XELJANZ 5 mg film-coated tablets
2. Qualitative and quantitative composition
Each film-coated tablet contains tofacitinib citrate, equivalent to 5 mg tofacitinib.
Excipient with known effect
Each tablet contains 59.44 mg lactose.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Film-coated tablet.
White, round tablet of 7.9 mm diameter, debossed “Pfizer” on one side and “JKI 5” on the reverse.
4. Clinical particulars
4.1 Therapeutic indications
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).
4.2 Posology and method of administration
Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of RA.
Posology
The recommended dose is 5 mg administered twice daily.
Dose adjustment
No dose adjustment is required when used in combination with methotrexate.
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 less than 750 cells/mm3.
Table 1: Low Absolute Lymphocyte Count
|
Low Absolute Lymphocyte Count (ALC) (see section 4.4)
|
|
Lab Value
(cells/mm3)
|
Recommendation
|
|
ALC greater than or equal to 750
|
Dose should be maintained.
|
|
ALC 500-750
|
For persistent (2 sequential values in this range on routine testing) decrease in this range, dosing should be interrupted until ALC is greater than 750.
When ALC is greater than 750, resume 5 mg twice daily.
|
|
ALC less than 500
|
If lab value confirmed by repeat testing within 7 days, dosing should be discontinued.
|
It is recommended not to initiate dosing in patients with an absolute neutrophil count (ANC) less than 1,000 cells/mm3.
Table 2: Low Absolute Neutrophil Count
|
Low Absolute Neutrophil Count (ANC) (see section 4.4)
|
|
Lab Value
(cells/mm3)
|
Recommendation
|
|
ANC greater than 1,000
|
Dose should be maintained.
|
|
ANC 500-1,000
|
For persistent (2 sequential values in this range on routine testing) decreases in this range, dosing should be interrupted until ANC is greater than 1,000.
When ANC is greater than 1,000, resume 5 mg twice daily.
|
|
ANC less than 500
|
If lab value confirmed by repeat testing within 7 days, dosing should be discontinued.
|
It is recommended not to initiate dosing in patients with haemoglobin less than 9 g/dL.
Table 3: Low Haemoglobin Value
|
Low Haemoglobin Value (Section 4.4)
|
|
Lab Value
(g/dL)
|
Recommendation
|
|
Less than or equal to 2 g/dL decrease and greater than or equal to 9.0 g/dL
|
Dose should be maintained.
|
|
Greater than 2 g/dL decrease or less than 8.0 g/dL
(Confirmed by repeat testing)
|
Dosing should be interrupted until haemoglobin values have normalised.
|
Special populations
Renal impairment
No dose adjustment is required in patients with mild (creatinine clearance 50-80 mL/min) or moderate (creatinine clearance 30-49 mL/min) renal impairment. XELJANZ dose should be reduced to 5 mg once daily in patients with severe (creatinine clearance <30 mL/min) renal impairment (see sections 4.4 and 5.2). Patients with severe renal impairment should remain on a reduced dose of 5 mg once daily even after haemodialysis.
Hepatic impairment
No dose adjustment is required in patients with mild hepatic impairment (Child Pugh A). The dose should be reduced to 5 mg once daily in patients with moderate hepatic impairment (Child Pugh B) (see sections 4.4 and 5.2). XELJANZ should not be used in patients with severe hepatic impairment (Child Pugh C) (see section 4.3).
Elderly
No dose adjustment is required in patients aged 65 years and older. There are limited data in patients aged 75 years and older.
For elderly patients who have difficulties swallowing, XELJANZ 5 mg tablets may be crushed and taken with water.
Paediatric population
The safety and efficacy of XELJANZ in children aged from 2 years to less than 18 years of age have not yet been established. No data are available.
There is no relevant use of XELJANZ in patients aged less than 2 years for the indication of juvenile idiopathic arthritis.
Drug-drug interactions
XELJANZ dose should be reduced to 5 mg once daily in patients receiving potent inhibitors of cytochrome (CYP) P450 3A4 (e.g., ketoconazole). XELJANZ dosage should be reduced to 5 mg once daily in patients receiving one or more concomitant medicinal products that result in both moderate inhibition of CYP3A4 as well as potent inhibition of CYP2C19 (e.g., fluconazole) (see sections 4.4 and 4.5).
Method of administration
Oral use.
XELJANZ is given orally with or without food.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Active tuberculosis (TB), 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).
4.4 Special warnings and precautions for use
Combination with other RA therapies
XELJANZ has not been studied and its use should be avoided in RA patients in combination with biological disease-modifying antirheumatic drugs (DMARDs) such as tumour necrosis factor (TNF) antagonists, interleukin (IL)-1R antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies, selective co-stimulation modulators and potent immunosuppressants such as azathioprine, ciclosporine and tacrolimus because of the possibility of increased immunosuppression and increased risk of infection.
There is a higher incidence of adverse events for the combination of XELJANZ with MTX versus XELJANZ as monotherapy.
Serious infections
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in RA patients receiving XELJANZ. The risk of opportunistic infections is higher in Asian geographic regions (see section 4.8).
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 eva luated 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.
Antituberculosis 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 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) were observed in clinical studies with XELJANZ. In patients treated with XELJANZ, the incidence of herpes zoster appears to be increased in Japanese and Korean patients, as well as in those patients with long standing RA who have previously received two or more biological DMARDs. Patients with an absolute lymphocyte count (ALC) less than 1,000 cells/mm3 may have an increased risk of herpes zoster (see section 4.2).
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. Periodic skin examination is recommended for patients who are at increased risk for skin cancer (see Table 4 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 XELJANZ in clinical trials 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 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 eva luated promptly for early identification of gastrointestinal perforation.
Cardiovascular risk
RA patients have an increased risk for cardiovascular disorders and 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 medicinal products such as methotrexate. 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.
Laboratory parameters
Lymphocytes
Treatment with XELJANZ 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 XELJANZ 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 XELJANZ was associated with an increased incidence of neutropenia (less than 2,000 cells/mm3) compared to placebo. It is not recommended to initiate XELJANZ treatment in patients with an ANC less than 1,000 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 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.
Lipid monitoring
Treatment with XELJANZ 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 XELJANZ therapy. Patients should be managed according to clinical guidelines for the management of hyperlipidaemia. Increases in total and LDL cholesterol associated with XELJANZ may be decreased to pretreatment levels with statin therapy.
Vaccinations
Prior to initiating XELJANZ, 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 XELJANZ. The decision to use live vaccines prior to XELJANZ treatment should take into account the degree of immunocompetence of 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 XELJANZ 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 XELJANZ.
Elderly
The elderly population in general has an increased risk of adverse events, of increased severity; caution should be used when treating the elderly, see section 4.8.
Lactose
XELJANZ contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
Potential for other medicinal products to influence the PK of XELJANZ
Since XELJANZ is metabolised by CYP3A4, interaction with medicinal products that inhibit or induce CYP3A4 is likely. XELJANZ exposure is increased when coadministered with potent inhibitors of CYP3A4 (e.g., ketoconazole) or when administration of one or more concomitant medications results in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole) (see section 4.2).
XELJANZ 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 XELJANZ.
Coadministration with ketoconazole (strong CYP3A4 inhibitor), fluconazole (moderate CYP3A4 and potent CYP2C19 inhibitor), tacrolimus (mild CYP3A4 inhibitor) and ciclosporine (moderate CYP3A4 inhibitor) increased XELJANZ AUC, while rifampicin (potent CYP inducer) decreased XELJANZ AUC. Coadministration of XELJANZ with potent CYP inducers (e.g., rifampicin) may result in a loss of or reduced clinical response (see Figure 1). Coadministration of potent inducers of CYP3A4 with XELJANZ is not recommended. Coadministration with ketoconazole and fluconazole increased XELJANZ Cmax, while tacrolimus, ciclosporine and rifampicin decreased XELJANZ Cmax. Concomitant administration with MTX 15-25 mg once weekly had no effect on the PK of XELJANZ in RA patients (see Figure 1).
Figure 1. Impact of Other Drugs on PK of XELJANZ
Note: Reference group is administration of XELJANZ alone
Potential for XELJANZ to influence the PK of other medicinal products
In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations exceeding 160 and 268 times the respective steady state total and free Cmax, respectively, of a 5 mg twice daily dose in RA patients. These in vitro results were confirmed by a human drug interaction study showing no changes in the PK of midazolam, a highly sensitive CYP3A4 substrate, when coadministered with XELJANZ.
In vitro studies indicate that tofacitinib does not significantly inhibit the activity of the major human drug metabolizing uridine 5'-diphospho-glucuronosyltransferases (UGTs), [UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7] at concentrations exceeding 535 and 893 times the steady state total and free Cmax of a 5 mg twice daily dose in RA patients.
In vitro data indicate that the potential for XELJANZ to inhibit transporters such as P-glycoprotein, organic anion transporting polypeptide, organic anionic or cationic transporters at therapeutic concentrations is also low.
Coadministration of XELJANZ did not have an effect on the PK of oral contraceptives, levonorgestrel and ethinyl estradiol, in healthy female volunteers.
In RA patients, coadministration of XELJANZ 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.
Coadministration of XELJANZ did not have an effect on the PK of metformin, indicating that XELJANZ does not interfere with the organic cationic transporter (OCT2) in healthy volunteers.
4.6 Fertility, pregnancy and lactation
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 (see section 5.3).
As a precautionary measure, the use of XELJANZ during pregnancy is contraindicated (see section 4.3).
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.
Breast-feeding
It is not known whether XELJANZ is secreted in human milk. A risk to the breast-fed child cannot be excluded. Tofacitinib was secreted in the milk of lactating rats (see section 5.3). As a precautionary measure, the use of XELJANZ during breast-feeding is contraindicated (see section 4.3).
Fertility
Formal studies of the potential effect on human fertility have not been conducted. Tofacitinib impaired female fertility but not male fertility in rats (see section 5.3).
4.7 Effects on ability to drive and use machines
XELJANZ has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
The safety data includes 6 double-blind, controlled, multicentre studies of varying durations from 6-24 months (Studies I-VI, see section 5.1). A total of 6194 patients (Phases 1, 2, 3 and long-term extension studies) were treated with any dose of XELJANZ, with a mean duration of 3.13 years, with 19405.8 patient-years of accumulated total drug exposure based on up to 8 years of continous exposure to XELJANZ.
All patients in these studies had moderate to severe RA. The study XELJANZ population had a mean age of 52.1 years and 83.2% were female.
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 Table 4, Adverse Drug Reactions (ADRs) based on all study durations).
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.
Tabulated list of adverse reactions
The ADRs listed in the table below are presented by System Organ Class (SOC) and frequency categories, defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) or rare (≥1/10,000 to <1/1,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 4: Adverse Drug Reactions
|
System Organ Class
|
Very Common
≥1/10
|
Common
≥1/100 to <1/10
|
Uncommon
≥1/1,000 to <1/100
|
Rare
≥1/10,000 to <1/1,000
|
|
Infections and infestations
|
Nasopharyngitis
|
Pneumonia
Influenza
Herpes zoster
Urinary tract infection
Sinusitis
Bronchitis
Pharyngitis
|
Sepsis
Tuberculosis
Pneumonia pneumococcal
Pneumonia bacterial
Diverticulitis
Pyelonephritis
Cellulitis
Arthritis bacterial
Herpes simplex
Gastroenteritis viral
Viral infection
|
TB of central nervous system
Meningitis cryptococcal
Urosepsis
Disseminated TB
Necrotizing fasciitis
Bacteraemia
Staphylococcal bacteraemia
Pneumocystis jirovecii pneumonia
Encephalitis
Atypical mycobacterial infection
Mycobacterium avium complex infection
Cytomegalovirus infection
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
|
|
|
Non-melanoma skin cancers
|
|
|
Blood and lymphatic system disorders
|
|
Leukopenia
Anaemia
|
Lymphopenia
Neutropenia
|
|
|
Metabolism and nutrition disorders
|
|
Dyslipidaemia
Hyperlipidaemia
|
Dehydration
|
|
|
Psychiatric disorders
|
|
Insomnia
|
|
|
|
Nervous system disorders
|
|
Headache
|
Paraesthesia
|
|
|
Vascular disorders
|
|
Hypertension
|
|
|
|
Respiratory, thoracic and mediastinal disorders
|
|
Dyspnoea
Cough
|
Sinus congestion
|
|
|
Gastrointestinal disorders
|
|
Abdominal pain
Vomiting
Diarrhoea
Nausea
Gastritis
Dyspepsia
|
|
|
|
Hepatobiliary disorders
|
|
|
Hepatic steatosis
|
|
|
Skin and subcutaneous tissue disorders
|
|
Rash
|
Erythema
Pruritus
|
|
|
Musculoskeletal and connective tissue disorders
|
|
Musculoskeletal pain
Arthralgia
|
Joint swelling
Tendonitis
|
|
|
General disorders and administration site conditions
|
|
Pyrexia
Oedema peripheral
Fatigue
|
|
|
|
Investigations
|
|
Hepatic enzyme increased
Blood cholesterol increased
Weight increased
Blood creatine phosphokinase increased
|
Transaminases increased
Liver function test abnormal
Gamma glutamyl-transferase increased
Blood creatinine increased
Low density lipoprotein increased
|
|
|
Injury, poisoning and procedural complications
|
|
|
Ligament sprain
Muscle strain
|
|
Description of selected adverse reactions
Overall infections
In controlled Phase 3 clinical studies, the rates of infections over 0-3 months in the 5 mg twice daily (total 616 patients) and 10 mg twice daily (total 642 patients) XELJANZ monotherapy groups were 16.2% (100 patients) and 17.9% (115 patients), respectively, compared to 18.9% (23 patients) in the placebo group (total 122 patients). In controlled Phase 3 clinical studies with background DMARDs, the rates of infections over 0-3 months in the 5 mg twice daily (total 973 patients) and 10 mg twice daily (total 969 patients) XELJANZ plus DMARD group were 21.3% (207 patients) and 21.8% (211 patients), respectively, compared to 18.4% (103 patients) in the placebo plus DMARD group (total 559 patients).
The most commonly reported infections were upper respiratory tract infections and nasopharyngitis (3.7% and 3.2%, respectively).
The overall incidence rate of infections with XELJANZ in the long-term safety all exposure population (total 4867 patients) was 46.1 patients with events per 100 patient-years (43.8 and 47.2 patients with events for 5 mg and 10 mg twice daily, respectively). For patients (total 1750) on monotherapy, the rates were 48.9 and 41.9 patients with events per 100 patient-years for 5 mg and 10 mg twice daily, respectively. For patients (total 3117) on background DMARDs, the rates were 41.0 and 50.3 patients with events per 100 patient-years for 5 mg and 10 mg twice daily, respectively.
Serious infections
In the 6-month and 24-month, controlled clinical studies, the rate of serious infections in the 5 mg twice daily XELJANZ monotherapy group was 1.7 patients with events per 100 patient-years. In the 10 mg twice daily XELJANZ monotherapy group the rate was 1.6 patients with events per 100 patient-years, the rate was 0 events per 100 patient-years for the placebo group, and the rate was 1.9 patients with events per 100 patient-years for the MTX group.
In studies of 6-, 12-, or 24-month duration, the rates of serious infections in the 5 mg twice daily and 10 mg twice daily XELJANZ plus DMARD groups were 3.6 and 3.4 patients with events per 100 patient-years, respectively, compared to 1.7 patients with events per 100 patient-years in the placebo plus DMARD group.
In the long-term safety all exposure population, the overall rates of serious infections were 2.4 and 3.0 patients with events per 100 patient-years for 5 mg and 10 mg twice daily XELJANZ groups, respectively. The most common serious infections included pneumonia, herpes zoster, urinary tract infection, cellulitis, gastroenteritis and diverticulitis. Cases of opportunistic infections have been reported (see section 4.4).
Serious infections in the elderly
Of the 4271 patients who enrolled in Studies I-VI (see section 5.1), a total of 608 RA patients were 65 years of age and older, including 85 patients 75 years and older. The frequency of serious infection among XELJANZ-treated patients 65 years of age and older was higher than those under the age of 65 (4.8 per 100 patient-years vs. 2.4 per 100 patient-years, respectively). As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly (see section 4.4).
Viral reactivation
In XELJANZ clinical trials, Japanese and Korean patients appeared to have a higher rate of herpes zoster than that observed in other populations, as do patients with long standing RA who have previously received two or more biological DMARDs. Patients with an ALC less than 1,000 cells/mm3 may have an increased risk of herpes zoster (see section 4.4).
Laboratory tests
Lymphocytes
In the controlled clinical studies, confirmed decreases in ALC below 500 cells/mm3 occurred in 0.3% of patients and for ALC between 500 and 750 cells/mm3 in 1.9% of patients for the 5 mg twice daily and 10 mg twice daily doses combined.
In the long-term safety population, confirmed decreases in ALC below 500 cells/mm3 occurred in 1.3% of patients and for ALC between 500 and 750 cells/mm3 in 8.4% of patients for the 5 mg twice daily and 10 mg twice daily doses combined.
Confirmed ALC less than 750 cells/mm3 were associated with an increased incidence of serious infections (see section 4.4).
Neutrophils
In the controlled clinical studies, confirmed decreases in ANC below 1,000 cells/mm3 occurred in 0.08% of patients for the 5 mg twice daily and 10 mg twice daily doses combined. There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group. There was no clear relationship between neutropenia and the occurrence of serious infections.
In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the controlled clinical studies (see section 4.4).
Liver enzyme tests
Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were uncommonly observed. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalisation of liver enzymes.
In the controlled portion of the Phase 3 monotherapy study (0-3 months), (Study I, see section 5.1), ALT elevations greater than 3x ULN were observed in 1.65%, 0.41%, and 0% of patients receiving placebo, XELJANZ 5 mg and 10 mg twice daily, respectively. In this study, AST elevations greater than 3x ULN were observed in 1.65%, 0.41% and 0% of patients receiving placebo, XELJANZ 5 mg and 10 mg twice daily, respectively.
In the Phase 3 monotherapy study (0-24 months) (Study VI, see section 5.1), ALT elevations greater than 3x ULN were observed in 7.1%, 3.0%, and 3.0% of patients receiving MTX, XELJANZ 5 mg and 10 mg twice daily, respectively. In this study, AST elevations greater than 3x ULN were observed in 3.3%, 1.6% and 1.5% of patients receiving MTX, XELJANZ 5 mg and 10 mg twice daily, respectively.
In the controlled portion of the Phase 3 studies on background DMARDs (0-3 months), (Study II-V, see section 5.1), ALT elevations greater than 3x ULN were observed in 0.9%, 1.24% and 1.14% of patients receiving placebo, XELJANZ 5 mg and 10 mg twice daily, respectively. In these studies, AST elevations greater than 3x ULN were observed in 0.72%, 0.5% and 0.31% of patients receiving placebo, XELJANZ 5 mg and 10 mg twice daily, respectively.
In the long-term extension studies, on monotherapy, ALT elevations greater than 3x ULN were observed in 1.1% and 1.4% of patients receiving XELJANZ 5 mg and 10 mg twice daily, respectively. AST elevations greater than 3x ULN were observed in <1.0% in both the tofacitinib 5 mg and 10 mg twice daily groups.
In the long-term extension studies, on background DMARDs, ALT elevations greater than 3x ULN were observed in 1.8% and 1.6% of patients receiving XELJANZ 5 mg and 10 mg twice daily, respectively. AST elevations greater than 3x ULN were observed in <1.0% in both the XELJANZ 5 mg and 10 mg twice daily groups.
Lipids
Elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were first assessed at one month following initiation of XELJANZ in the controlled double-blind clinical trials of RA. Increases were observed at this time point and remained stable thereafter.
Changes in lipid parameters from baseline through the end of the study (6-24 months) in the controlled clinical studies in RA are summarised below:
• Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 20% in the XELJANZ 10 mg twice daily arm at Month 12, and increased by 16% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm at Month 24.
• Mean HDL cholesterol increased by 17% in the XELJANZ 5 mg twice daily arm and 18% in the XELJANZ 10 mg twice daily arm at Month 12, and increased by 19% in the XELJANZ 5 mg twice daily arm and 20% in the XELJANZ 10 mg twice daily arm at Month 24.
Upon withdrawal of XELJANZ treatment, lipid levels returned to baseline.
Mean LDL cholesterol/HDL cholesterol ratios and Apolipoprotein B (ApoB)/ApoA1 ratios were essentially unchanged in XELJANZ-treated patients.
In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.
In the long-term safety populations, elevations in the lipid parameters remained consistent with what was seen in the controlled clinical studies.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
United Kingdom
Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
Ireland
Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.
4.9 Overdose
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.
5. Pharmacological properties
5.1 Pharmacodynamic properties
