Tofacitinib


Thông tin thuốc gốc
Chỉ định và Liều dùng
Oral
Psoriatic arthritis
Adult: In patients who have inadequate response or intolerance to prior DMARD therapy: In combination with methotrexate or other non-biologic DMARDs: As immediate-release tab: 5 mg bid. As extended-release tab: 11 mg once daily. Do not initiate dosing if ALC <500 cells/mm3, ANC <1,000 cells/mm3, and Hb <9 g/dL. Dose reduction, interruption or discontinuation may be required if serious infection occurs or according to the severity of patient’s laboratory abnormalities (refer to detailed product guideline).

Oral
Rheumatoid arthritis
Adult: In moderately to severely active rheumatoid arthritis (RA) in patients who have inadequate response or intolerance to 1 or more DMARDs: As monotherapy or in combination with methotrexate or other non-biologic DMARDs: As immediate-release tab: 5 mg bid. As extended-release tab: 11 mg once daily. Do not initiate dosing if absolute lymphocyte count (ALC) <500 cells/mm3, absolute neutrophil count (ANC) <1,000 cells/mm3, and Hb <9 g/dL. Dose reduction, interruption or discontinuation may be required if serious infection occurs or according to the severity of patient’s laboratory abnormalities (refer to detailed product guideline).

Oral
Ulcerative colitis
Adult: In moderately to severely active ulcerative colitis in patients who have inadequate or loss of response, or intolerance to either conventional therapy or biologic agent: As immediate-release tab: Induction: 10 mg bid for 8 weeks, may be extended for 8 more weeks in patient who do not achieve adequate therapeutic benefit. Max treatment duration: 16 weeks. Maintenance: 5 mg bid, may be increased to 10 mg bid in patient with failed prior tumour necrosis factor (TNF) antagonist therapy or patient with decreased response to 5 mg bid maintenance therapy. Use the lowest effective dose for the shortest possible duration to achieve or maintain therapeutic response. Do not initiate dosing if ALC <500 cells/mm3, ANC <1,000 cells/mm3, and Hb <9 g/dL Dose reduction, interruption or discontinuation may be required if serious infection occurs or according to the severity of patient’s laboratory abnormalities (refer to detailed product guideline).
Special Patient Group
Patients taking potent CYP3A4 inhibitors (e.g. ketoconazole), or a combination of moderate CYP3A4 and potent CYP2C19 inhibitors (e.g. fluconazole): As immediate-release tab: Reduce tofacitinib total daily dose by 50% e.g. 5 mg once daily in patients receiving 5 mg bid; 5 mg bid in patients receiving 10 mg bid.
Renal Impairment
Patient on haemodialysis: As immediate-release tab: 5 mg once daily, when the indicated dose in normal renal function is 5 mg bid; 5 mg bid, when the indicated dose in normal renal function is 10 mg bid.
CrCl (mL/min) Dosage 
<30  As immediate-release tab: 5 mg once daily, when the indicated dose in normal renal function is 5 mg bid; 5 mg bid, when the indicated dose in normal renal function is 10 mg bid.
Hepatic Impairment
Moderate (Child-Pugh class B): As immediate-release tab: 5 mg once daily, when the indicated dose in normal hepatic function is 5 mg bid; 5 mg bid, when the indicated dose in normal hepatic function is 10 mg bid. Severe (Child-Pugh class C): Contraindicated.
Chống chỉ định
Active infection including localised infections, active TB, serious infections (e.g. sepsis, opportunistic infections). Dosage of 10 mg bid: Heart failure, previous venous thromboembolism (either DVT or pulmonary embolism), inherited coagulation disorder, malignancy, patients undergoing major surgery. Severe hepatic impairment (Child-Pugh class C). Pregnancy and lactation. Concomitant use with biologic DMARDs, potent immunosuppressants (e.g. azathioprine, 6-mercaptopurine, tacrolimus, ciclosporin), live vaccines; and hormonal contraceptives or HRT (10 mg bid dose).
Thận trọng
Patients with history of serious or opportunistic infection, chronic or recurrent infection, exposure to TB, chronic or interstitial lung disease, underlying conditions predisposing to infection (e.g. diabetes mellitus); baseline heart rate <60 beats per minute, conduction abnormalities, syncope or arrhythmia, ischaemic heart disease, heart failure; pre-existing gastrointestinal narrowing (extended-release tab). Patients with risks of thrombosis or pulmonary embolism (e.g. smoking, obesity, immobilisation), gastrointestinal perforation (e.g. history of diverticulitis), viral reactivation (e.g. 10 mg bid dose, long-standing RA, Japanese or Korean race), CV risk factors (e.g. hypertension, hyperlipidaemia), and those who have resided in or travelled to areas with endemic TB or mycoses. Asian race. Severe renal and moderate hepatic impairment.
Phản ứng phụ
Significant: Malignancy (e.g. lymphoma, non-melanoma skin cancer), Epstein-Barr virus-associated post-transplant lymphoproliferative disorder, bone marrow suppression (e.g. lymphocytosis, lymphocytopenia, neutropenia, anaemia), CV effects (e.g. decreased heart rate, prolonged PR interval), gastrointestinal perforation, obstructive symptoms (extended-release tab); elevated liver enzymes, lipid abnormalities (e.g. increased total cholesterol, LDL, HDL); hypersensitivity reactions (e.g. angioedema, urticaria).
Blood and lymphatic system disorders: Leucopenia.
Gastrointestinal disorders: Diarrhoea, nausea, vomiting, abdominal pain, dyspepsia, gastritis.
General disorders and admin site conditions: Pyrexia, fatigue, peripheral oedema.
Hepatobiliary disorders: Hepatic steatosis.
Injury, poisoning and procedural complications: Ligament sprain, muscle strain.
Investigations: Increased blood creatine phosphokinase and creatinine, increased weight.
Metabolism and nutrition disorders: Dehydration, dyslipidaemia.
Musculoskeletal and connective tissue disorders: Arthralgia, musculoskeletal pain, joint swelling, tendonitis.
Nervous system disorders: Headache, paraesthesia.
Psychiatric disorders: Insomnia.
Respiratory, thoracic and mediastinal disorders: Nasopharyngitis, upper respiratory tract infection, dyspnoea, cough, sinus congestion.
Skin and subcutaneous tissue disorders: Rash, erythema, pruritus.
Vascular disorders: Hypertension.
Potentially Fatal: Serious infections caused by bacterial, mycobacterial, invasive fungal, viral or other opportunistic pathogens (e.g. active pulmonary or extrapulmonary TB, disseminated cryptococcosis and pneumocystosis, multidermatomal herpes zoster, oesophageal candidiasis, cytomegalovirus and BK virus infections, listeriosis); thrombosis including pulmonary embolism, DVT and arterial embolism (10 mg bid dose); interstitial lung disease.
MonitoringParameters
Monitor neutrophil/platelet counts and Hb at baseline, after 4-8 weeks, and every 3 months thereafter; lymphocyte counts at baseline and every 3 months thereafter; lipid profile 4-8 weeks after treatment initiation and periodically thereafter; LFTs and renal function tests; ECG, heart rate, and blood pressure at baseline and periodically thereafter; periodic skin examination. Conduct viral hepatitis, latent and active TB screening prior to and during therapy. Closely monitor for signs or symptoms of infection, TB, abdominal symptoms, and pulmonary embolism during and after treatment.
Tương tác
Increased risk of gastrointestinal perforation with corticosteroids and NSAIDs. Increased exposure with moderate CYP3A4 and potent CYP2C19 inhibitors (e.g. tacrolimus, ciclosporin, ketoconazole, fluconazole). Increased risk of reduced or loss of clinical response with potent CYP3A4 inducers (e.g. rifampicin).
Potentially Fatal: Additive immunosuppression and increased risk of infection with biologic DMARDs, potent immunosuppressants (e.g. azathioprine, 6-mercaptopurine, ciclosporin, tacrolimus), and live vaccines.
Food Interaction
St. John's wort may decrease tofacitinib serum concentration.
Tác dụng
Description: Tofacitinib is a selective inhibitor of Janus kinase (JAK) enzymes (particularly JAK1, JAK2, JAK3) which are intracellular enzymes involved in the activation of signal transducers and activators of transcription (STATs) that regulates gene expression and intracellular activity, and stimulation of haematopoiesis and immune cell function. Inhibition of JAKs results to suppression of immune response, reduced activation of T lymphocytes and release of a range of pro-inflammatory cytokines.
Pharmacokinetics:
Absorption: Rapidly absorbed from the gastrointestinal tract (immediate-release tab). Absolute bioavailability: 74%. Time to peak plasma concentration: 0.5-1 hour (immediate-release tab); 4 hours (extended-release tab).
Distribution: Equally distributed to RBC and plasma. Volume of distribution: 87 L. Plasma protein binding: Approx 40%, mainly to albumin.
Metabolism: Metabolised in the liver mainly by CYP3A4 enzyme, and to a lesser extent by CYP2C19 enzyme to inactive metabolites.
Excretion: Mainly via urine (30% as unchanged drug). Elimination half-life: Approx 3 hours (immediate-release); approx 6 hours (extended-release).
Đặc tính

Chemical Structure Image
Tofacitinib

Source: National Center for Biotechnology Information. PubChem Database. Tofacitinib, CID=9926791, https://pubchem.ncbi.nlm.nih.gov/compound/Tofacitinib (accessed on Jan. 23, 2020)

Bảo quản
Store between 20-25°C. Follow applicable procedures for receiving, handling, administration, and disposal.
Phân loại MIMS
Phân loại ATC
L04AA29 - tofacitinib ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.
References
Anon. Tofacitinib. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 30/07/2019.

Anon. Tofacitinib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 30/07/2019.

Buckingham R (ed). Tofacitinib. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 30/07/2019.

Joint Formulary Committee. Tofacitinib. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 30/07/2019.

Pfizer New Zealand Limited. Jaqinus 5 mg Film-Coated Tablet data sheet 22 November 2018. Medsafe. http://www.medsafe.govt.nz/. Accessed 30/07/2019.

Xeljanz Tablet, Film Coated; Xeljanz XR Tablet, Extended Release (Pfizer Laboratories Div Pfizer Inc). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 30/07/2019.

Xeljanz Tablet, Film Coated; Xeljanz XR Tablet, Extended Release (U.S. Pharmaceuticals). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 04/01/2018.

Xeljanz, Xeljanz XR: Drug Safety Communication - Due to an Increased Risk of Blood Clots and Death with Higher Dose. U.S. FDA. https://www.fda.gov/. Accessed 30/07/2019.

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