XELJANZ 1 mg/mL

/ Pfizer

Tofacitinib may be used as monotherapy or in combination with methotrexate (MTX).
See prescribing information for full details.

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).

* 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

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.
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. In a randomised post-authorisation safety study in patients with rheumatoid arthritis who were 50 years of age or older with at least one additional cardiovascular risk factor, a dose dependent increased risk for VTE was observed with tofacitinib compared to TNF inhibitors.
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, immobilisation, 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.
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.
Tofacitinib should not be initiated in patients with active infections, including localised infections.
The risks and benefits of treatment should be considered prior to initiating tofacitinib in patients:
• with recurrent infections,
• with a history of a serious or an opportunistic infection,
• who have resided or travelled in areas of endemic mycoses
• who have underlying conditions that may predispose them to infection
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 65 years of age and older, tofacitinib should only be used if no suitable treatment alternatives are available.
Tuberculosis
The risks and benefits of treatment should be considered prior to initiating tofacitinib in patients:
• who have been exposed to TB,
• 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. Consultation with a healthcare professional with expertise in the treatment of TB is recommended to aid in the decision about whether initiating antituberculosis therapy is appropriate for an individual patient. 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.
In patients treated with tofacitinib, the incidence of herpes zoster appears to be increased in:
• Japanese or Korean patients.
• Patients with an ALC less than 1,000 cells/mm3.
• Patients with long standing RA who have previously received two or more biological disease modifying antirheumatic drugs (DMARDs).
At least one confirmed case of progressive multifocal leukoencephalopathy (PML) has been reported in RA patients receiving tofacitinib in the post marketing setting. PML can be fatal and should be considered in the differential diagnosis in immunosuppressed patients with new onset or worsening neurological symptoms.
Major adverse cardiovascular events (including myocardial infarction)
Major adverse cardiovascular events (MACE) have been observed in patients taking tofacitinib. 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 myocardial infarctions was observed with tofacitinib compared to TNF inhibitors. 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.
Malignancies particularly NMSC, lung cancer and lymphoma, was observed with tofacitinib. 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.
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).
Fractures
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. Lymphocyte counts less than 750 cells/mm3 were associated with an increased incidence of serious infections. 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 adult 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 adult patients with a haemoglobin value less than 9 g/dL and in paediatric patients with 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.
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, particularly pJIA and jPsA 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). If the history of chickenpox is considered doubtful or unreliable it is recommended to test for antibodies against 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.
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.

Potential for other medicinal products to influence the pharmacokinetics (PK) of tofacitinib
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.
See prescribing information for full details.

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.

Should be discarded after 60 days of first opening.
Storage after first opening: Store at 25°C