Xeljanz 5 mg & 10 mg FC tablets

Rheumatoid arthritis

XELJANZ 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. XELJANZ can be given as monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate (see sections 4.4 and 4.5).

Psoriatic arthritis

XELJANZ 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 (see section 5.1).

Ulcerative colitis

XELJANZ 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 medicine (see section 5.1).

Treatment should be initiated and supervised by medical practitioners experienced in the diagnosis and treatment of conditions for which XELJANZ is indicated.

Posology

Rheumatoid arthritis and psoriatic arthritis

The recommended dose is 5 mg administered twice daily.

Dose adjustment

No dose adjustment is required when used in combination with MTX.

Ulcerative colitis

The recommended dose is 10 mg given orally twice daily for induction for 8 weeks and 5 mg given twice daily for maintenance. 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. XELJANZ induction therapy should be discontinued in any patient who shows no evidence of therapeutic benefit by week 16. For some patients, such as those who have failed prior tumour necrosis factor (TNF) antagonist therapy, consideration should be given to continuation of the 10 mg twice daily dose for maintenance in order to maintain therapeutic benefit (see section 5.1). Patients who experience a decrease in response on XELJANZ 5 mg twice daily maintenance therapy may benefit from an increase to XELJANZ 10 mg administered twice daily. In patients who have responded to treatment with XELJANZ, corticosteroids may be reduced and/or discontinued in accordance with standard of care.

Retreatment in UC

If therapy is interrupted, restarting treatment with XELJANZ can be considered. If there has been a loss of response, reinduction with XELJANZ 10 mg twice daily may be considered. The treatment interruption period in clinical studies extended up to 1 year. Efficacy may be regained by 8 weeks of 10 mg twice daily therapy (see section 5.1).

Dose interruption and discontinuation

XELJANZ treatment should be interrupted if a patient develops a serious infection until the infection is controlled. Interruption of dosing may be needed for management of dose-related laboratory abnormalities including lymphopenia, neutropenia, and anaemia. As described in Tables 1, 2 and 3 below, recommendations for temporary dose interruption or permanent discontinuation of treatment are made according to the severity of laboratory abnormalities (see section 4.4). It is recommended not to initiate dosing in patients with an absolute lymphocyte count (ALC) less than 750 cells/mm 3.

• Hypersensitivity to the tofacitinib or to any of the excipients listed in section 6.1
• Untreated pulmonary tuberculosis (active and latent) or untreated extra pulmonary tuberculosis, serious infections such as sepsis, or opportunistic infections (see section 4.4)
• Severe hepatic impairment (see section 4.2)
• Pregnancy and lactation (see section 4.6)
• Patients with treatment nau00efve / experienced HIV infections

XELJANZ 10 mg twice daily is contraindicated in patients who have one or more of the following conditions:

• Use of combined hormonal contraceptives or hormone replacement therapy
• Heart failure
• Previous venous thromboembolism, either deep venous thromboembolism or pulmonary embolism
• Inherited coagulation disorder
• Malignancy
• Patients undergoing major surgery

Combination with other therapies

XELJANZ 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 XELJANZ with MTX versus XELJANZ as monotherapy in RA clinical studies. The use of XELJANZ in combination with phosphodiesterase 4 inhibitors has not been studied in tofacitinib clinical studies.

Serious infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving XELJANZ. Rheumatoid arthritis patients taking corticosteroids may be predisposed to infection. XELJANZ should not be initiated in patients with active infections, including localised infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ 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 XELJANZ. 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 XELJANZ 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). 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 XELJANZ 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 XELJANZ. Patients with latent TB, who test positive, should be treated with standard antimycobacterial therapy before administering XELJANZ. Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ 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 anti-tuberculosis 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) were observed in clinical studies with XELJANZ. In patients treated with XELJANZ, the incidence of herpes zoster appears to be increased in:

• Patients with an ALC less than 1 000 cells/mm 3 (see section 4.2)
• Patients with long standing RA who have previously received two or more biological disease modifying antirheumatic drugs (DMARDs)
• Patients treated with 10 mg twice daily

The impact of XELJANZ on chronic viral hepatitis reactivation is unknown. Patients screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ.

Malignancy and lymphoproliferative disorder

The risks and benefits of XELJANZ treatment should be considered prior to initiating therapy in patients with current or a history of malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy. The possibility exists for XELJANZ to affect host defences against malignancies. Lymphomas have been observed in patients treated with XELJANZ. Patients with RA, particularly those with highly active disease may be at a higher risk (up to several-fold) than the general population for the development of lymphoma. The effect of XELJANZ on the development of lymphoma is uncertain. Other malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. The effect of XELJANZ on the development and course of malignancies is not known.

Non-melanoma skin cancer

NMSCs have been reported in patients treated with XELJANZ. The risk of NMSC may be higher in patients treated with XELJANZ 10 mg twice daily than in patients treated with 5 mg twice daily. Periodic skin examination is recommended for patients who are at increased risk for skin cancer (see Table 6 in section 4.8).

Pulmonary embolism

Pulmonary embolism (PE) has been observed in patients taking XELJANZ in clinical trials and post-marketing reports. XELJANZ 10 mg twice daily is contraindicated in patients who are at high risk for pulmonary embolism (see also section 4.3). Additional risk factors that should be considered in determining the patientu2019s risk for PE are older age, obesity, smoking status, and immobilisation.

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 XELJANZ in RA clinical trials and in the post-marketing setting although the role of Janus kinase (JAK) inhibition in these events is not known.

Gastrointestinal perforations

Events of gastrointestinal perforation have been reported in clinical trials although the role of JAK inhibition in these events is not known. XELJANZ 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.

Cardiovascular risk

RA and PsA patients have an increased risk for cardiovascular disorders. Patients treated with XELJANZ should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care.

Liver enzymes

Treatment with XELJANZ 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 XELJANZ treatment in patients with elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST), particularly when initiated in combination with potentially hepatotoxic medicines 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 XELJANZ should be interrupted until this diagnosis has been excluded.

Hypersensitivity

In post-marketing experience, cases of medicine hypersensitivity associated with XELJANZ administration have been reported. Allergic reactions included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, XELJANZ should be discontinued immediately.

Laboratory parameters

Lymphocytes

Treatment with XELJANZ was associated with an increased incidence of lymphopenia compared to placebo. Lymphocyte counts less than 750 cells/mm 3 were associated with an increased incidence of serious infections. It is not recommended to initiate or continue XELJANZ treatment in patients with a confirmed lymphocyte count less than 750 cells/mm 3. 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 XELJANZ was associated with an increased incidence of neutropenia (less than 2 000 cells/mm 3) compared to placebo. It is not recommended to initiate XELJANZ treatment in patients with an ANC less than 1 000 cells/mm 3. 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 XELJANZ has been associated with decreases in haemoglobin levels. It is not recommended to initiate XELJANZ treatment in patients with a haemoglobin value less than 9 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.

Potential for other medicines to influence the pharmacokinetics (PK) of tofacitinib.

Since tofacitinib is metabolised by CYP3A4, interaction with medicines that inhibit or induce CYP3A4 is likely. Tofacitinib exposure is increased when co-administered with potent inhibitors of CYP3A4 (e.g., ketoconazole) or when administration of one or more concomitant medicines results in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole) (see section 4.2). Tofacitinib exposure is decreased when co-administered with potent CYP inducers (e.g., rifampicin). Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to significantly alter the PK of XELJANZ. Co-administration 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. Co-administration of tofacitinib with potent CYP inducers (e.g., rifampicin) may result in a loss of or reduced clinical response (see Figure 1). Co-administration of potent inducers of CYP3A4 with tofacitinib is not recommended. Co-administration with ketoconazole and fluconazole increased tofacitinib Cmax, while tacrolimus, ciclosporin and rifampicin decreased tofacitinib Cmax. Concomitant administration with MTX 15 u2013 25 mg once weekly had no effect on the PK of tofacitinib in RA patients (see Figure 1).

Figure 1. Impact of other medicines on PK of tofacitinib.

Note: Reference group is administration of tofacitinib alone.

a XELJANZ dose should be reduced to 5 mg twice daily in patients receiving 10 mg twice daily. XELJANZ dose should be reduced to 5 mg once daily in patients receiving 5 mg twice daily (see section 4.2).

Potential for tofacitinib to influence the PK of other medicine

Co-administration of tofacitinib did not have an effect on the PK of oral contraceptives, levonorgestrel and ethinyl estradiol, in healthy female volunteers. In RA patients, co-administration 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.

Women of childbearing potential/contraception in females

Women of childbearing potential should be advised to use effective contraception during treatment with XELJANZ and for at least 4 weeks after the last dose.

Pregnancy

There are no adequate and well-controlled studies on the use of XELJANZ in pregnant women. XELJANZ has been shown to be teratogenic in rats and rabbits, and to affect parturition and peri/postnatal development (see section 5.3). As a precautionary measure, the use of XELJANZ during pregnancy is contraindicated (see section 4.3).

Breastfeeding

It is not known whether XELJANZ is secreted in human milk. A risk to the breastfed child cannot be excluded. XELJANZ was secreted in the milk of lactating rats (see section 5.3). As a precautionary measure, the use of XELJANZ during breastfeeding is contraindicated (see section 4.3).

Fertility

Formal studies of the potential effect on human fertility have not been conducted. XELJANZ impaired female fertility but not male fertility in rats (see section 5.3).

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

Summary of the safety profile

Rheumatoid arthritis

The most common serious adverse reactions were serious infections (see section 4.4). The most common serious infections reported with XELJANZ were pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, TB and other mycobacterial infections, cryptococcus, histoplasmosis, oesophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus, BK virus infections and listeriosis were reported with XELJANZ. Some patients have presented with disseminated rather than localised disease. Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis).

The most commonly reported adverse reactions during the first 3 months in controlled clinical trials were headache, upper respiratory tract infections, nasopharyngitis, diarrhoea, nausea and hypertension (see Tabulated list of adverse reactions). The proportion of patients who discontinued treatment due to adverse reactions during first 3 months of the double-blind, placebo or MTX controlled studies was 3,8 % for patients taking XELJANZ. The most common infections resulting in discontinuation of therapy were herpes zoster and pneumonia.

Psoriatic arthritis

Overall, the safety profile observed in patients with active PsA treated with XELJANZ was consistent with the safety profile observed in patients with RA treated with XELJANZ.

Ulcerative colitis

The most commonly reported adverse reactions in patients receiving XELJANZ 10 mg twice daily in the induction studies were headache, nasopharyngitis, nausea, and arthralgia. In the induction and maintenance studies, across XELJANZ and placebo treatment groups, the most common categories of serious adverse reactions were gastrointestinal disorders and infections, and the most common serious adverse reaction was worsening of UC.

Overall, the safety profile observed in patients with UC treated with XELJANZ was consistent with the safety profile of XELJANZ in the RA indication.

Tabulated list of adverse reactions

The ADRs listed in the table below are from clinical studies in patients with RA, PsA, and UC and are presented by System Organ Class (SOC) and frequency categories, defined using the following convention: very common (u2265 1/10), common (u2265 1/100 to < 1/10), uncommon (u2265 1/1 000 to < 1/100), rare (u2265 1/10 000 to < 1/1 000), very rare (< 1/10 000), or not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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 XELJANZ. 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.