Tofacitinib


Generic Medicine Info
Indications and Dosage
Oral
Psoriatic arthritis
Adult: In patients who have inadequate response or intolerance to prior or 1 or more DMARD therapy: In combination with methotrexate or other non-biologic DMARDs: As conventional tab: 5 mg bid. As extended-release tab: 11 mg once daily. Do not initiate dosing in patients with ALC <500 cells/mm3, ANC <1,000 cells/mm3, and Hb <9 g/dL. Dose 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: For moderately to severely active cases in patients who have inadequate response or intolerance to 1 or more DMARDs: Monotherapy or in combination with methotrexate or other non-biologic DMARDs: As conventional tab: 5 mg bid. As extended-release tab: 11 mg once daily. Do not initiate dosing in patients with absolute lymphocyte count (ALC) <500 cells/mm3, absolute neutrophil count (ANC) <1,000 cells/mm3, and Hb <9 g/dL. Dose 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
Ankylosing spondylitis
Adult: In patients who have an inadequate response or intolerance to conventional treatment or 1 or more tumour necrosis factor (TNF) blockers: As conventional tab: 5 mg bid. As extended-release tab: 11 mg once daily. Do not initiate dosing in patients with ALC <500 cells/mm3, ANC <1,000 cells/mm3, and Hb <9 g/dL. Dose 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
Polyarticular juvenile idiopathic arthritis
Child: ≥2 years In patients who have an inadequate response or intolerance to previous DMARDs therapy or 1 or more TNF blockers: Monotherapy or in combination with methotrexate: 10-<20 kg: As oral solution: 3.2 mg bid; 20-<40 kg: As oral solution: 4 mg bid; ≥40 kg: As conventional tab or oral solution: 5 mg bid. Do not initiate dosing in patients with ALC <500 cells/mm3, ANC <1,000 cells/mm3, and Hb <9 g/dL. Dose 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: For moderately to severely active cases in patients who have inadequate or loss of response, or intolerance to either conventional therapy or biologic agent: As conventional tab: Induction: 10 mg bid for 8 weeks, may be extended for 8 more weeks in patients who do not achieve adequate therapeutic response. Max treatment duration: 16 weeks. Discontinue therapy if adequate response is not reached after 16 weeks. Maintenance: 5 mg bid, may be increased to 10 mg bid in patients with decreased response to 5 mg bid maintenance therapy or those who failed to respond to prior TNF blocker therapy. Use the lowest effective dose for the shortest possible duration to maintain therapeutic response. As extended-release tab: Induction: 22 mg once daily for 8 weeks, may continue dosing for 8 more weeks based on therapeutic response. Max treatment duration: 16 weeks. Stop therapy if adequate response is not reached after 16 weeks. Maintenance: 11 mg once daily, may be increased to 22 mg once daily in patients with loss of response to 11 mg once daily maintenance therapy. Use the lowest effective dose for the shortest possible duration to maintain therapeutic response. Do not initiate dosing in patients with ALC <500 cells/mm3, ANC <1,000 cells/mm3, and Hb <9 g/dL. Dose 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): Reduce tofacitinib total daily dose by 50%. In adults: As conventional tab: 5 mg once daily if receiving 5 mg bid; 5 mg bid if taking 10 mg bid. As extended-release tab: 5 mg conventional tab once daily in patients receiving 11 mg extended-release tab once daily; 11 mg once daily in those taking 22 mg once daily. In children ≥2 years: As oral solution: 10-<20 kg: 3.2 mg once daily if receiving 3.2 mg bid; 20-<40 kg: 4 mg once daily if taking 4 mg bid; As conventional tab or oral solution: ≥40 kg: 5 mg once daily if receiving 5 mg bid.
Renal Impairment
Rheumatoid arthritis; Psoriatic arthritis; Ankylosing spondylitis:
Adult: Moderate to severe and patient on haemodialysis: As conventional tab: 5 mg once daily, when the indicated dose in normal renal function is 5 mg bid. As extended-release tab: 5 mg conventional tab once daily, when the indicated dose in normal hepatic function is 11 mg extended-release tab once daily. For patients undergoing haemodialysis, give doses after dialysis session on dialysis days. If a dose was taken prior to dialysis, supplemental dose is not recommended after dialysis.

Ulcerative colitis:
Adult: Moderate to severe and patient on haemodialysis: As conventional 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. As extended-release tab: 5 mg conventional tab once daily, when the indicated dose in normal hepatic function is 11 mg extended-release tab once daily; 11 mg once daily when the indicated dose in normal hepatic function is 22 mg once daily. For patients undergoing haemodialysis, give doses after dialysis session on dialysis days. If a dose was taken prior to dialysis, supplemental dose is not recommended after dialysis.

Polyarticular juvenile idiopathic arthritis:
Child: Moderate to severe and patient on haemodialysis: As oral solution: 10-<20 kg: 3.2 mg once daily if receiving 3.2 mg bid; 20-<40 kg: 4 mg once daily if taking 4 mg bid; As conventional tab or oral solution: ≥40 kg: 5 mg once daily if receiving 5 mg bid. For patients undergoing haemodialysis, give doses after dialysis session on dialysis days. If a dose was taken prior to dialysis, supplemental dose is not recommended after dialysis.
Hepatic Impairment
Rheumatoid arthritis; Psoriatic arthritis; Ankylosing spondylitis:
Adult: Moderate (Child-Pugh class B): As conventional tab: 5 mg once daily, when the indicated dose in normal hepatic function is 5 mg bid. As extended-release tab: 5 mg conventional tab once daily, when the indicated dose in normal hepatic function is 11 mg extended-release tab once daily. Severe (Child-Pugh class C): Contraindicated.

Ulcerative colitis:
Adult: Moderate (Child-Pugh class B): As conventional 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. As extended-release tab: 5 mg conventional tab once daily, when the indicated dose in normal hepatic function is 11 mg extended-release tab once daily; 11 mg once daily when the indicated dose in normal hepatic function is 22 mg once daily. Severe (Child-Pugh class C): Contraindicated.

Polyarticular juvenile idiopathic arthritis:
Child: Moderate (Child-Pugh class B): As oral solution: 10-<20 kg: 3.2 mg once daily if receiving 3.2 mg bid; 20-<40 kg: 4 mg once daily if taking 4 mg bid; As conventional tab or oral solution: ≥40 kg: 5 mg once daily if receiving 5 mg bid. Severe (Child-Pugh class C): Contraindicated.
Contraindications
Active infection including localised infections, active TB, serious infections (e.g. sepsis, opportunistic infections). Severe hepatic impairment (Child-Pugh class C). Pregnancy and lactation. Concomitant use with biologic DMARDs, potent immunosuppressants (e.g. azathioprine, 6-mercaptopurine, tacrolimus, ciclosporin), and live vaccines.
Special Precautions
Patient with history of serious or opportunistic infection, chronic or recurrent infection, exposure to TB, underlying conditions predisposing to infection (e.g. diabetes); history of chronic or interstitial lung disease, current or history of malignancy other than successfully treated non-melanoma skin cancer; baseline heart rate <60 beats per minute, sick sinus syndrome, sinoatrial or atrioventricular block, history of syncope or arrhythmia, ischaemic heart disease, heart failure, other CV risk factors (e.g. coronary artery disease, stable angina pectoris), hyperlipidaemia; known risk factors for venous thromboembolism (e.g. history, MI within previous 3 months, hypertension, inherited coagulation disorders, obesity [BMI ≥30], major surgery, immobilisation), gastrointestinal perforation (e.g. history of diverticulitis), and viral reactivation (e.g. ALC <1,000 cells/mm3, use of 10 mg bid dose, long-standing rheumatoid arthritis previously received ≥2 DMARDs, Japanese or Korean patients); pathologic or iatrogenic pre-existing severe gastrointestinal narrowing (particularly for extended-release tab). Current or past smokers. Individuals who have resided in or travelled to areas with endemic TB or mycoses. Dosage of 10 mg bid in rheumatoid arthritis patients ≥50 years with at least 1 CV risk factor. Asian patients. Extended-release tab is not interchangeable or substitutable with oral solution. Moderate to severe renal and moderate hepatic impairment. Elderly, especially >65 years.
Adverse Reactions
Significant: Malignancy (e.g. lymphoma, solid tumours, lung cancer, non-melanoma skin cancer), Epstein-Barr virus-associated post-transplant lymphoproliferative disorder, reactivation of viral infection (e.g. herpes zoster, hepatitis B), bone marrow suppression (e.g. lymphocytosis, lymphocytopenia, neutropenia, anaemia), CV effects (e.g. decreased heart rate, prolonged PR interval), gastrointestinal perforation, elevated liver enzymes, lipid abnormalities (e.g. increased total cholesterol, LDL, HDL); hypersensitivity reactions (e.g. urticaria, angioedema). Rarely, obstructive symptoms in individuals with known stricture (after taking extended-release tab).
Blood and lymphatic system disorders: Leucopenia.
Gastrointestinal disorders: Diarrhoea, nausea, vomiting, abdominal pain, dyspepsia, gastritis.
General disorders and administration site conditions: Pyrexia, peripheral oedema, fatigue.
Hepatobiliary disorders: Hepatic steatosis.
Injury, poisoning and procedural complications: Ligament sprain, muscle strain.
Investigations: Increased blood creatine phosphokinase and serum 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, influenza, sinusitis, bronchitis, pharyngitis, cough, dyspnoea, sinus congestion.
Skin and subcutaneous tissue disorders: Rash, acne vulgaris, 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, pneumonia, UTI, cellulitis, diverticulitis, multidermatomal herpes zoster, oesophageal candidiasis, cytomegalovirus and BK virus infections, listeriosis); interstitial lung disease, serious CV events (e.g. MI, stroke); thrombosis including pulmonary embolism, DVT and arterial thrombosis.
Monitoring Parameters
Perform viral hepatitis, latent and active TB screening prior to and during therapy. Obtain neutrophil/platelet counts and Hb at baseline, following 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; LFTs and renal function tests; ECG, heart rate, and blood pressure at baseline and regularly thereafter. Conduct periodic skin exams in patients at risk of skin cancer. Closely monitor for signs or symptoms of infection, TB (including patients who tested negative for latent TB before therapy initiation), new-onset abdominal symptoms, and venous thromboembolism during and after treatment.
Drug Interactions
Increased risk of gastrointestinal perforation with corticosteroids and NSAIDs. Increased exposure with moderate or potent CYP3A4 (e.g. ketoconazole) and potent CYP2C19 inhibitors (e.g. fluconazole). 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. Increased risk of serious infections when coadministered with methotrexate or corticosteroids.
Action
Description: Tofacitinib is a selective inhibitor of Janus kinase (JAK) enzymes (particularly JAK1 and JAK3, and to a lesser extent, JAK2) which are intracellular enzymes involved in the stimulation of haematopoiesis and immune cell function via a signalling pathway. It prevents phosphorylation and activation of signal transducers and activators of transcription (STATs) thereby modulating the JAKs signalling pathway. The inhibition of JAKs results in the prevention of cytokine- or growth factor-mediated gene expression and immune intracellular activity, reduction of circulating CD16/56+ natural killer cells, serum IgG, IgA, IgM and C-reactive protein, and elevation of B cells.
Pharmacokinetics:
Absorption: Rapidly and well absorbed (conventional tab). Bioavailability: 74%. Time to peak plasma concentration: 0.5-1 hour (conventional tab, oral solution); 4 hours (extended-release tab).
Distribution: Equally distributed between RBC and plasma. Volume of distribution: 87 L. Plasma protein binding: Approx 40%, mainly to albumin.
Metabolism: Metabolised in the liver by CYP3A4, and to a lesser extent by CYP2C19 isoenzyme to inactive metabolites.
Excretion: Mainly via urine (30%, as unchanged drug). Elimination half-life: Approx 3 hours (conventional tab, oral solution); approx 6-8 hours (extended-release tab).
Chemical Structure

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)

Storage
Conventional/extended-release tab: Store between 20-25°C. Protect from moisture. Oral solution: Store between 15-30°C. Protect from light.
MIMS Class
Disease-Modifying Anti-Rheumatic Drugs (DMARDs) / Immunosuppressants
ATC Classification
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 09/02/2022.

Anon. Tofacitinib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 09/02/2022.

Buckingham R (ed). Tofacitinib. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/02/2022.

FDA Requires Warnings About Increased Risk of Serious Heart-Related Events, Cancer, Blood Clots, and Death for JAK Inhibitors that Treat Certain Chronic Inflammatory Conditions. U.S. FDA. https://www.fda.gov. Accessed 09/02/2022.

Joint Formulary Committee. Tofacitinib. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/02/2022.

Pfizer New Zealand Limited. Jaqinus 5 mg Film-Coated Tablet data sheet 27 August 2021. Medsafe. http://www.medsafe.govt.nz. Accessed 09/02/2022.

Tofacitinib (Xeljanz): New Measures to Minimise Risk of Major Adverse Cardiovascular Events and Malignancies. Medicines & Healthcare products Regulatory Agency. https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency. Accessed 09/02/2022.

Xeljanz 5 and 10 mg Film-Coated Tablets, 11 mg Prolonged-Release Tablets, and 1 mg/mL Oral Solution (Pfizer Europe MA EEIG). European Medicines Agency [online]. Accessed 09/02/2022.

Xeljanz Film Coated Tablet, Xeljanz XR Tablet Extended Release, and Xeljanz Solution (Pfizer Laboratories Div Pfizer Inc). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 09/02/2022.

Xeljanz Film-Coated Tablets 5mg (Pfizer [Malaysia] Sdn. Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 09/02/2022.

Disclaimer: This information is independently developed by MIMS based on Tofacitinib from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2022 MIMS. All rights reserved. Powered by MIMS.com
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