Xeljanz

/ Pfizer

Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of conditions for which tofacitinib is indicated.
Rheumatoid arthritis:
The recommended dose is 5 mg tablets administered twice daily, or one extended-release tablet (11 mg) which should not be exceeded.
No dose adjustment is required when used in combination with MTX.
Psoriatic arthritis:
The recommended dose is 5 mg tablets administered twice daily, which should not be exceeded. No dose adjustment is required when used in combination with MTX.
Ankylosing spondylitis:
The recommended dose is 5 mg administered twice daily.
Ulcerative colitis:
Induction treatment– The recommended dose is 10 mg given orally twice daily for induction for 8 weeks. For patients who do not achieve adequate therapeutic benefit by week 8, the induction dose of 10 mg twice daily can be extended for an additional 8 weeks (16 weeks total), followed by 5 mg twice daily for maintenance. Tofacitinib induction therapy should be discontinued in any patient who shows no evidence of therapeutic benefit by week 16.
Maintenance treatment- The recommended dose for maintenance treatment is tofacitinib 5 mg given orally twice daily.
Avoid Tofacitinib in patients at increased risk for thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis.
Tofacitinib 10 mg twice daily for maintenance treatment is not recommended in patients with UC who have known major adverse cardiovascular events (MACE) and malignancy risk factors, unless there is no suitable alternative treatment available.
Polyarticular JIA and juvenile PsA (children between 2 and 18 years of age):
Tofacitinib may be used as monotherapy or in combination with MTX.
See prescribing information for the recommended dose in patients 2 years of age and older.
Elderly:
No dose adjustment is required in patients aged 65 years and older. There are limited data in patients aged 75 years and older.
Renal Impairment:
For patients with Creatinine clearance < 30 mL/min- dose should be reduced to 5 mg once daily when the indicated dose in the presence of normal renal function is 5 mg twice daily or 11 mg extended release once daily. Dose should be reduced to 5 mg twice daily when the indicated dose in the presence of normal renal function is 10 mg twice daily.
Patients with severe renal impairment should remain on a reduced dose even after haemodialysis.
Hepatic Impairment:
Severe Impairment- Tofacitinib should not be used in patients with severe hepatic impairment.
Moderate Impairment- Dose should be reduced to 5 mg once daily when the indicated dose in the presence of normal hepatic function is 5 mg twice daily or 11 mg extended release once daily.  Dose should be reduced to 5 mg twice daily when the indicated dose in the presence of normal hepatic function is 10 mg twice daily.
Paediatric population:
The safety and efficacy of tofacitinib in children less than 2 years of age with polyarticular JIA and juvenile PsA has not been established. No data are available. The safety and efficacy of tofacitinib in children less than 18 years of age with other indications (e.g., ulcerative colitis) has not been established. No data are available.
See prescribing information for full details.

Rheumatoid arthritis
Tofacitinib in combination with methotrexate (MTX) is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs (DMARDs). Tofacitinib can be given as monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate.
Psoriatic arthritis
Tofacitinib in combination with MTX is indicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior disease-modifying antirheumatic drug (DMARD) therapy.
Ankylosing spondylitis
Tofacitinib is indicated for the treatment of adult patients with active ankylosing spondylitis (AS) who have responded inadequately to conventional therapy.
Ulcerative colitis
Tofacitinib is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent.
Juvenile idiopathic arthritis (JIA)
Tofacitinib is indicated for the treatment of active polyarticular juvenile idiopathic arthritis (rheumatoid factor positive [RF+] or negative [RF-] polyarthritis and extended oligoarthritis), and juvenile psoriatic arthritis (PsA) in patients 2 years of age and older, who have responded inadequately to previous therapy with disease modifying antirheumatic drugs DMARDs.
Tofacitinib can be given in combination with methotrexate (MTX) or as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.

– Hypersensitivity to the active substance or to any of the excipients.
– Active tuberculosis (TB), serious infections such as sepsis, or opportunistic infections.
– Severe hepatic impairment.
– Pregnancy and lactation.

Tofacitinib should only be used if no suitable treatment alternatives are available in patients:
-65 years of age and older;
-patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors (such as current or past long-time smokers);
-patients with malignancy risk factors (e.g. current malignancy or history of malignancy)
Use in patients 65 years of age and older:
Considering the increased risk of serious infections, myocardial infarction, and malignancies and all cause mortality with tofacitinib in patients 65 years of age and older, tofacitinib should only be used in these patients if no suitable treatment alternatives are available.
Combination with other therapies:
Tofacitinib has not been studied and its use should be avoided in combination with biologics such as TNF antagonists, interleukin (IL)-1R antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies, IL-17 antagonists, IL-12/IL-23 antagonists, anti-integrins, selective co-stimulation modulators and potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporin and tacrolimus because of the possibility of increased immunosuppression and increased risk of infection.
There was a higher incidence of adverse events for the combination of tofacitinib with MTX versus tofacitinib as monotherapy in RA clinical studies.
The use of tofacitinib in combination with phosphodiesterase 4 inhibitors has not been studied in tofacitinib clinical studies.
Venous thromboembolism (VTE):
Serious VTE events including pulmonary embolism (PE), some of which were fatal, and deep vein thrombosis (DVT), have been observed in patients taking tofacitinib.
For patients with UC: Avoid tofacitinib in patients at increased risk for thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis.
In patients with cardiovascular or malignancy risk factors tofacitinib should only be used if no suitable treatment alternatives are available. In patients with VTE risk factors other than MACE or malignancy risk factors, tofacitinib should be used with caution. VTE risk factors other than MACE or malignancy risk factors include previous VTE, patients undergoing major surgery, use of combined hormonal contraceptives or hormone replacement therapy, inherited coagulation disorder. Patients should be re-evaluated periodically during tofacitinib treatment to assess for changes in VTE risk.
For patients with RA with known risk factors for VTE, consider testing D-dimer levels after approximately 12 months of treatment. If D-dimer test result is ≥ 2× ULN, confirm that clinical benefits outweigh risks prior to a decision on treatment continuation with tofacitinib.
Promptly evaluate patients with signs and symptoms of VTE and discontinue tofacitinib in patients with suspected VTE, regardless of dose or indication.
Retinal venous thrombosis:
Retinal venous thrombosis (RVT) has been reported in patients treated with tofacitinib. The patients should be advised to promptly seek medical care in case they experience symptoms suggestive of RVT.
Serious infections:
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. The risk of opportunistic infections is higher in Asian geographic regions.  Rheumatoid arthritis patients taking corticosteroids may be predisposed to infection.
Tofacitinib should not be initiated in patients with active infections, including localised infections.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib. Treatment should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with tofacitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.
As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes. In patients over 65 years of age tofacitinib should only be used if no suitable treatment alternatives are available.
Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection.
Tuberculosis:
The risks and benefits of treatment should be considered prior to initiating tofacitinib in patient who have been exposed to TB, or who have resided or travelled in areas of endemic TB.
Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of tofacitinib.
Patients with latent TB, who test positive, should be treated with standard antimycobacterial therapy before administering tofacitinib.
Antituberculosis therapy should also be considered prior to administration of tofacitinib in patients who test negative for TB but who have a past history of latent or active TB and where an adequate course of treatment cannot be confirmed; or those who test negative but who have risk factors for TB infection. Patients should be closely monitored for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.
Viral reactivation:
Viral reactivation and cases of herpes virus reactivation (e.g., herpes zoster) have been observed in patients receiving tofacitinib.
The impact of tofacitinib on chronic viral hepatitis reactivation is unknown. Patients screened positive for hepatitis B or C were excluded from clinical studies. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with tofacitinib.
Major adverse cardiovascular events (including myocardial infarction):
Major adverse cardiovascular events (MACE) have been observed in patients taking tofacitinib. In patients 65 years of age and older, patients who are current or past long-time smokers, and patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, tofacitinib should only be used if no suitable treatment alternatives are available.
Malignancies and lymphoproliferative disorder:
Tofacitinib may affect host defences against malignancies.
In a randomised post authorisation safety study in patients with RA who were 50 years of age or older with at least one additional cardiovascular risk factor, an increased incidence of malignancies, particularly NMSC, lung cancer and lymphoma, was observed with tofacitinib compared to TNF inhibitors.
NMSC, lung cancers and lymphoma in patients treated with tofacitinib have also been observed in other clinical studies and in the post marketing setting.
Other malignancies in patients treated with tofacitinib were observed in clinical studies and the post-marketing setting, including, but not limited to, breast cancer, melanoma, prostate cancer, and pancreatic cancer.
In patients 65 years of age and older, patients who are current or past long-time smokers, and patients with other malignancy risk factors (e.g. current malignancy or history of malignancy other than a successfully treated non-melanoma skin cancer) tofacitinib should only be used if no suitable treatment alternatives are available.
Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
Interstitial lung disease:
Caution is also recommended in patients with a history of chronic lung disease as they may be more prone to infections. Events of interstitial lung disease (some of which had a fatal outcome) have been reported in patients treated with tofacitinib in RA clinical studies and in the post-marketing setting although the role of Janus kinase (JAK) inhibition in these events is not known. Asian RA patients are known to be at higher risk of interstitial lung disease, thus caution should be exercised in treating these patients.
Gastrointestinal perforations:
Events of gastrointestinal perforation have been reported in clinical studies although the role of JAK inhibition in these events is not known. Tofacitinib should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis, patients with concomitant use of corticosteroids and/or nonsteroidal anti-inflammatory drugs). Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of gastrointestinal perforation.
Fractures:
Fractures have been observed in patients treated with tofacitinib.
Tofacitinib should be used with caution in patients with known risk factors for fractures such as elderly patients, female patients and patients with corticosteroid use, regardless of indication and dosage.
Liver enzymes:
Treatment with tofacitinib was associated with an increased incidence of liver enzyme elevation in some patients. Caution should be exercised when considering initiation of tofacitinib treatment in patients with elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST), particularly when initiated in combination with potentially hepatotoxic medicinal products such as MTX. Following initiation, routine monitoring of liver tests and prompt investigation of the causes of any observed liver enzyme elevations are recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of tofacitinib should be interrupted until this diagnosis has been excluded.
Hypersensitivity:
In post-marketing experience, cases of hypersensitivity associated with tofacitinib administration have been reported. Allergic reactions included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, tofacitinib should be discontinued immediately.
Laboratory parameters:
Lymphocytes: Treatment with tofacitinib was associated with an increased incidence of lymphopenia compared to placebo. It is not recommended to initiate or continue tofacitinib treatment in patients with a confirmed lymphocyte count less than 750 cells/mm3. Lymphocytes should be monitored at baseline and every 3 months thereafter.
Neutrophils: Treatment with tofacitinib was associated with an increased incidence of neutropenia (less than 2,000 cells/mm3) compared to placebo. It is not recommended to initiate tofacitinib treatment in patients with an ANC less than 1,000 cells/mm3 and in paediatric patients with an ANC less than 1,200 cells/mm3. ANC should be monitored at baseline and after 4 to 8 weeks of treatment and every 3 months thereafter.
Haemoglobin: Treatment with tofacitinib has been associated with decreases in haemoglobin levels. It is not recommended to initiate tofacitinib treatment in patients with a haemoglobin value less than 9 g/dL and in paediatric patients with a haemoglobin value less than 10 g/dL. Haemoglobin should be monitored at baseline and after 4 to 8 weeks of treatment and every 3 months thereafter.
Lipid monitoring: Treatment with tofacitinib was associated with increases in lipid parameters such as total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. Assessment of lipid parameters should be performed after 8 weeks following initiation of tofacitinib therapy. Patients should be managed according to clinical guidelines for the management of hyperlipidaemia.
Hypoglycaemia in patients treated for diabetes: There have been reports of hypoglycaemia following initiation of tofacitinib in patients receiving medication for diabetes. Dose adjustment of anti-diabetic medication may be necessary in the event that hypoglycaemia occurs.
Vaccinations:
Prior to initiating tofacitinib, it is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines. It is recommended that live vaccines not be given concurrently with tofacitinib. The decision to use live vaccines prior to tofacitinib treatment should take into account the pre-existing immunosuppression in a given patient.
Prophylactic zoster vaccination should be considered in accordance with vaccination guidelines. Particular consideration should be given to patients with longstanding RA who have previously received two or more biological DMARDs. If live zoster vaccine is administered; it should only be administered to patients with a known history of chickenpox or those that are seropositive for varicella zoster virus (VZV).
Vaccination with live vaccines should occur at least 2 weeks but preferably 4 weeks prior to initiation of tofacitinib or in accordance with current vaccination guidelines regarding immunomodulatory medicinal products. No data are available on the secondary transmission of infection by live vaccines to patients receiving tofacitinib.
Gastrointestinal obstruction with a non-deformable extended-release formulation:
Caution should be used when administering tofacitinib extended-release tablets to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other medicinal products utilising a non-deformable extended-release formulation.
See prescribing information for full details.

Common: Pneumonia, influenza, herpes zoster, urinary tract infection, sinusitis, bronchitis, nasopharyngitis, pharyngitis, lymphopenia, anaemia, headache, hypertension, cough, abdominal pain,vomiting, diarrhoea, nausea, gastritis, dyspepsia, rash , acne, arthralgia, oedema peripheral , blood creatine phosphokinase increased.
See prescribing information for full details.

Potential for other medicinal products to influence the pharmacokinetics (PK) of tofacitinib:
Since tofacitinib is metabolised by CYP3A4, interaction with medicinal products that inhibit or induce CYP3A4 is likely. Tofacitinib exposure is increased when coadministered with potent inhibitors of CYP3A4 (e.g., ketoconazole) or when administration of one or more concomitant medicinal products results in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole).
Tofacitinib exposure is decreased when coadministered with potent CYP inducers (e.g., rifampicin). Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to significantly alter the PK of tofacitinib.
Coadministration with ketoconazole (strong CYP3A4 inhibitor), fluconazole (moderate CYP3A4 and potent CYP2C19 inhibitor), tacrolimus (mild CYP3A4 inhibitor) and ciclosporin (moderate CYP3A4 inhibitor) increased tofacitinib AUC, while rifampicin (potent CYP inducer) decreased tofacitinib AUC. Coadministration of tofacitinib with potent CYP inducers (e.g., rifampicin) may result in a loss of or reduced clinical response. Coadministration of potent inducers of CYP3A4 with tofacitinib is not recommended. Coadministration with ketoconazole and fluconazole increased tofacitinib Cmax, while tacrolimus, ciclosporin and rifampicin decreased tofacitinib Cmax. Concomitant administration with MTX 15-25 mg once weekly had no effect on the PK of tofacitinib in RA patients.
Potential for tofacitinib to influence the PK of other medicinal products:
Coadministration of tofacitinib did not have an effect on the PK of oral contraceptives, levonorgestrel and ethinyl estradiol, in healthy female volunteers.
In RA patients, coadministration of tofacitinib with MTX 15-25 mg once weekly decreased the AUC and Cmax of MTX by 10% and 13%, respectively. The extent of decrease in MTX exposure does not warrant modifications to the individualised dosing of MTX.

Pregnancy:
There are no adequate and well-controlled studies on the use of tofacitinib in pregnant women. Tofacitinib has been shown to be teratogenic in rats and rabbits, and to affect parturition and peri/postnatal development.
As a precautionary measure, the use of tofacitinib during pregnancy is contraindicated.
Women of childbearing potential/contraception in females:
Women of childbearing potential should be advised to use effective contraception during treatment with tofacitinib and for at least 4 weeks after the last dose.
Breast-feeding:
Tofacitinib is excreted in human milk. The effects of tofacitinib on the breast-fed infant from published literature and post-marketing data is unknown and is limited to a small number of cases with no causally related adverse events. A risk to the breast-fed child cannot be excluded. As a precautionary measure, the use of tofacitinib during breast-feeding is contraindicated.

In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. There is no specific antidote for overdose with tofacitinib. Treatment should be symptomatic and supportive.
Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate that more than 95% of the administered dose is expected to be eliminated within 24 hours.

Shelf life after first opening:
5 mg: 30 days for 28 and 60 tablets per bottle, 135 days for 180 tablets per bottle.
10 mg: 60 days
XR 11 mg: 30 days
 Storage:
5 mg: Store below 25°C
10 mg: Store below 30°C
XR 11 mg: Store below 30°C