMIANT ®)
RECOMMENDATION FOR PRESCRIBER	PRIOR to the TREATMENT, EXPLAIN THOROUGHLY the efficacy and risks (including risk of exposure to fetus) IN WRITING to patients or their family members and OBTAIN their WRITTEN CONSENT.  Kindly refer to the information below – especially on pregnancy and breastfeeding PATIENT OFF-LABEL CONSENT FORM [BR/1269] is required - prior to starting the therapy.
Pregnancy	If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.  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.  Olumiant 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 Olumiant the parents should be informed of the potential risk to the foetus.
Lactation	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 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.
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
Therapeutic indications	Leaflet: Rheumatoid arthritis and atopic dermatitis
Dosage Recommendation for COVID-19   *Renal Impairment *Hepatic Impairment	CLINICAL MANAGEMENT OF CONFIRMED COVID-19 CASE IN ADULT AND PAEDIATRIC (Annex 2e):  For COVID-19 Category 4b & 5b: •    4mg OD oral x 14 days or until hospital discharge (whichever earlier) •    Avoid in patients with previous history of thrombosis.   •    Renal adjustment (based on eGFR): eGFR Dose recommended ≥9 years old, Adolescents & Adults 2 to <9 years old ≥60 4mg OD 2mg OD 30-59 2mg OD 1mg OD 15-29 1mg OD Not recommended <15 / Dialysis / ESRD / AKI Not recommended Not recommended   ·     Hepatic impairment prior to treatment initiation: o    Mild to moderate impairment: No dosage adjustment necessary. o    Severe impairment: Use is not recommended (has not been studied). o    ALT/AST increased: If baricitinib-induced liver injury is suspected, interrupt therapy and further evaluate until DILI is excluded.     Body weight, sex, race, and ethnicity did not have a clinically relevant effect on the PK of baricitinib. The mean effects of intrinsic factors on PK parameters (AUC and Cmax) were generally within the inter-subject PK variability of baricitinib. Therefore, no dose adjustment is needed based on these patient factors.   Note: Tocilizumab is preferred over Baricitinib in those with poor gut absorption and eGFR<15ml/min
Paediatrics	Leaflet: The safety, efficacy and pharmacokinetics of baricitinib have not yet been established in a paediatric population (less than 18 years old)  However, based on UptoDate: Baricitinib: Drug Information: COVID-19 (hospitalized patients), treatment: Very limited data available: o  Children 2 to <9 years: Oral: 2 mg once daily in combination with remdesivir. o  Children ≥9 years and Adolescents: Oral: 4 mg once daily in combination with remdesivir. o  Duration of baricitinib is 14 days or until hospital discharge, whichever is first (FDA 2020). o  The role of baricitinib in the treatment of COVID-19 is evolving. The NIH states that data are insufficient to recommend for or against the use of baricitinib in pediatric patients (NIH 2021). Pediatric dosing is based on ongoing clinical trials for other indications (FDA 2020).  Please note that the use of baricitinib in paediatrics is NOT MENTIONED in CLINICAL MANAGEMENT OF CONFIRMED COVID-19 CASE IN ADULT AND PAEDIATRIC (Annex 2e), Ministry of Health, Malaysia [Aug 2021]
Geriatrics	Leaflet; Age ≥ 65 years or ≥ 75 years has no effect on baricitinib exposure (Cmax and AUC).  Based on UptoDate: Baricitinib: Drug Information: Geriatrics dosing is the same normal adults dosing
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 x 10^9 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 x 10^9 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
Administration	Oral:  ·     May be administered with or without food. ·     For patients unable to swallow tablets whole, the tablet may be chewed (although the tablet is NOT designed to be swollen); ensure entire dose is swallowed. ·     Alternatively, the tablet may be dispersed in a small amount (5 to 10 mL) of liquid (water, whole milk, green tea, miso soup); the tablet will disperse in <5 minutes. A small amount of food may be added to the liquid mixture; the entire mixture should be consumed at one time (manufacturer data on file).  Nasogastric feeding tube (NG tube):  ·     Place required number of tablets to achieve desired dose in a container with ~30 mL of room temperature water. ·     Gently swirl the tablet(s) to disperse; ensure tablets are sufficiently dispersed to pass through syringe tip. ·     Withdraw entire contents of container into an appropriate syringe and immediately administer through NG tube. ·     For small tubes (<12 French), hold the syringe horizontally and shake during administration to avoid clogging of tube. ·     Rinse container with a minimum of 15 mL of room temperature water, withdraw contents into the syringe, and administer through NG tube (FDA 2021).  Gastrostomy feeding tube (G tube):  ·     Place required number of tablets to achieve desired dose in a container with ~15 mL (minimum: 10 mL) of room temperature water. ·     Gently swirl the tablet(s) to disperse; ensure tablets are sufficiently dispersed to pass through syringe tip. ·     Withdraw entire contents of container into an appropriate syringe and immediately administer through G tube. ·     Rinse container with an additional ~15 mL (minimum: 10 mL) of room temperature water, withdraw contents into the syringe, an  Due to the teratogenicity concern of Baricitinib tablet, it is not recommended to crush the tablet (in order to protect our healthcare workers).
Contraindications	Hypersensitivity(especially if serious allergic or anaphylactic reaction)
Special Warnings and Precautions for Use	Infections §  Baricitinib is associated with an increased rate of infections such as upper respiratory tract infections compared to placebo. §  The risks and benefits of treatment with Olumiant 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 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 §  Tuberculosis : 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.  Haematological abnormalities §  Absolute Neutrophil Count (ANC) < 1 x 10^9 cells/L, Absolute Lymphocyte Count (ALC) < 0.5 x 10^9 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 x 109 cells/L, ALC < 0.5 x 109 cells/L or haemoglobin < 8 g/dL observed during routine patient management §  The risk of lymphocytosis is increased in elderly patients with rheumatoid arthritis. Rare cases of lymphoproliferative disorders have been reported.  Viral reactivation §  Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster, herpes simplex), were reported in clinical studies. §  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. o Patients, who were positive for hepatitis C antibody but negative for hepatitis C virus RNA, were allowed to participate. o 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.  Vaccination §  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.  Lipids §  Dose dependent increases in blood lipid parameters were reported in patients treated with baricitinib compared to placebo. §  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.  Hepatic transaminase elevations §  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. §  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.  Malignancy §  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.  Venous Thromboembolism §  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 discontinued and patients should be evaluated promptly, followed by appropriate treatment.  Immunosuppressive medicinal products §  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.
Adverse reactions	System Organ Class Very common ≥ 10% Common 1 - 10% Uncommon 0.1 - 1% Infections and infestations Upper respiratory tract infections (a) Herpes zoster, Herpes simplex Gastroenteritis Urinary tract infections Pneumonia   Blood and lymphatic system disorders   Thrombocytosis >600 x 10^9 cells/L Neutropaenia <1 x 10^9 cells/L Metabolism and nutrition disorders Hypercholesterolaemia   Hypertriglyceridaemia Gastrointestinal disorders   Nausea   Hepatobiliary disorders   ALT increased ≥3 x ULN AST increased ≥3 x ULN Skin and subcutaneous tissue disorders   Rash Acne Immune disorders     Swelling of the face, Urticaria Respiratory, thoracic, mediastinal disorders     Pulmonary embolism Vascular disorders     Deep Vein Thrombosis Investigations     Weight increased Creatine phosphokinase increased >5 x ULN  (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).
Potential Drug interactions	In particular, tell your doctor or pharmacist before taking Olumiant if you are taking: o   probenecid (for gout) - may increase the levels of Olumiant in your blood. With concomitant probenecid, the recommended dose of Olumiant is half of normal dose o   injectable anti-rheumatic medicine o   injectable medicines that depress the immune system, including targeted biologic (antibody) therapies o   immunosuppresants, such as azathioprine, tacrolimus or ciclosporin o   Janus kinase (JAK) inhibitors, such as ruxolitinib o  medicines that may increase risk of diverticulitis such as a non-steroidal anti-inflammatory medicines and/or corticosteroids
Tablet properties	Film-coated tablet, no score  Excipients:  Tablet cores Film coating • cellulose, microcrystalline • croscarmellose sodium • magnesium stearate • mannitol • iron oxide red (E172) • lecithin (soya) (E322) • macrogol • poly (vinyl alcohol) • talc • titanium dioxide (E171)
References	1.    UptoDate: Baricitinib (Drug Information) – Accessed online on 19 Aug 2021 2.    Olumiant 2mg Tablet & 4mg Tablet - PI_EU_SPC (by Lilly del Caribe, Inc.) - Updated on 24 June 2020 3.    Package leaflet: Information for the patient (by Eli Lilly and Company Limited) - Updated in Oct 2020 4.    CLINICAL MANAGEMENT OF CONFIRMED COVID-19 CASE IN ADULT AND PAEDIATRIC (Annex 2e), Ministry of Health, Malaysia [Aug 2021] 5.    Baricitinib: Safety Data Sheet (by Lilly) – Updated on 19 Dec 2018 6.    FACT SHEET FOR HEALTHCARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) OF BARICITINIB - Eli Lilly and Company, Indianapolis, USA – Revised on July 2021  JCK Ho @ 19.08.2021