Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

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) 
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. 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 (see sections 4.8 and 5.1).

In a post hoc exploratory analysis within this study, in patients with known VTE risk factors, occurrences of subsequent VTEs were observed more frequently in tofacitinib-treated patients that, at 12 months treatment, had D-dimer level ≥2× ULN versus those with D-dimer level <2×ULN; this was not evident in TNF inhibitor-treated patients. Interpretation is limited by the low number of VTE events and restricted D-dimer test availability (only assessed at Baseline, Month 12, and at the end of the study). In patients who did not have a VTE during the study, mean D-dimer levels were significantly reduced at Month 12 relative to Baseline across all treatment arms. However, D-dimer levels ≥2× ULN at Month 12 were observed in approximately 30% of patients without subsequent VTE events, indicating limited specificity of D-Dimer testing in this study.

In patients with cardiovascular or malignancy risk factors (see also section 4.4 “Major adverse cardiovascular events including myocardial infraction)” and “Malignancies and lymphoproliferative disorders”) 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, 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 (see section 4.8). 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 (see section 4.8). The risk of opportunistic infections is higher in Asian geographic regions (see section 4.8). Rheumatoid arthritis patients taking corticosteroids may be predisposed to infection.

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 (see section 4.8). In patients 65 years of age and older, tofacitinib should only be used if no suitable treatment alternatives are available (see section 5.1).

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. Discontinuation and monitoring criteria for lymphopenia are discussed in section 4.2.

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 (see section 4.8).

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 (see section 4.2).
• Patients with long standing RA who have previously received two or more biological disease modifying antirheumatic drugs (DMARDs).




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.

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 (see sections 4.8 and 5.1). 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 (see section 5.1).

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 (see sections 4.8 and 5.1).

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 (see section 5.1). Periodic skin examination is recommended for all patients, particularly those who are at increased risk for skin cancer (see Table 7 in section 4.8).

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 (see section 4.8 liver enzyme tests). 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. For recommended modifications based on lymphocyte counts, see section 4.2.

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. For recommended modifications based on ANC, see section 4.2.

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. For recommended modifications based on haemoglobin level, see section 4.2.

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. Increases in total and LDL cholesterol associated with tofacitinib may be decreased to pretreatment levels with statin 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.

Excipients contents

Propylene glycol
This medicinal product contains 2.39 mg propylene glycol in each mL.
Examples of propylene glycol exposures based on daily doses (see section 4.2) are as follows:
•   A dose of 3.2 mg twice daily of XELJANZ 1 mg/mL oral solution administered to a child weighing 10 kg to < 20 kg would result in a propylene glycol exposure of 1.53 mg/kg/day.
•   A dose of 4 mg twice daily of XELJANZ 1 mg/mL oral solution administered to a child weighing 20 kg to <40 kg would result in a propylene glycol exposure of 0.96 mg/kg/day.
•   A dose of 5 mg twice daily of XELJANZ 1 mg/mL oral solution administered to a child weighing
≥40 kg would result in a propylene glycol exposure of 0.60 mg/kg/day.

Sodium benzoate
This medicinal product contains 0.9 mg sodium benzoate in each mL.

Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially ‘sodium-free’.





Effects on Driving

4.7    Effects on ability to drive and use machines

Tofacitinib has no or negligible influence on the ability to drive and use machines.