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XELJANZ / XELJANZ XR (tofacitinib)

Health Professional Information

SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength

Clinically Relevant Nonmedicinal Ingredients

Oral

Tofacitinib tablets / 5 mg tofacitinib and 10 mg (as tofacitinib citrate)

Tofacitinib extended-release tablets / 11 mg tofacitinib (as tofacitinib citrate)

For a complete listing see Dosage Forms, Composition and Packaging section.

Indications And Clinical Use

Rheumatoid Arthritis

XELJANZ/XELJANZ XR (tofacitinib ), in combination with methotrexate (MTX), is indicated for reducing the signs and symptoms of rheumatoid arthritis (RA ,) in adult patients with moderately to severely active RA who have had an inadequate response to MTX.

In cases of intolerance to MTX, physicians may consider the use of XELJANZ/XELJANZ XR (tofacitinib) as monotherapy.

Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biological disease-modifying anti-rheumatic drugs (bDMARDs) or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Psoriatic Arthritis

XELJANZ (tofacitinib ), in combination with methotrexate (MTX) or another conventional synthetic disease-modifying antirheumatic drug (DMARD), is indicated for reducing the signs and symptoms of psoriatic arthritis (PsA) in adult patients with active PsA when the response to previous DMARD therapy has been inadequate.

Limitations of Use: Use of XELJANZ in combination with biological disease-modifying anti-rheumatic drugs (bDMARDs) or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Ulcerative Colitis

XELJANZ (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) with an inadequate response, loss of response or intolerance to either conventional UC therapy or a TNFα inhibitor.

Limitations of Use: Use of XELJANZ in combination with biological UC therapies or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Pediatrics (<18 years of age)

The safety and effectiveness of XELJANZ/XELJANZ XR in pediatric patients have not been established. Therefore XELJANZ/XELJANZ XR should not be used in this patient population (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY ).

Geriatrics (>65 years of age)

The frequency of serious infection among XELJANZ treated subjects 65 years of age and older was higher than among those under the age of 65. Therefore, caution should be used when treating the elderly with XELJANZ/XELJANZ XR (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY ).

Contraindications

XELJANZ/XELJANZ XR (tofacitinib) is contraindicated:

  • In patients with known hypersensitivity to tofacitinib or any of its components. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.
  • In patients with severe hepatic impairment.
  • During pregnancy and breastfeeding.

Warnings And Precautions

WARNING: RISK OF SERIOUS INFECTIONS

Patients treated with XELJANZ/XELJANZ XR (tofacitinib) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ/XELJANZ XR until the infection is controlled.

Reported infections include:

  • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ/XELJANZ XR use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ/XELJANZ XR use.
  • Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized disease.
  • Bacterial, viral, and other infections due to opportunistic pathogens.

Treatment with XELJANZ/XELJANZ XR should not be initiated in patients with active infections including chronic or localized infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy (see ADVERSE REACTIONS).

MALIGNANCIES
Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications (see WARNINGS AND PRECAUTIONS).

THROMBOSIS
Rheumatoid arthritis patients with at least one cardiovascular (CV) risk factor had a higher rate of all-cause mortalityand thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, with XELJANZ 10 mg twice daily compared to those treated with 5 mg twice daily or TNF blockers. Many of these adverse events were serious and some resulted in death. Avoid XELJANZ/XELJANZ XR in patients at risk of thrombosis. Discontinue XELJANZ/XELJANZ XR and promptly evaluate patients with symptoms of thrombosis (see WARNINGS AND PRECAUTIONS, Cardiovascular).

For patients with ulcerative colitis (UC), use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response (see DOSAGE AND ADMINISTRATION).

General

Specific to XELJANZ XR :

As with any other non-deformable material, caution should be used when administering XELJANZ XR 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 drugs utilizing a non-deformable extended release formulation.

Cardiovascular

Heart Rate Decrease and PR Interval Prolongation: XELJANZ caused a decrease in heart rate and a prolongation of the PR interval (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, and ADVERSE REACTIONS). Caution should be observed in patients with a low heart rate at baseline (< 60 beats per minute), a history of syncope or arrhythmia, sick sinus syndrome, sinoatrial block, atrioventricular (AV) block, ischemic heart disease, or congestive heart failure. Concomitant medications that result in a decrease in heart rate and/or PR interval prolongation should be avoided to the extent possible during treatment with XELJANZ/XELJANZ XR (see DRUG INTERACTIONS).

Thrombosis
Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, was observed at an increased incidence in patients treated with XELJANZ in a large, ongoing post-marketing study. Rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular (CV) risk factor treated with XELJANZ 10 mg twice a day had a higher rate of all-cause mortality, including sudden CV death, and thrombosis compared to those treated with XELJANZ 5 mg given twice daily or TNF blockers. Many of these events were serious and some resulted in death (see SERIOUS WARNINGS AND PRECAUTIONS BOX).

In a long-term extension study in patients with ulcerative colitis (UC), four cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with advanced cancer.

A dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended for the treatment of RA or psoriatic arthritis (PsA) (see DOSAGE AND ADMINISTRATION).

For the treatment of UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response (see DOSAGE AND ADMINISTRATION).

Avoid XELJANZ/XELJANZ XR in patients that may be at increased risk of thrombosis. Discontinue XELJANZ/XELJANZ XR and promptly evaluate patients with symptoms of thrombosis.”

Gastrointestinal Perforations

Events of gastrointestinal perforation have been reported with XELJANZ in rheumatoid arthritis patients, although the role of JAK inhibition in these events is not known. Many patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids. The relative contribution of these concomitant medications versus XELJANZ to the development of gastrointestinal perforations is not known.

There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with ulcerative colitis (UC), and many of them were receiving background corticosteroids.

XELJANZ/XELJANZ XR should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., use of concomitant NSAIDs and/or corticosteroids, patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation (see ADVERSE REACTIONS).

Hepatic/Biliary/Pancreatic

XELJANZ/XELJANZ XR is contraindicated in patients with severe hepatic impairment.

Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo (see WARNINGS AND PRECAUTIONS – Laboratory parameters and ADVERSE REACTIONS).

Evaluate liver enzymes before initiating XELJANZ and thereafter according to routine patient management (see WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests). Prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury (DILI). If increases in ALT (alanine transaminase) or AST (aspartate transaminase) are observed and DILI is suspected, the administration of XELJANZ/XELJANZ XR should be interrupted until the diagnosis is excluded.

Most of the liver enzyme abnormalities in RA and PsA patients occurred in studies with background DMARD (primarily methotrexate) therapy.

One case of DILI was reported in a RA patient treated with tofacitinib 10 mg BID for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN associated concurrently with total bilirubin value greater than 2x ULN, which required hospitalization and a liver biopsy.

In UC patients, XELJANZ treatment with 5 and 10 mg BID was also associated with an increased incidence of liver enzyme elevation compared to placebo, with a trend for higher incidence with the 10 mg BID as compared to the 5 mg BID (see WARNINGS AND PRECAUTIONS – Laboratory parameters, and ADVERSE REACTIONS).

The impact of XELJANZ/XELJANZ XR on chronic viral hepatitis reactivation is unknown. XELJANZ/XELJANZ XR has not been studied in patients with positive hepatitis B virus or hepatitis C virus serology, and should therefore not be used in these populations.

XELJANZ/XELJANZ XR has not been studied in patients with severe hepatic impairment, and should not be used in these patients. XELJANZ XR should not be used in patients with moderate to severe hepatic impairment Dose adjustment of XELJANZ is recommended for patients with moderate hepatic impairment (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY).

Immune

Hypersensitivity Reactions: Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients treated with XELJANZ/XELJANZ XR. Some events were serious. If a hypersensitivity reaction is suspected, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction (see CONTRAINDICATIONS and ADVERSE REACTIONS).

Immunocompromised Patients: XELJANZ/XELJANZ XR can increase the risk of infections and immunosuppression when co-administered with potent immunosuppressants such as cyclosporine, azathioprine and tacrolimus. Combined use of XELJANZ/XELJANZ XR with potent immunosuppressive drugs has not been studied and is not recommended (see DRUG INTERACTIONS).

Immunizations

No data are available on the secondary transmission of infection by live vaccines to patients receiving XELJANZ/XELJANZ XR. It is recommended that all patients be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating XELJANZ/XELJANZ XR therapy and that live vaccines not be given concurrently with XELJANZ/XELJANZ XR. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunomodulatory agents.

In patients being considered for XELJANZ/XELJANZ XR therapy, live zoster vaccine should only be administered to patients with a known history of chickenpox or those that are seropositive for varicella zoster virus. Vaccination should occur at least 2 weeks but preferably 4 weeks before initiating immunomodulatory agents such as XELJANZ/XELJANZ XR.

In a clinical trial, a varicella naïve patient treated with XELJANZ and methotrexate developed disseminated infection with the vaccine strain of the varicella zoster virus 16 days after vaccination. A satisfactory immune response to the vaccine was developed 6 weeks post-vaccination.

In a randomized, double-blind, placebo-controlled study in 200 adult RA patients treated with XELJANZ 10 mg BID or placebo, humoral responses to concomitant pneumococcal and influenza vaccines were assessed. The percentages of patients achieving a satisfactory humoral response to pneumococcal vaccines were lower for the XELJANZ group than the placebo group. This effect was more pronounced for patients receiving background methotrexate. A total of 31.6% XELJANZ-treated subjects and 61.8% placebo-treated subjects who received background methotrexate achieved a ≥ 2-fold increase in antibody concentrations to ≥ 6 of 12 pneumococcal antigens.

In the same study, the proportion of patients achieving protective antibody levels to the influenza antigens was lower in the XELJANZ group (64.9%) compared to the placebo group (92.7%) in patients receiving background methotrexate. However, the difference in humoral response to the influenza vaccine was small with 50.9% of patients in the XELJANZ group and 58.2% in the placebo group with background methotrexate achieving a ≥ 4-fold increase in antibody titers to ≥ 2 of 3 influenza antigens.

Infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving immunomodulatory agents, including biologic DMARDs and XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcus, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infections, and listeriosis were reported with XELJANZ (see ADVERSE REACTIONS). Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids. Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis).

Patients treated with XELJANZ 10 mg BID are at higher risk of serious infections, and herpes zoster infections compared to those treated with 5 mg BID. The incidence rate per 100 person-years (PYs) for herpes zoster opportunistic infections in the UC 52 week maintenance study was higher in patients treated with XELJANZ 10 mg BID (6.64) as compared to XELJANZ 5 mg BID (2.05) or placebo (0.97).(see ADVERSE REACTIONS)

XELJANZ/XELJANZ XR should not be administered in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ/XELJANZ XR in patients:

  • with chronic or recurrent infections,
  • who have been exposed to tuberculosis,
  • with a history of a serious or an opportunistic infection,
  • who have resided or travelled in areas of endemic tuberculosis or endemic mycoses; or
  • with 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/XELJANZ XR. XELJANZ/XELJANZ XR 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/XELJANZ XR 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. 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 RA patients treated with XELJANZ in clinical trials and in the post-marketing setting.

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.

For discontinuation and monitoring criteria for lymphopenia see WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests.

Treatment with XELJANZ was associated with increased rates of infections in Asian patients compared to other races (see WARNINGS AND PRECAUTIONS – Special Populations and ADVERSE REACTIONS). XELJANZ/XELJANZ XR should be used with caution in this population.

Tuberculosis
Patients should be evaluated and tested for latent or active infection prior to administration of XELJANZ/XELJANZ XR and periodically (e.g. annually) while taking XELJANZ/XELJANZ XR.

Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Antituberculosis therapy should also be considered prior to administration of XELJANZ/XELJANZ XR in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but have risk factors for tuberculosis infection.

Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ/XELJANZ XR.

Viral Reactivation
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) were observed in clinical studies with XELJANZ. Post-marketing cases of hepatitis B reactivation have been reported in patients treated with XELJANZ (see ADVERSE REACTIONS). The impact of XELJANZ/XELJANZ XR on chronic viral hepatitis reactivation is unknown. Patients who 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/XELJANZ XR.

Laboratory Parameters

Lymphopenia: Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.

Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, XELJANZ/XELJANZ XR should be discontinued.

For recommended monitoring and dose modifications based on lymphocyte counts see WARNINGS AND PRECAUTIONSMonitoring and Laboratory Tests and DOSAGE AND ADMINISTRATION.

Neutropenia: Treatment with XELJANZ was associated with an increased incidence of neutropenia (<2000/mm3) compared to placebo.

Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low neutrophil count (i.e., ANC (absolute neutrophil count) <1000/mm3). For patients who develop a persistent ANC of 500-1000/mm3, interrupt dosing until ANC is >1000 cells/mm3. In patients who develop an absolute neutrophil count <500 cells/mm3, discontinue treatment. For recommended monitoring and dose modification based on ANC, see WARNINGS AND PRECAUTIONSMonitoring and Laboratory Tests and DOSAGE AND ADMINISTRATION.

Anemia: Treatment with tofacitinib has been associated with decreases in hemoglobin levels. Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with low hemoglobin values (i.e., <9 g/dL). Treatment with XELJANZ/XELJANZ XR should be interrupted in patients who develop hemoglobin levels <8 g/dL or whose hemoglobin level drops >2 g/dL on treatment.

For recommended monitoring and dose modification based on hemoglobin results, see WARNINGS AND PRECAUTIONSMonitoring and Laboratory Tests and DOSAGE AND ADMINISTRATION.

Liver Enzyme Elevations: Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo (see WARNINGS AND PRECAUTIONS – Hepatic/Biliary/Pancreatic, and ADVERSE REACTIONS). Most of these abnormalities in RA and PsA patients occurred in studies with background DMARD (primarily methotrexate) therapy.

In UC patients, XELJANZ treatment with 5 and 10 mg BID was also associated with an increased incidence of liver enzyme elevation compared to placebo, with a trend for higher incidence with the 10 mg BID dose as compared to the 5 mg BID dose.

One patient treated with XELJANZ 10 mg BID in the maintenance UC study experienced an increase in liver enzymes which decreased upon discontinuation of treatment. The case was adjudicated as possible DILI, while noting ultrasound findings of fatty liver.

Routine monitoring of liver enzymes and prompt investigation of the cause of liver enzyme elevations is recommended to identify potential cases of DILI (see WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests).

Lipid Elevations: Treatment with XELJANZ was associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol (see ADVERSE REACTIONS).

Maximum effects were generally observed within 6 weeks. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

Assessment of lipid parameters should be performed at baseline and approximately 4-8 weeks following initiation of XELJANZ/XELJANZ XR therapy, and every 6 months thereafter (see WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests). Patients should be managed according to local clinical guidelines for the management of hyperlipidemia.

Malignancies and Lymphoproliferative Disorder

Malignancies have been observed in patients treated with XELJANZ. In patients treated with XELJANZ, malignancies were observed in clinical studies and the post marketing setting including but not limited to: lymphomas, lung cancer, breast cancer, colorectal cancer, gastric cancer, melanoma, prostate cancer, pancreatic cancer and renal cell carcinoma.

Consider the risks and benefits of XELJANZ/XELJANZ XR treatment 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/XELJANZ XR in patients who develop a malignancy. Recommendations for non-melanoma skin cancer are presented below.

Rheumatoid Arthritis

In the 5 controlled clinical studies, 5- malignancies (excluding non-melanoma skin cancers (NMSC)) were diagnosed in patients receiving XELJANZ 5 mg BID, and 8 malignancies (excluding NMSC) were diagnosed in patients receiving XELJANZ 10 mg BID, compared to 0 malignancies (excluding NMSC) in patients in the placebo/placebo plus DMARD group during the first 12 months. Lymphomas and solid cancers have also been observed in the long-term extension study in patients treated with XELJANZ (see ADVERSE REACTIONS). Patients with RA particularly those with highly active disease, may be at a higher risk (several fold) than the general population for the development of lymphoma.

In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

Psoriatic Arthritis

In the 2 controlled PsA clinical trials, there were 3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus csDMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus csDMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus csDMARD group (12 months exposure). Malignancies have also been observed in the long‑term extension study in PsA patients treated with XELJANZ.

Ulcerative Colitis

In the 4 controlled clinical studies for ulcerative colitis (up to 52 week treatment), no malignancies (excluding NMSC) were reported with XELJANZ. In the long-term extension open-label study, malignancies (excluding NMSC) have been observed in patients treated with XELJANZ 10 mg BID, including solid cancers and lymphoma.

Non Melanoma Skin Cancer

Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ.
NMSC is a dose related adverse reaction, with a greater risk in patients treated with 10 mg BID of XELJANZ than in patients treated with 5 mg BID. Periodic skin examination is recommended.

In the UC 52 week maintenance study, NMSC was reported in 3 patients (1.5%) treated with 10 mg BID, as compared with no reported events in patients treated with 5 mg BID and 1 patient (0.5%) treated with placebo. In the long-term open label extension study, NMSC was reported in 6 patients in the 10 mg BID group and 2 patients in the 5 mg BID group.

Monitoring and Laboratory Tests

Lipid tests should be performed at baseline, approximately 4-8 weeks after initiation with XELJANZ/XELJANZ XR and every 6 months thereafter.

Liver enzymes tests are recommended. If DILI is suspected, the administration of XELJANZ/XELJANZ XR should be interrupted until this diagnosis has been excluded.

Assessment of renal function is recommended prior to initiation of XELJANZ/XELJANZ XR (see DOSAGE AND ADMINISTRATION).

Lymphocyte, neutrophil and hemoglobin tests should be performed at baseline, approximately 4-8 weeks after initiation with XELJANZ/XELJANZ XR treatment, and every 3 months thereafter (see DOSAGE AND ADMINISTRATION for recommended dose adjustment based on these laboratory tests).

Vital signs: Patients should be monitored for pulse rate and blood pressure at baseline and periodically during treatment with XELJANZ/XELJANZ XR (see WARNINGS AND PRECAUTIONSCardiovascular, ADVERSE REACTIONS, and DRUG INTERACTIONS).

Musculoskeletal

Treatment with XELJANZ was associated with increases in creatine kinase (CK). Maximum effects were generally observed within 6 months. Rhabdomyolysis was reported in one patient treated with XELJANZ. Creatine kinase levels should be checked in patients with symptoms of muscle weakness and/or muscle pain to evaluate for evidence of rhabdomyolysis. Increases in CK were reported more frequently in patients treated with XELJANZ 10 mg as compared to those treated with 5 mg BID (see ADVERSE REACTIONS).

Renal

XELJANZ XR is not recommended in patients with moderate (CLcr ≥30 and <60 mL/min), or severe renal insufficiency (CLcr ≥15 and <30 mL/min), including patients with end-stage renal disease (ESRD) but not limited to those undergoing hemodialysis.

Dosage adjustment of XELJANZ is recommended in patients with moderate and severe renal impairment (see WARNINGS AND PRECAUTIONS – Special Populations, DOSAGE AND ADMINISTRATION, and ACTION AND CLINICAL PHARMACOLOGY). In clinical trials, XELJANZ was not evaluated in patients with baseline creatinine clearance values (estimated by the Cockcroft-Gault equation) less than 40 mL/min.

Respiratory

Interstitial Lung Disease: Events of interstitial lung disease (ILD) have been reported in RA clinical trials with XELJANZ, although the role of JAK inhibition in these events is not known. All patients who developed ILD were taking concomitant methotrexate, corticosteroids and/or sulfasalazine, which have been associated with ILD. Asian patients had an increased risk of ILD (see WARNINGS AND PRECAUTIONS – Special Populations).

XELJANZ/XELJANZ XR should be used with caution in patients with a risk or history of ILD.

Special Populations

Pregnant Women : XELJANZ/XELJANZ XR is contraindicated during pregnancy (see CONTRAINDICATIONS). There are no adequate and well-controlled studies on the use of XELJANZ/XELJANZ XR in pregnant women. XELJANZ has been shown to be teratogenic in rats and rabbits, and have effects in rats on female fertility, parturition, and peri/postnatal development. (see TOXICOLOGY).

Women of reproductive potential should be advised to use effective contraception during XELJANZ/XELJANZ XR treatment and for 4 to 6 weeks after the last dose.

Nursing Women : XELJANZ was secreted in milk of lactating rats. It is not known whether XELJANZ/XELJANZ XR is excreted in human milk. XELJANZ/XELJANZ XR is contraindicated in women who breastfeed (see CONTRAINDICATIONS and TOXICOLOGY).

Pediatrics (<18 years of age) : The safety and effectiveness of XELJANZ/XELJANZ XR in pediatric patients have not been established. Therefore XELJANZ/XELJANZ XR should not be used in this patient population (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY).

Geriatrics (>65 years of age) : The frequency of serious infection among XELJANZ treated subjects 65 years of age and older was higher than among those under the age of 65. Caution should be used when treating the elderly with XELJANZ/XELJANZ XR (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY).

Asian Patients : Asian patients have an increased risk of herpes zoster and opportunistic infections. Asian patients with RA also have an increased risk of interstitial lung disease. An increased incidence of some adverse events such as elevated transaminases (ALT, AST) and decreased white blood cells (WBCs) were also observed. Therefore, XELJANZ/XELJANZ XR should be used with caution in Asian patients (see ADVERSE REACTIONS).

Adverse Reactions

Adverse Drug Reaction Overview

Rheumatoid Arthritis

During controlled clinical trials, 8.0% (11.0 events/100 patient- years) of patients in the 5 mg BID in the XELJANZ group were hospitalized due to serious adverse reactions compared to 7.8% (9.1 events/100 patient years) and 3.8% (13.0 events/100 patient - years) of patients in the adalimumab and placebo group, respectively.

The most common serious adverse reactions (SAEs) were osteoarthritis and serious infections, including pneumonia, cellulitis, herpes zoster, and urinary tract infection. During the first 3 months, serious infections (those requiring parenteral antibiotics or hospitalization) were reported in 0.7% (2.8 events/100 patient years) and 0.2% (0.6 events/100 patient years) of patients treated with XELJANZ or placebo, respectively. From 0-12 months, serious infections were reported in 2.4% (3.2 events/100 patient years) of XELJANZ treated patients (see WARNINGS AND PRECAUTIONS).

Deaths occurred in 0.4% (0.6 events/100 patient-years) of patients in the 5 mg BID XELJANZ group, compared to 0.5% (0.6 events/100 patient-years) and 0.2% (0.5 events/100 patient-years) of patients in the adalimumab and placebo groups, respectively.

The most commonly reported adverse reactions during the first 3 months in controlled clinical trials (occurring in ≥ 2% of patients treated with XELJANZ monotherapy or in combination with DMARDs) were upper respiratory tract infections, headache, nasopharyngitis, and diarrhea. Additionally, bronchitis, urinary tract infection, herpes zoster, rheumatoid arthritis, back pain and hypertension were also reported in the 5 mg BID XELJANZ group in the long-term extension trial.

The proportion of patients who discontinued treatment due to any adverse reactions during the first 3 months in double-blind placebo-controlled studies was 7.8% for patients taking 5 mg BID of XELJANZ and 3.7% for placebo-treated patients. In the long-term extension trial, the proportion of patients who discontinued treatment due to any adverse reaction was 24.8% (6.78 events/100 patient-years) for all patients, 27.9% (6.67 events/100 patient-years) for patients taking 5 mg BID of XELJANZ, and 23.8% (6.83 events/100 patient-years) for patients taking 10 mg BID of tofacitinib. The most common adverse reactions that resulted in discontinuation of XELJANZ were infections. Pneumonia was the most common adverse reactions leading to discontinuation of therapy followed by blood creatinine increased and herpes zoster.

Following completion of the Phase 2/3, open-label, uncontrolled, long-term extension follow-up trial (up to 114 months) from the Phase 2 studies and Phase 3 clinical program, there were 4040 subjects with 16113 patient-years of exposure to tofacitinib. The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose. Tofacitinib 10 mg BID is not recommended in RA patients. Overall, the safety profile of XELJANZ 5 mg BID in the long-term extension study was comparable to what was seen in the controlled clinical trials.

Asian Patients: Asian patients had higher rates of herpes zoster, opportunistic infections, elevated transaminases (ALT, AST) and decreased WBCs. Asian patients with RA also have an increased risk of interstitial lung disease. Therefore, XELJANZ/ XELJANZ XR should be used with caution in Asian patients.

Psoriatic Arthritis

The safety data includes 2 double‑blind, controlled, multicenter studies: study PsA-I (A3921091) with a 12‑month duration and study PsA-II (A3921125) with a 6‑month duration; both included a 3‑month placebo‑controlled period. All patients in the clinical studies were required to receive treatment with a stable dose of a csDMARD. An additional long‑term, open‑label clinical study was conducted and included patients with PsA who originally participated in either of the 2 double‑blind, controlled clinical studies.

A total of 783 patients were treated with any dose of XELJANZ in PsA clinical studies resulting in 1238 patient-years of exposure. Of these, 635 patients were exposed to XELJANZ for at least one year.

The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions (≥2%) in patients treated with XELJANZ 5mg BID during the first 3 months in placebo‑controlled clinical studies were bronchitis, diarrhea, dyspepsia, headache, nasopharyingitis, nausea.

The proportion of patients who discontinued treatment due to any adverse reactions during the first 3‑months of the double-blind placebo‑controlled studies was 3.2% for XELJANZ‑treated patients and 2.5% for placebo-treated patients.

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

Four randomized, double-blind, placebo-controlled studies and one open-label study were conducted in patients with moderately to severely active UC: two similar 8-week pivotal Phase 3 induction studies (OCTAVE Induction 1 and 2), one 52-week pivotal Phase 3 maintenance study (OCTAVE Sustain), and one dose-ranging Phase 2 induction study (A3921063). A long-term open-label uncontrolled extensions study was also conducted (see CLINICAL TRIALS). In the 52-week OCTAVE Sustain study, 99 patients were treated with 5 mg BID, and 113 patients with 10 mg BID for 52 weeks.

In the induction studies, the most common categories of serious adverse events were gastrointestinal disorders and infections. The most common serious adverse events (excluding events reported as ulcerative colitis) were abdominal pain, anal abscess, and drug hypersensitivity. The most common adverse events (≥ 5%) were headache and nasopharyngitis.

In the maintenance study, the most common categories of serious adverse events were gastrointestinal disorders, infections, injuries, and nervous system disorders. All serious adverse events were single reports (excluding events reported as ulcerative colitis). The most common adverse events (≥ 5%) (excluding events reported as ulcerative colitis) in patients treated with 5 mg BID were nasopharyngitis, arthralgia, headache, and upper respiratory tract infection. In patients treated with 10 mg BID, the most common adverse events were nasopharyngitis, arthralgia, blood creatine phosphokinase increased, upper respiratory tract infection, rash, hypercholesterolemia, and herpes zoster.

In induction studies, adverse events were reported in 515 subjects (54.9%) treated with 10 mg BID and 155 subjects (55.0%) treated with placebo. In the maintenance study, adverse events were reported in 143 subjects (72.2%) treated with 5 mg BID, 156 subjects (79.6%) treated with 10 mg BID, and 149 subjects (75.3%) treated with placebo”.

In induction and maintenance studies, the most frequent reason for study discontinuation was worsening of ulcerative colitis. Excluding discontinuations due to worsening of ulcerative colitis, the proportion of patients who discontinued due to adverse reactions was less than 5% in any of the XELJANZ or placebo treatment groups in these studies.

Four cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily.

Overall, the safety profile observed in UC patients treated with XELJANZ was consistent with the safety profile of XELJANZ across indications. Dose-dependent risks seen in patients treated with XELJANZ 10 mg BID in comparison with 5 mg BID include the following: herpes zoster infections, serious infections, and NMSC.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Rheumatoid Arthritis

Table 1 below lists the adverse events (regardless of causality) occurring in ≥1% of patients treated with XELJANZ during the double-blind, placebo-controlled portion of the RA studies.

Table 1: Summary of Adverse Events Reported by ≥ 1 % of RA Patients Treated with XELJANZ (All Causalities) - All Phase 3 Studies (up to 3 months)

Body

System/Adverse

Event

XELJANZ

5mg BID

(N=1216)

Placebo

(N=681)

Adalimumab

40 mg SC q2w

(N=204)

Infections and infestations

Upper respiratory tract infection

53 (4.4)

23 (3.4)

7 (3.4)

Nasopharyngitis

48 (3.9)

19 (2.8)

7 (3.4)

Urinary tract infection

25 (2.1)

12 (1.8)

7 (3.4)

Bronchitis

14 (1.2)

10 (1.5)

4 (2.0)

Blood and lymphatic system disorders

Anemia

15 (1.2)

8 (1.2)

0

Metabolism and nutrition disorders

Hypercholesterolaemia

12 (1.0)

3 (0.4)

1 (0.5)

Nervous system disorders

Headache

54 (4.4)

15 (2.2)

5 (2.5)

Dizziness

13 (1.1)

8 (1.2)

3 (1.5)

Vascular disorders

Hypertension

20 (1.6)

7 (1.0)

0

Gastrointestinal disorders

Diarrhoea

45 (3.7)

16 (2.3)

2 (1.0)

Nausea

32 (2.6)

18 (2.6)

3 (1.5)

Dyspepsia

19 (1.6)

11 (1.6)

3 (1.5)

Abdominal pain upper

23 (1.9)

5 (0.7)

3 (1.5)

Vomiting

21 (1.7)

10 (1.5)

0

Constipation

16 (1.3)

6 (0.9)

2 (1.0)

Gastritis

12 (1.0)

7 (1.0)

0

Gastroenteritis

12 (1.0)

5 (0.7)

0

Hepatobiliary Disorders

Alanine aminotransferase increased

14 (1.2)

7 (1.0)

1 (0.5)

Musculoskeletal and connective tissue disorders

Rheumatoid arthritis

17 (1.4)

17 (2.5)

1 (0.5)

Back pain

18 (1.5)

5 (0.7)

1 (0.5)

Arthralgia

13 (1.1)

16 (2.3)

4 (2.0)

General disorders and administration site conditions

Oedema peripheral

17 (1.4)

16 (2.3)

3 (1.5)

Pyrexia

13 (1.1)

5 (0.7)

1 (0.5)

Psoriatic Arthritis

The incidence rates and types of adverse drug reactions reported in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

Ulcerative Colitis

Table 2 below lists adverse drug reactions reported by ≥ 1% of patients treated with XELJANZ – UC Phase 2 and Phase 3 Induction Studies

Table 2: Summary of Adverse Drug Reactions (adverse events for which there is evidence of causality) Reported by ≥ 1% of Patients Treated with XELJANZ – UC Phase 2 and Phase 3 Induction Studies (up to 8 weeks)
*
includes: hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low density lipoprotein increased, low density lipoprotein abnormal, or lipids increased.
±
the total number of subjects with adverse reactions and the total number of subjects with adverse reactions for each body system include all adverse drug reactions (those reported by ≥ 1% of subjects treated with XELJANZ and those reported by < 1% of subjects treated with XELJANZ); the total also includes some subjects who reported more than one adverse drug reaction (which inflates the percentage)

Body

System±/Adverse

Drug Reaction

XELJANZ

10 mg BID

(N=938)

Placebo

(N=282)

Subjects with one or more ADR (%)

494 (52.7)

130 (46.1)

Blood and lymphatic system disorders

26 (2.8)

10 (3.5)

Anemia

22 (2.3)

9 (3.2)

Gastrointestinal disorders 82 (8.7) 26 (9.2)

Nausea

28 (3.0)

11 (3.9)

Abdominal pain

25 (2.7)

11 (3.9)

Vomiting

9 (1.0)

3 (1.1)

Dyspepsia

12 (1.3)

1(0.4)

General disorders and administration site conditions 48 (5.1) 13 (4.6)

Fatigue

17 (1.8)

5 (1.8)

Pyrexia

24 (2.6)

4 (1.4)

Infections and infestations 111 (11.8) 24 (8.5)

Nasopharyngitis

56 (6.0)

14 (5.0)

Influenza

9 (1.0)

3 (1.1)

Urinary tract infection

11 (1.2)

1 (0.4)

Pharyngitis

10 (1.1)

1 (0.4)

Investigations

65 (6.9)

4 (1.4)

Blood creatine phosphokinase increased

25 (2.7)

3 (1.1)

Elevated cholesterol levels*

31 (3.3)

0

Musculoskeletal and connective tissue disorders 33 (3.5) 12 (4.3)

Arthralgia

27 (2.9)

12 (4.3)

Nervous system disorders 77 (8.2) 20 (7.1)

Headache

73 (7.8)

19 (6.7)

Respiratory 14 (1.5) 8 (2.8)

Cough

13 (1.4)

7 (2.5)

Skin and Subcutaneous Tissue Disorders 18 (1.9) 9 (3.2)

Rash

12 (1.3)

2 (0.7)

Vascular disorders 9 (1.0) 1 (0.4)

Hypertension

9 (1.0)

1 (0.4)

Table 3: Summary of Adverse Drug Reactions (adverse events for which there is evidence of causality) Reported by ≥ 1% of Patients Treated with XELJANZ– UC Phase 3 Maintenance Study (up to 12 months)
*
includes: hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low density lipoprotein increased, low density lipoprotein abnormal, or lipids increased.
±
The total number of subjects with adverse reactions and the total number of subjects with adverse reactions for each body system include all adverse drug reactions (those reported by ≥ 1% of subjects treated with XELJANZ and those reported by < 1% of subjects treated with XELJANZ); the total also includes some subjects who reported more than one adverse drug reaction (which inflates the percentage)

Body

System±/Adverse Drug Reaction

XELJANZ

5mg BID

(N=198)

XELJANZ

10mg BID

(N=196)

Placebo

(N=198)

Subjects with one or more ADR (%)

166 (83.8)

207 (100)

153 (77.3)

Blood and lymphatic system disorders

9 (4.5)

5 (2.6)

3 (1.5)

Anemia

8(4.0)

4 (2.0)

3 (1.5)

Gastrointestinal disorders 16 (8.1) 32 (16.3) 26 (13.1)

Diarrhea

3 (1.5)

9 (4.6)

5 (2.5)

Nausea

1 (0.5)

8 (4.1)

5 (2.5)

Abdominal pain

5 (2.5)

7 (3.6)

11 (5.6)

Vomiting

3 (1.5)

6 (3.1)

2 (1.0)

Dyspepsia

4 (2.0)

1 (0.5)

2 (1.0)

General disorders and administration site conditions 12 (6.1) 11 (5.6) 17 (8.6)

Fatigue

8 (4.0)

4 (2.0)

11 (5.6)

Pyrexia

3 (1.5)

6 (3.1)

5 (2.5)

Infections and infestations 51 (25.8) 65 (33.2) 37 (18.7)

Nasopharyngitis

19 (9.6)

27 (13. 8)

11 (5.6)

Herpes zoster

3 (1.5)

10 (5.1)

1 (0.5)

Influenza

4 (2.0)

7 (3.6)

7 (3.5)

Urinary tract infection

5 (2.5)

6 (3.1)

4 (2.0)

Bronchitis

5 (2.5)

6 (3.1)

3 (1.5)

Sinusitis

6 (3.0)

2 (1.0)

2 (1.0)

Pharyngitis

6 (3.0)

1 (0.5)

3 (1.5)

Gastroenteritis viral

0

3 (1.5)

2 (1.0)

Viral infection

2 (1.0)

1 (0.5)

1 (0.5)

Injury, poisoning and procedural complications 2 (1.0) 2 (1.0) 0

Ligament sprain

1 (0.5)

2 (1.0)

0

Investigations 19 (9.6) 38 (19.4) 7 (3.5)

Elevated cholesterol levels*

9 (4.5)

18 (9.2)

3 (1.5)

Blood creatine phosphokinase increased

6 (3.0)

13 (6.6)

4 (2.0)

Weight increased

3 (1.5)

4 (2.0)

0

Gamma glutamyltransferase increased,

1 (0.5)

3 (1.5)

0

Musculoskeletal and connective tissue disorders 19 (9.6) 19 (9.7) 25 (12.6)

Arthralgia

17 (8.6)

17 (8.7)

19 (9.6)

Musculoskeletal pain

1 (0.5)

2 (1.0)

5 (2.5)

Neoplasms benign, malignant and unspecified (including cysts and polyps) 0 2 (1.0) 1 (0.5)

Non-melanoma skin cancers

0

2 (1.0)

1 (0.5)

Nervous system disorders 18 (9.1) 7 (3.6) 12 (6.1)

Headache

17 (8.6)

6 (3.1)

12 (6.1)

Psychiatric 3 (1.5) 1 (0.5) 1 (0.5)

Insomnia

3 (1.5)

1 (0.5)

1 (0.5)

Respiratory 6 (3.0) 8 (4.1) 6 (3.0)

Cough

6 (3.0)

5 (2.6)

5 (2.5)

Dyspnea

0

2 (1.0)

1 (0.5)

Skin and Subcutaneous Tissue Disorders 7 (3.5) 12 (6.1) 17 (8.6)

Rash

6 (3.0)

11 (5.6)

8 (4.0)

Vascular disorders 4 (2.0) 4 (2.0) 1 (0.5)

Hypertension

4 (2.0)

4 (2.0)

1 (0.5)

Overall Infections

Rheumatoid Arthritis

In the five controlled trials, during 0 to 3 months exposure, the overall frequency of infections was 20% in the 5 mg BID XELJANZ group, and 18% in the placebo group.

In the long-term extension trial, overall frequency of infections was 67.7% (39.63 events/100 patient-years) in all XELJANZ group; 65.5% of patients (33.22 events/100 patient-years) and 68.4% of patients (42.24 events/100 patient-years) in the 5 mg and 10 BID of tofacitinib, respectively.

The most commonly reported infections were upper respiratory tract infections, nasopharyngitis, bronchitis, herpes zoster and urinary tract infections.

Psoriatic Arthritis

The incidence rates and types of overall infections in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

Ulcerative Colitis

In the randomised 8-week Phase 2/3 induction studies, the proportions of patients with infections were 21.1% (198 patients) in the XELJANZ 10 mg BID group compared to 15.2% (43 patients) in the placebo group. In the randomised 52-week Phase 3 maintenance study, the proportion of patients with infections were 35.9% (71 patients) in the 5 mg BID and 39.8% (78 patients) in the 10 mg BID XELJANZ groups, compared to 24.2% (48 patients) in the placebo group.

In the maintenance study, results suggested that the risk of opportunistic infection was possibly dose related: XELJANZ 10 mg BID (2.0%), XELJANZ 5 mg BID (1.0%), and placebo (0.5%). All opportunistic infections were herpes zoster infections. Herpes zoster was reported more frequently with XELJANZ 10 mg BID (5.1%), as compared to XELJANZ 5 mg BID (1.5%), or placebo (0.5%), indicating that the risk of herpes zoster is dose related.

In the entire treatment experience with XELJANZ, the most commonly reported infection was nasopharyngitis, occurring in 18.2% of patients (211 patients).

Serious Infections

Rheumatoid Arthritis

In the five controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.6 events/100 patient years) who received placebo and 8 patients (2.8 events/100 patient - years) who received 5 mg BID of XELJANZ.

During the 0 to 12 months exposure, the overall frequencies of serious infections were 2.4% (3.2 events/100 patient - years) for the 5 mg BID XELJANZ group.

In the long-term extension trial, the most common serious infections reported with XELJANZ included pneumonia, cellulitis, appendicitis, diverticulitis, gastroenteritis, urinary tract infection, and herpes zoster (see WARNINGS AND PRECAUTIONS).

Psoriatic arthritis

The incidence rates and types of serious infections in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

Ulcerative Colitis

The incidence rates and types of serious infections in the UC clinical trials were generally similar to those reported in RA clinical trials with XELJANZ.

Patients treated with XELJANZ 10 mg BID had a higher rate of serious infections compared to those treated with 5 mg twice daily.

Tuberculosis

Cases of tuberculosis have been reported with treatment with XELJANZ

Rheumatoid Arthritis

In the five controlled trials, during 0 to 3 months exposure, no cases of tuberculosis were reported in patients who received placebo or 5 mg BID of XELJANZ.

During the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg BID of XELJANZ.

In the long-term extension trial, adjudicated tuberculosis events were reported in 0.6% patients (0.15 events/100 patient-year) who received XELJANZ: 0.4% of patients (0.10 events/100 patient-year) and 0.6% of patients (0.17 events/100 patient-years) in the 5mg and 10mg BID of tofacitinib, respectively.

Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days) (see WARNINGS AND PRECAUTIONS).

Psoriatic Arthritis

The incidence rates of tuberculosis in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

Opportunistic Infections (excluding tuberculosis)

Rheumatoid Arthritis

In the five controlled trials, during 0 to 3 months exposure, opportunistic infections were reported in 0 patients who received placebo and 2 (0.2%) patients (0.7 events/100 patient years) who received 5 mg BID of XELJANZ.

During the 0 to 12 months exposure, opportunistic infections were reported in 3 (0.3%) patients (0.3 events/100 patient years) who received 5 mg BID of XELJANZ.
The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days).

The similar frequency of opportunistic infections was observed in the long-term extension trial with XELJANZ treatment up to 114 months.

Psoriatic Arthritis

The incidence rates and types of opportunistic infections in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

Ulcerative Colitis

In the maintenance study, Herpes zoster was reported more frequently with XELJANZ 10 mg BID (5.1%), as compared to XELJANZ 5 mg BID (1.5%), or placebo (0.5%), indicating that the risk of herpes zoster is dose related.

Also, opportunistic herpes zoster infections (including serious cases, such as, disseminated, meningoencephalitis, ophthalmologic) were reported in patients treated with XELJANZ 10 mg twice daily.

Malignancy (excluding non-melanoma skin cancer)

Rheumatoid Arthritis

In the five controlled trials, during the 0 to 3 months exposure, malignancies (excluding non-melanoma skin cancer) were reported in 0 patients who received placebo and 2 (0.2%) patients (0.7 events/100 patient - years) who received 5 mg BID of XELJANZ.

During the 0 to 12 months exposure, malignancies (excluding non-melanoma skin cancer) were reported in 5 (0.4%) patients (0.6 events/100 patient - years) who received 5 mg BID of XELJANZ.

In the long-term extension trial, overall frequency of malignancies (excluding non-melanoma skin cancer) was 3.1% (0.83 events/100 patient-years) in all XELJANZ-treated patients; 3.4% of patients (0.8 events/100 patient-years) and 3% of patients (0.84 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively.

The most common types of malignancy, (excluding non-melanoma skin cancer), including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma and malignant melanoma (see WARNINGS AND PRECAUTIONS).

Psoriatic Arthritis

The incidence rates of malignancies (excluding NMSC) in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

Ulcerative Colitis

In the controlled clinical studies (up to 52 week treatment), no malignancies (excluding NMSC) were reported with Xeljanz.

In the long-term extension open-label study, malignancies (excluding NMSC) have been observed in patients treated with XELJANZ 10 mg BID, including solid cancers and lymphoma.

Non-Melanoma Skin Cancer

NMSC is a dose related adverse reaction, with a greater risk in patients treated with 10 mg BID of XELJANZ than in patients treated with 5 mg BID.

Rheumatoid Arthritis

In the five controlled trials, during the 0 to 3 months exposure, NMSC was reported in 1 (0.2%) patient (0.6 events/100 patient - years) who received placebo and 2 (0.2%) patients (0.7 events/100 patient - years) who received 5 mg BID of XELJANZ.

During the 0 to 12 months exposure, NMSC was reported in 3 (0.3%) patients (0.3 events/100 patient - years) who received 5 mg BID of XELJANZ.

In the long-term extension trial, overall frequency of NMSC was 2.6% (0.71 events/100 patient-years) in all XELJANZ-treated patients; 2.5% of patients (0.6 events/100 patient-years) and 2.6% of patients (0.75 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively.

Psoriatic Arthritis

The incidence rates of NMSC in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Rheumatoid Arthritis

Blood and Lymphatic System Disorders: neutropenia

Cardiovascular: congestive heart failure, myocardial infarction

Gastrointestinal Disorders: abdominal pain

General Disorders and Administration site conditions: Influenza

Hepatobiliary Disorders: hepatic steatosis

Infections and infestations: sepsis, pneumonia bacterial, pneumonia pneumococcal, pyelonephritis, cellulitis, gastroenteritis viral, viral infection, herpes simplex, herpes zoster, tuberculosis of central nervous system, encephalitis, necrotising fasciitis, meningitis cryptococcal, disseminated tuberculosis, urosepsis, pneumocystis jiroveci pneumonia, staphylococcal bacteraemia, tuberculosis, arthritis bacterial, atypical mycobacterial infection, mycobacterium avium complex infection, cytomegalovirus infection, bacteraemia, diverticulitis

Injury, Poisoning and Procedural Complications: muscle strain, fall

Investigations: transaminases increased, blood creatinine increased, gamma glutamyltransferase increased, liver function test abnormal, weight increased, blood creatine phosphokinase increased, hepatic enzyme increased, low density lipoprotein increased, blood cholesterol increased

Metabolism and Nutrition Disorders: dehydration, dyslipidemia, hyperlipidemia

Musculoskeletal and Connective Tissue Disorders: tendonitis, joint swelling, musculoskeletal pain, ligament sprain

Neoplasm Benign, Malignant and Unspecified (Including Cysts and Polyps): non-melanoma skin cancers

Nervous System Disorders: paraesthesia

Psychiatric Disorders: insomnia

Respiratory, Thoracic and Mediastinal Disorders: sinus congestion, cough, dyspnoea

Skin and Subcutaneous Tissue Disorders: erythema, pruritus

Psoriatic Arthritis ÷

The incidence rates of less common clinical trial adverse drug reactions (<1%) in the two controlled Phase 3 PsA clinical studies were generally similar to those reported in RA clinical studies.

Ulcerative Colitis

Blood and Lymphatic System Disorders: neutropenia, lymphopenia, leukopenia

Gastrointestinal Disorders: gastritis

General Disorders and Administration Site Conditions: oedema peripheral

Hepatobiliary Disorders: hepatic steatosis

Infections and Infestations: pneumonia, pyelonephritis, cellulitis, herpes simplex, tuberculosis, arthritis bacterial, cytomegalovirus infection, diverticulitis

Injury, Poisoning and Procedural Complications: muscle strain

Investigations: hepatic enzyme increased, transaminases increased, blood creatinine increased, liver function test abnormal, low density lipoprotein increased

Metabolism and Nutrition Disorders: dehydration

Musculoskeletal and Connective Tissue Disorders: tendonitis, joint swelling

Neoplasm Benign, Malignant and Unspecified (Including Cysts and Polyps): non-melanoma skin cancers, solid cancers, lymphomas

Nervous System Disorders: paraesthesia

Respiratory, Thoracic and MediastinalDisorders: sinus congestion

Skin and Subcutaneous Tissue Disorders: erythema, pruritus

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory Tests - Rheumatoid Arthritis and Ulcerative Colitis

Creatine Kinase
Treatment with XELJANZ was associated with increases in creatine kinase (CK). Maximum effects were generally observed within 6 months. Rhabdomyolysis was reported in one patient treated with XELJANZ.

CK levels should be checked in patients with symptoms of muscle weakness and/or muscle pain to evaluate for evidence of rhabdomyolysis (see WARNINGS AND PRECAUTIONS).

ECG Findings: In placebo-controlled Phase 2 clinical trials, steady-state treatment with 5-10 mg BID XELJANZ was associated with statistically significant 4-7 bpm decreases in heart rate and 4-10 ms increases in the PR interval compared with placebo (see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS).

Lipids
Treatment with XELJANZ was associated with dose related increases in lipid parameters

Elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) generally reached maximal effects at 6 weeks following initiation of XELJANZ in the controlled RA double-blind clinical trials. Changes in lipid parameters from baseline through the end of the study (6-12 months) in the controlled clinical studies in RA are summarized below:

  • Mean LDL cholesterol increased by 14% in the XELJANZ 5 mg BID arm.
  • Mean HDL cholesterol increased by 16% in the XELJANZ 5 mg BID arm.
  • Mean LDL/HDL ratios were essentially unchanged in XELJANZ -treated patients.

In the five controlled RA clinical trials, 4.4% of patients treated with 5 mg BID, initiated lipid-lowering medication while on study.

In the RA long-term safety population, elevations in the lipid parameters remained consistent with what was seen in the controlled clinical studies.

Liver Enzyme Tests
Confirmed increases in liver enzymes >3x upper limit of normal (ULN) were uncommonly observed. In those 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 normalization of liver enzymes.

In the controlled portion of the RA Phase 3 monotherapy study (0-3 months), ALT elevations >3x ULN were observed in 1.65% and 0.41% of patients receiving placebo and 5 mg respectively. In this study, AST elevations >3x ULN were observed in 1.65%, and 0.41% of patients receiving placebo and 5 mg BID, respectively.

In the controlled portion of the RA Phase 3 studies on background DMARDs (0-3 months), ALT elevations >3x ULN were observed in 0.9% and 1.24% of patients receiving placebo and 5 mg BID, respectively. In these studies, AST elevations >3x ULN were observed in 0.72% and 0.52% of patients receiving placebo and 5 mg BID, respectively.

In the RA long-term extension trial, ALT and AST elevations greater than 3x ULN were observed in 2.2% and 1.1% of all XELJANZ-treated patients, respectively. Overall, total bilirubin elevations greater than 2x ULN were observed in 3 (0.1%) patients. Increases to ≥5x and ≥10x ULN were observed for both ALT (0.5% and 0.2% of patients, respectively) and AST (0.3% and 0.1% of patients, respectively) in all patients treated with XELJANZ.

In RA patients taking 5 mg BID of XELJANZ, the ALT and AST elevations greater than 3x ULN were observed in 2.4% and 1.3% of patients, respectively. There was no subject who had the total bilirubin elevations greater than 2x ULN. Increases to ≥5 and ≥10x ULN were observed for both ALT (0.4% and 0.1% of patients, respectively) and AST (0.2% and 0% of patients, respectively).

In RA patients taking 10 mg twice daily of tofacitinib, the ALT and AST elevations greater than 3x ULN were observed in 2.1% and 1.1% of patients, respectively. The total bilirubin elevations greater than 2x ULN were observed in 3 (0.1%) patients. Increases to ≥5 and ≥10x ULN were observed for both ALT (0.5% and 0.2% of patients, respectively) and AST (0.3% and 0.1% of patients, respectively).

Two patients treated with 10 mg BID of tofacitinib in the RA long-term extension trial were assessed as probable DILI by the adjudication committee. One of the two patients had other possible causes of alcohol intake and methotrexate.

In the clinical studies in UC, changes in liver enzyme tests observed with XELJANZ 5 mg BID treatment were similar to the changes observed in clinical studies in RA.

In UC patients, XELJANZ treatment with 5 and 10 mg BID was also associated with an increased incidence of liver enzyme elevation compared to placebo, with a trend for higher incidence with the 10 mg BID as compared to the 5 mg BID dose.

One patient with XELJANZ 10 mg BID in the maintenance UC study experienced an increase in liver enzymes which decreased upon discontinuation of treatment. The case was adjudicated as possible DILI, while noting ultrasound findings of fatty liver

Lymphocytes
In the five controlled RA clinical trials, confirmed decreases in absolute lymphocyte counts below 500 cells/mm3 occurred in 0.2% of patients for the 5 mg BID XELJANZ group during 12 months of exposure.

Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections (see WARNINGS AND PRECAUTIONS).

In the RA long-term extension trial, cases of lymphopenia have been reported in 181 (4.0%) patients (1.11 events/100 patient-years) treated with XELJANZ; 4.5% of patients (1.07 events/100 patient-years) and 3.9% of patients (1.12 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively. Confirmed decreased in absolute lymphocyte counts below 500 cells/mm3 occurred in 1.3% of all XELJANZ-treated patients; 1.1% of patients for the 5 mg BID XELJANZ group, and 1.4% of patients for the 10 mg BID tofacitinib group.

In the 52-week maintenance study in UC, a single absolute lymphocyte count below 500 cells/mm3 was reported in 2.6% (n=5) of patients treated with 10 mg BID, and was not reported in patients treated with 5 mg BID or placebo. No patients in any treatment group had confirmation of a lymphocyte count below 500 cells/mm3 based on two sequential tests.

Neutrophils
In the controlled RA clinical studies, confirmed decreases in ANC below 1000/mm3 occurred in 0.08% of patients in the 5 mg BID XELJANZ group during 12 months of exposure. There were no confirmed decreases in ANC below 500/mm3 observed in any treatment group.

There was no clear relationship between neutropenia and the occurrence of serious infections.

In the long-term extension trial, cases of neutropenia have been reported in 86 (1.9%) patients (0.52 events/100 patient-years) treated with XELJANZ; 4.0% of patients (0.97 events/100 patient-years) and 1.2% of patients (0.35 events/100 patient-years) in the 5 mg and 10 mg BID of tofacitinib, respectively. Confirmed decreased in ANC below 1000 cells/mm3 occurred in 0.2% in all XELJANZ-treated patients; 0.4% of patients for the 5 mg BID XELJANZ group, and 0.1% of patients for the 10 mg BID tofacitinib group.

In the clinical studies in UC, changes in neutrophils observed with XELJANZ treatment were similar to the changes observed in clinical studies in RA.

Serum Creatinine
In the controlled RA clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however, with increasing duration of exposure in the long-term extension trial, up to 6.9% of patients were discontinued from XELJANZ treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.

In the UC studies, an increase of more than 50% in serum creatinine was reported in 1.6% of patients predominantly treated with XELJANZ 5 mg BID, and 3.4% of those predominantly treated with XELJANZ 10 mg BID.

Laboratory Tests – Psoriatic Arthritis

In the controlled clinical trials in PsA, changes in hematologic and clinical chemistry findings observed with XELJANZ treatment were similar to the changes observed in clinical trials in RA.

Post-Marketing Adverse Drug Reactions

Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: drug hypersensitivity reactions including angioedema and urticaria (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS)

Serious infections: viral reactivation (hepatitis B reactivation) (see WARNINGS AND PRECAUTIONS)

Vascular disorders: Thrombosis (deep vein thrombosis, pulmonary embolism, and arterial thrombosis) (see WARNINGS AND PRECAUTIONS)

Drug Interactions

Overview

In vitro studies indicate that tofacitinib does not significantly inhibit the activity of the major human drug metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations exceeding 80 times the steady state Cmax of a 5 and 10 mg BID dose in patients treated with tofacitinib. In vitro studies also indicated a low risk of induction of CYP3A4 (2-fold mRNA at 6.25 µM), CYP2B6 (2-fold mRNA at 12.5 µM), and CYP1A2 (no enzyme changes) at clinically relevant concentrations (total Cmax of 0.186 µM).

In vitro, tofacitinib is a substrate for multidrug resistance (MDR) 1, but not for breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1/1B3, or organic cationic transporter (OCT) 1/2. In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, MDR1, organic anion transporter (OAT) P1B1/1B3, OCT2, OAT1/3, cationic transporters or multidrug resistance‑associated protein (MRP) at therapeutic concentrations is also low.

Tofacitinib exposure is increased when XELJANZ is coadministered with potent CYP3A4 inhibitors (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). Tofacitinib exposure is decreased when XELJANZ is coadministered with potent CYP3A4 inducers (e.g. rifampin). Inhibitors of CYP2C19 or P-glycoprotein are unlikely to alter the PK of tofacitinib.

The 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 250 times the steady state Cmax of a 5 and 10 mg twice daily dose in RA, PsA and UC patients.

The oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in patients. Therefore, coadministration with XELJANZ/XELJANZ XR is not expected to result in clinically relevant increases in the metabolism of CYP substrates.

Drug-Drug Interactions

Table 4: Summary of Drug-Drug Interactions
 
Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

Drug

Reference

Effect

Clinical Comment

Methotrexate

CT

Coadministration with methotrexate (15-25 mg MTX once weekly) had no effect on the PK of tofacitinib and decreased methotrexate AUC (area under the curve) and Cmax by 10% and 13% respectively.

No dose adjustment is required for either drug.

Ketoconazole

CT

Coadministration of ketoconazole, a strong CYP3A4 inhibitor, with a single dose of XELJANZ increased the AUC and Cmax of tofacitinib by 103% and 16%, respectively

XELJANZ XR is not recommended in patients coadministered with strong inhibitors of CYP3A4.

The recommended dose is half the daily dose indicated for patients not receiving strong CYP3A4 inhibitors concomitantly, i.e., in patients already taking:

XELJANZ 10 mg twice daily, reduce the dose to XELJANZ 5 mg twice daily or

XELJANZ 5 mg twice daily, reduce the dose to XELJANZ 5 mg once daily.

Fluconazole

CT

Coadministration of fluconazole, a moderate inhibitor of CYP3A4 and a strong inhibitor of CYP2C19, increased the AUC and Cmax of tofacitinib by 79% and 27%, respectively

XELJANZ XR is not recommended in patients coadministered with medications that result in moderate inhibition of CYP3A4 and potent inhibition of CYP2C19.

The recommended dose is half the daily dose indicated for patients not receiving concomitant medications that result in moderate inhibition of CYP3A4 and potent inhibition of CYP2C19, i.e., in patients already taking:

XELJANZ 10 mg twice daily, reduce the dose to XELJANZ 5 mg twice daily or

XELJANZ 5 mg twice daily, reduce the dose to XELJANZ 5 mg once daily.

Tacrolimus and Cyclosporine

CT

Coadministration of tacrolimus, a mild inhibitor of CYP3A4, increased the AUC of tofacitinib by 21% and decreased the Cmax of tofacitinib by 9%.


Coadministration of cyclosporine, a moderate inhibitor of CYP3A4, increased the AUC of tofacitinib by 73% and decreased Cmax of tofacitinib by 17%.

There is a risk of added immunosuppression when XELJANZ/XELJANZ XR is co-administered with potent immunosuppressive drugs (e.g: tacrolimus, cyclosporine, azathioprine). The combined use with these potent immunosuppressives has not been studied in patients and is not recommended.

Rifampin

CT

Coadministration of rifampin, a strong CYP3A4 inducer, decreased the AUC and Cmax of tofacitinib by 84% and 74%, respectively

Coadministration of XELJANZ/XELJANZ XR with potent inducers of CYP3A4 may result in loss of or reduced clinical response /efficacy.

Midazolam

CT

Coadministration of XELJANZ with midazolam, a highly sensitive CYP3A4 substrate, had no effect on midazolam PK

No dosage adjustment is required for CYP3A4 substrates such as midazolam.

Oral contraceptives (Ethinyl Estradiol and Levonorgestrel)

CT

Coadministration of XELJANZ with oral contraceptives had no effect on the PK of either oral contraceptive in healthy females

No dose adjustment is required for either oral contraceptives ethinyl estradiol and levonorgestrel.

Metformin

CT

Coadministration of XELJANZ with metformin, a substrate of Organic Cationic Transporter and Multidrug and Toxic Compound Extrusion, had no effect on the PK of metformin

No dosage adjustment is required for metformin.

The impact of extrinsic factors on tofacitinib pharmacokinetics is summarized in Figure 1 and 2 with dosage adjustment recommendations.

Figure 1: Impact of Co-administered drugs on Pharmacokinetics of Tofacitinib

 
Note: Reference group is administration of tofacitinib alone; PK=Pharmacokinetics; CI=Confidence Interval
a In RA patients the recommended dose is XELJANZ 5 mg once daily. In UC patients receiving 10 mg twice daily, XELJANZ dosage should be reduced to 5 mg twice daily, and in UC patients receiving 5 mg twice daily, XELJANZ dosage should be reduced to 5 mg once daily

Figure 2: Impact of Tofacitinib on Pharmacokinetics of Co-administered Drugs

 
Note: Reference group is administration of concomitant medication alone; OCT = Organic Cationic Transporter; MATE = Multidrug and Toxic Compound Extrusion; PK=Pharmacokinetics; CI=Confidence Interval

Drugs that Decrease Heart Rate and/or Prolong the PR Interval: XELJANZ resulted in a decrease in heart rate and an increase in the PR interval (see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS). Caution should be observed if XELJANZ/XELJANZ XR is used concomitantly with other drugs that lower heart rate and/or prolong the PR interval, such as antiarrhythmics, beta blockers, alpha2 adrenoceptor agonists, non-dihydropyridine calcium channel blockers, digitalis glycosides, cholinesterase inhibitors, sphingosine-1 phosphate receptor modulators, and some HIV protease inhibitors.

Combination with other therapies

XELJANZ/XELJANZ XR has not been studied and is not indicated to be used in combination with biologics such as TNF antagonists, interleukin (IL)-1R antagonists, IL-6R antagonists, IL‑17 antagonists, IL-12/IL-23 antagonists, anti‑CD20 monoclonal antibodies, anti-integrins, selective co-stimulation modulators, and potent immunosuppressants such as azathioprine, 6-mercaptopurine, cyclosporine, and tacrolimus because of the possibility of increased immunosuppression and increased risk of infection.

The use of XELJANZ/XELJANZ XR in combination with phosphodiesterase 4 inhibitors has not been studied in XELJANZ clinical trials.

Drug-Food Interactions

Grapefruit juice affects CYP450 3A-mediated metabolism and concomitant administration with XELJANZ/XELJANZ XR should be avoided.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Drug-Herb Interactions

St John’s Wort is a CYP3A4 inducer and co-administration with XELJANZ/XELJANZ XR may result in loss of or reduced clinical response.

Drug-Lifestyle Interactions

No formal studies have been conducted on the effects on the ability to drive and use machines.

Dosage And Administration

Dosing Considerations

There is a risk of added immunosuppression when XELJANZ/ XELJANZ XR is coadministered with potent immunosuppressive drugs (e.g. azathioprine, tacrolimus, cyclosporine). Combined use of XELJANZ/ XELJANZ XR with potent immunosuppressants or biologic DMARDS (tumor necrosis factor (TNF) antagonists, interleukin 1 receptor (IL-1R) antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies, IL-17 antagonists, IL-12/IL-23 antagonists and selective co-stimulation modulators) has not been studied in RA, PsA and UC patients and its use should be avoided.

Recommended Dose and Dosage Adjustment

Rheumatoid Arthritis XELJANZ/ XELJANZ XR Posology

Adults :

XELJANZ / XELJANZ XR is to be used in combination with methotrexate.

XELJANZ / XELJANZ XR, monotherapy may be considered in cases of intolerance to methotrexate.

The recommended dose of XELJANZ is 5 mg administered twice daily. The recommended dose of XELJANZ XR is 11 mg once daily

XELJANZ / XELJANZ XR is given orally with or without food.

Swallow XELJANZ XR tablets whole and intact. Do not crush, split, or chew.

Switching between XELJANZ Tablets and XELJANZ XR Tablets
Where appropriate, patients treated with XELJANZ 5 mg twice daily may be switched to XELJANZ XR 11 mg once daily the day following the last dose of XELJANZ 5 mg.

Where appropriate, patients treated with XELJANZ XR 11 mg once daily may be switched to XELJANZ 5 mg twice daily 24 hours following the last dose of XELJANZ XR 11 mg.

Patients treated with XELJANZ XR 11 mg once daily who require a dose reduction due to renal or hepatic impairment or drug interactions may be switched to XELJANZ 5 mg once daily, 24 hours following the last dose of XELJANZ XR 11 mg once daily (see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS).

Psoriatic Arthritis XELJANZ Posology

Adults :
The recommended dose of XELJANZ is 5 mg administered twice daily in combination with MTX or another csDMARD.

Ulcerative Colitis XELJANZ Posology

Adults :
The recommended dose is 10 mg given orally twice daily for induction for at least 8 weeks and 5 mg given twice daily for maintenance.

Depending on therapeutic response; 10 mg twice daily may also be used for maintenance in some patients. However, the lowest effective dose possible should be used for maintenance therapy to minimize adverse effects (see WARNINGS AND PRECAUTIONS).

XELJANZ induction therapy should be discontinued in patients who show no evidence of adequate therapeutic benefit by Week 16.

In patients who have responded to treatment with XELJANZ, corticosteroids may be cautiously reduced and/or discontinued in accordance with standard of care.

Dose Modification due to Serious Infections and Cytopenias (see Tables 5-7 below)

  • It is recommended that XELJANZ/XELJANZ XR not be initiated in patients with an absolute neutrophil count (ANC) less than 1000/mm3, hemoglobin (Hgb) levels < 9 g/d, or with a lymphocyte count less than 500 cells/mm3 (see WARNINGS AND PRECAUTIONS).
  • Dose interruption is recommended for management of lymphopenia, neutropenia and anemia (see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS).
  • Avoid use of XELJANZ/XELJANZ XR if a patient develops a serious infection until the infections is controlled
Table 5: Dose Adjustments for Neutropenia

Low ANC

Lab Value

(cells/mm3)

Recommendation

ANC >1000

Maintain dose

ANC 500-1000

For persistent decreases in this range, interrupt or reduce administration with XELJANZ/XELJANZ XR until ANC is >1000 cells/mm3

  • For patients receiving XELJANZ 5 mg twice daily, interrupt XELJANZ dosing. When ANC is > 1000, resume XELJANZ 5 mg twice daily.

RA patients:

  • When ANC is > 1000 cells/mm3, resume XELJANZ XR 11 mg once daily.

UC patients:

  • For patients receiving XELJANZ 10 mg twice daily, reduce dose to XELJANZ 5 mg twice daily. When ANC is > 1000, increase to XELJANZ 10 mg twice daily based on clinical response.

ANC <500

(Confirmed by repeat testing)

Discontinue treatment with XELJANZ/XELJANZ XR

Table 6: Dose Adjustments for Anemia

Low Hemoglobin Value

Lab Value

(g/dL)

Recommendation

< 2 g/dL decrease and ≥ 9.0 g/dL

Maintain dose

≥ 2 g/dL decrease or < 8.0 g/dL

(Confirmed by repeat testing)

Interrupt the administration of XELJANZ/XELJANZ XR until hemoglobin values have normalized

Table 7: Dose Adjustments for Lymphopenia Low Lymphocyte Count

Low Lymphocyte Count

Lab Value

(cells/mm3)

Recommendation

Lymphocyte count greater than or equal to 500

Maintain dose

Lymphocyte count less than 500

(Confirmed by repeat testing)

Discontinue XELJANZ/XELJANZ XR

Dose Modification in Patients with Renal or Hepatic Impairment

XELJANZ

  • XELJANZ is contraindicated in patients with severe hepatic impairment
    In patients with moderate (CLcr ≥30 and <60 mL/min) or severe (CLcr ≥15 and <30 mL/min) renal insufficiency - (including patients with ESRD but not limited to those undergoing
    • The recommended dose is XELJANZ 5 mg once daily when the indicated dose in the presence of normal renal function is XELJANZ 5 mg twice daily.
    • The recommended dose is XELJANZ 5 mg twice daily when the indicated dose in the presence of normal renal function is XELJANZ 10 mg twice daily.
    • Use XELJANZ with caution in this patient population
    • For patients undergoing hemodialysis, dose should be administered after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended in patients after dialysis.
    • Patients with severe renal insufficiency should remain on a reduced dose even after hemodialysis.
  • In patients with moderate hepatic impairment:
    • The recommended dose is XELJANZ 5 mg once daily when the indicated dose in the presence of normal hepatic function is XELJANZ 5 mg twice daily.
    • The recommended dose is XELJANZ 5 mg twice daily when the indicated dose in the presence of normal hepatic function is XELJANZ 10 mg twice daily.
    • Use XELJANZ with caution in this patient population.

XELJANZ XR

  • XELJANZ XR is contraindicated in patients with severe hepatic impairment and should not be used in patients with moderate hepatic impairment.
  • XELJANZ XR is not recommended in patients with moderate (CLcr ≥30 and <60 mL/min), or severe (CLcr ≥15 and <30 mL/min), renal insufficiency (including patients with ESRD but not limited to those undergoing hemodialysis).

In patients with moderate hepatic impairment or moderate to severe renal insufficiency, XELJANZ 5 mg once daily may be considered.

Dose Modification Due to Drug Interactions

Coadministration of potent inducers of CYP3A4 (e.g. rifampin) with XELJANZ/XELJANZ XR may result in loss of efficacy or reduced clinical response to XELJANZ/XELJANZ XR. Coadministration of potent inducers of CYP3A4 with XELJANZ/XELJANZ XR is not recommended.

XELJANZ

  • In patients receiving potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g ketoconazole) or one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g. fluconazole),
    • Reduce XELJANZ dose to 5 mg twice daily in patients taking 10 mg twice daily
    • Reduce XELJANZ dose to 5 mg once daily in patients taking 5 mg twice daily

XELJANZ XR
  • XELJANZ XR is not recommended in patients
    • Receiving potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g ketoconazole).
    • Receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g. fluconazole).

In patients with dose modifications due to drug interactions, XELJANZ 5 mg once daily may be considered.

Special Populations

Geriatrics (>65 years)

No dosage adjustment is required in patients aged 65 years and older (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY).

Pediatrics (<18 years of age)

The safety and efficacy of XELJANZ/XELJANZ XR in children aged from neonates to less than 18 years of age has not yet been established. Therefore XELJANZ/XELJANZ XR should not be used in this patient population (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY).

Missed Dose

For a missed dose, resume at the next scheduled dose.

Overdosage

There is no experience with overdose of XELJANZ/XELJANZ XR (tofacitinib). There is no specific antidote for overdose with XELJANZ/XELJANZ XR. Treatment should be symptomatic and supportive. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment.

Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicates that more than 95% of the administered dose is expected to be eliminated within 24 hours.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action And Clinical Pharmacology

Mechanism of Action

Tofacitinib is a potent, selective inhibitor of the JAK family of kinases with a high degree of selectivity against other kinases in the human genome. In kinase assays, tofacitinib, inhibits JAK1, JAK2, JAK3, and to a lesser extent TyK2. In cellular settings where JAK kinases signal in pairs, tofacitinib preferentially inhibits signaling by heterodimeric receptors associated with JAK3 and/or JAK1 with functional selectivity over receptors that signal via pairs of JAK2. Inhibition of JAK1 and JAK3 by tofacitinib blocks signaling through the common gamma chain-containing receptors for several cytokines, including IL-2, -4,-7,-9, -15, and -21. These cytokines are integral to lymphocyte activation, proliferation, and function and inhibition of their signaling may thus result in modulation of multiple aspects of the immune response. In addition, inhibition of JAK1 will result in attenuation of signaling by additional pro-inflammatory cytokines, such as IL-6 and Type I interferons. At higher exposures, inhibition of erythropoietin signaling could occur via inhibition of JAK2 signaling.

Pharmacodynamics

In patients with RA, treatment with XELJANZ (tofacitinib) was associated with dose-dependent reductions of circulating CD16/56+ natural killer cells, with estimated maximum reductions occurring at approximately 8-10 weeks after initiation of therapy. These changes generally resolved within 2-6 weeks after discontinuation of treatment. Treatment with XELJANZ was associated with dose-dependent increases in B cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte subsets were small and inconsistent. The clinical significance of these changes is unknown.

Changes in total serum IgG, M, and A levels over 6-month dosing of patients with RA were small, not dose-dependent and similar to those seen on placebo.

After treatment with XELJANZ in patients with RA, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing. Changes in CRP observed with XELJANZ treatment do not reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic activity compared to the half-life.

Similar changes in T cells, B cells and serum CRP have been observed in patients with active PsA, although reversibility was not assessed. Total serum immunoglobulins were not assessed in patients with active PsA.

Patients with UC were not studied.

Pharmacokinetics (PK)

XELJANZ

Following oral administration of XELJANZ, the PK profile of XELJANZ is characterized by rapid absorption (peak plasma concentrations are reached within 0.5-1 hour), rapid elimination (half-life of ~3 hours) and dose-proportional increases in systemic exposure in the therapeutic dose range. Steady state concentrations are achieved in 24-48 hours with negligible accumulation after BID administration.

A geometric mean accumulation ratio (Rac) of 1.12 following BID dosing indicates little difference between single dose and steady state concentrations as well as the predictability of steady state PK from single dose data. The dose-AUC relationship was adequately described by a linear model fit to log-both sides transformed data while the dose - Cmax relationship were best described by a nonlinear sigmoidal, hyperbolic model fit to log-transformed Cmax data. Although the nonlinear model provided better description of the dose - Cmax relationship relative to a linear model, when compared to 5 mg, the mean model predicted relative changes in dose-normalized Cmax were approximately +7% for 10 mg, +2% for 30 mg, and -10% for 50 mg doses. These small changes from linearity support the conclusion that XELJANZ Cmax is approximately dose proportional at least up to 5 times the 10 mg dose.

XELJANZ XR

Following oral administration of XELJANZ XR, peak plasma tofacitinib concentrations are reached at 4 hours and the half‑life is ~6 hours. Steady state concentrations are achieved within 48 hours with negligible accumulation (accumulation ratio: 1.12) after once daily (QD) administration. At steady state, Cmin for XELJANZ XR 11 mg QD is approximately 29% lower and Ctrough is approximately 26% lower compared to XELJANZ 5 mg BID. Area under the curve (AUC) and Cmax of tofacitinib for XELJANZ XR 11 mg administered once daily are equivalent to those of XELJANZ 5 mg administered twice daily.

Pharmacokinetics in Patients with Moderately to Severely Active UC

Population PK analysis in UC patients indicated that PK characteristics were similar to that of RA patients. There were no clinically relevant differences in tofacitinib exposure (AUC), based on age, weight, gender and race, after accounting for differences in renal function (i.e., creatinine clearance) between patients. The between-subject variability (% coefficient of variation) in AUC of tofacitinib is estimated to be approximately 23% to 25% in UC patients.

Absorption:

XELJANZ

Tofacitinib is well-absorbed, with an absolute oral bioavailability of 74% following administration of XELJANZ. Coadministration of XELJANZ with a high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical trials, XELJANZ was administered without regard to meal.

XELJANZ XR

Coadministration of XELJANZ XR with a high-fat meal resulted in no changes in AUC while Cmax was increased by 27% and Tmax was extended by approximately 1 hour.

Distribution:

After intravenous administration, the volume of distribution is 87 L. The protein binding of tofacitinib is ~40%). Tofacitinib binds predominantly to albumin and does not appear to bind to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.

Metabolism:

Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule.

Excretion:

Approximately 94% of a radioactive dose of XELJANZ was recovered from the urine (80%) and feces (14%), with the majority of excreted radioactivity recovered within 24 hours after dosing.

Table 8: Summary of Tofacitinib Pharmacokinetic Parameters after Repeated Oral Administration of XELJANZ 10 mg BID or Single IV Administration in Humans
 
N/A = Not available; Cmax = maximum plasma concentration; t½ = terminal elimination half-life; AUC0-12 = area under the plasma concentration-time curve from time 0 to 12 hours post dose; CL = total systemic clearance; Vss = volume of distribution at steady state

Oral Administration

IV Administration

Cmax

(ng/mL)

t½

(h)

AUC0-12hrs

(ng·h/mL)

Clearance

(L/h)

Volume of distribution (L)

Healthy Volunteers

79.4

3.0

311

25

87

RA Patients

116

3.62

507

N/A

(no IV data)

N/A

(no IV data)

PsA Patients

88.9

3.74

436

N/A

(no IV data)

N/A

(no IV data)

UC Patients

91

3.05

404

N/A

(no IV data)

N/A

(no IV data)

Table 9: Summary of Tofacitinib Pharmacokinetic Parameters after Repeated Oral Administration of XELJANZ XR 11 mg QD in Humans
 
Cmax = maximum plasma concentration; t½ = terminal elimination half-life; AUC0-24 = area under the plasma concentration-time curve from time 0 to 24 hours post dose
 

Cmax

(ng/mL)

t½

(h)

AUC0-24hrs

(ng·h/mL)

Tmax (h)

Healthy Volunteers

38.23

5.89

269

4.0

Special Populations and Conditions

Rheumatoid Arthritis and Ulcerative Colitis

Pediatrics (< 18 years of age):

The pharmacokinetics, safety and effectiveness of tofacitinib in pediatric patients have not been established; therefore, XELJANZ/XELJANZ XR should not be used in this patient population. Pharmacokinetic of tofacitinib was characterized in an open-label, non-randomized, multi-center, Phase 1 study conducted in pediatric patients (aged from 2 to less than 18 years) with juvenile idiopathic arthritis. A total of 26 patients were enrolled in this study and treated at dosing regimens based on the children’s age and body weight. The study consisted of 3 cohorts based on subject age with at least 8 subjects per cohort. Based on limited data, the PK profile of tofacitinib appears to be characterized by a rapid absorption (peak plasma concentrations were reached within 0.5-1 hour) and a rapid elimination. The average half-lives for tofacitinib were approximately 2.6h, 1.9h, and 1.8h for the Cohorts 1 (12 to <18 years), 2 (6 to <12 years) and 3 (2 to <6 years), respectively, with individual values ranging from 1.4 to 3.1h across all cohorts.

Geriatrics (>65 years of age):

Population PK analysis in RA patients indicated that elderly patients 80 years of age were estimated to have <5% higher XELJANZ AUC relative to the mean age of 55 years. Of the 3315 patients who enrolled in studies I to V, a total of 505 (15%) RA patients were 65 years of age and older, including 71 (2%) patients 75 years and older. The frequency of serious infection among XELJANZ treated subjects 65 years of age and older was higher than those under the age of 65.

There were not enough elderly patients treated with XELJANZ (n=77) in the UC program to adequately study the effects of XELJANZ in this population. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly (see WARNINGS AND PRECAUTIONS).

Gender :

Based on population PK analysis, female RA patients were estimated to have 7% lower XELJANZ AUC compared to male RA patients. Female UC patients were estimated to have 15.2% higher XELJANZ AUC compared to male UC patients.

Race :

In RA patients, no major differences (<5%) were estimated in XELJANZ AUC between White, Black and Asian RA patients by population PK analysis. In UC patients, population PK analysis indicated that Asian patients had 7.3% higher XELJANZ AUC compared to non-Asian patients. There was a higher incidence of adverse events in Asian patients. Therefore, XELJANZ/XELJANZ XR should be used with caution in Asian patients (see WARNINGS AND PRECAUTIONS).

Body Weight :

Population PK analysis in RA patients indicated that systemic exposure (AUC) of XELJANZ in the extremes of body weight (40 kg, 140 kg) were similar to that of a 70 kg patient. An approximately linear relationship between body weight and volume of distribution was observed, resulting in higher peak (Cmax) and lower trough (Cmin) concentrations in lighter patients. However, this difference is not considered to be clinically relevant. The between-subject variability (% coefficient of variation) in AUC of XELJANZ is estimated to be approximately 27%. Population PK analysis in UC patients also indicated that XELJANZ AUC did not significantly change with patient body weight.

Hepatic Impairment:

XELJANZ/XELJANZ XR is contraindicated in patients with severe hepatic impairment (see CONTRAINDICATIONS). Subjects with mild and moderate hepatic impairment had 3%, and 65% higher XELJANZ AUC, respectively, compared with healthy subjects.

No dose adjustment of XELJANZ/XELJANZ XR is required in patients with mild hepatic impairment. XELJANZ XR has not been studied in patients with moderate and severe hepatic impairment. Therefore, XELJANZ XR should not be used in patients with moderate hepatic impairment.

The recommended total daily dose in patients with moderate hepatic impairment is half the total daily dose recommended for patients with normal hepatic function. The recommended dose is XELJANZ 5 mg twice daily when the indicated dose in the presence of normal hepatic function is XELJANZ 10 mg twice daily; the recommended dose is XELJANZ 5 mg once daily when the indicated dose in the presence of normal hepatic function is XELJANZ 5 mg twice daily (see DOSAGE AND ADMINISTRATION).

XELJANZ/XELJANZ XR has not been studied in patients with severe hepatic impairment or in patients with positive hepatitis B virus or hepatitis C virus serology, and should not be used in these populations.

Renal Impairment:

Subjects with mild, moderate, and severe renal impairment had 37%, 43% and 123% higher XELJANZ AUC, respectively, compared with healthy subjects. In subjects with end-stage renal disease (ESRD) undergoing hemodialysis, the contribution of dialysis to the total clearance of tofacitinib was relatively small.

In subjects with ESRD undergoing hemodialysis, mean AUC was approximately 40% higher compared with historical healthy subject data, consistent with approximately 30% contribution of renal clearance to the total clearance of tofacitinib. Dose adjustment is recommended in ESRD patients undergoing hemodialysis (see DOSAGE AND ADMINISTRATION).

No dose adjustment of XELJANZ/XELJANZ XR is required in patients with mild renal impairment. XELJANZ XR has not been studied in patients with moderate and severe renal impairment. Therefore, XELJANZ XR is not recommended in patients with moderate and severe renal impairment, including patients with ESRD undergoing hemodialysis.

The recommended total daily dose in patients with moderate or severe renal impairment, including patients with ESRD but not limited to those undergoing hemodialysis undergoing, is half the total daily dose recommended for patients with normal renal function. The recommended dose is XELJANZ 5 mg twice daily when the indicated dose in the presence of normal renal function is XELJANZ 10 mg twice daily; the recommended dose is XELJANZ 5 mg once daily when the indicated dose in the presence of normal renal function is XELJANZ 5 mg twice daily (see DOSAGE AND ADMINISTRATION).

In clinical trials, XELJANZ/XELJANZ XR was not evaluated in patients with baseline creatinine clearance values (estimated by the Cockroft-Gault equation) less than 40 mL/min.

Genetic Polymorphism:

Mean Cmax and AUC0-∞ values of tofacitinib following administration of XELJANZ in poor metabolizers of CYP2C19 (carriers of CYP2C19*2/*2, CYP2C19*2/*3 or CYP2C19*3/*3 alleles) were approximately 15% and 17% greater, respectively, than those in normal metabolizers, indicating that CYP2C19 is a minor contributor of XELJANZ clearance.

The impact of intrinsic factors on tofacitinib following administration of XELJANZ pharmacokinetics is summarized in Figure 3 with dosage adjustment recommendations.

Figure 3: Impact of Intrinsic Factors on Tofacitinib Pharmacokinetics

 
PK=Pharmacokinetics; CI=Confidence Interval
 
Note: Reference values for weight, age, gender, and race comparisons are 70 kg, 55 years, male, and white, respectively; reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function.
a
In RA patients the recommended dose is XELJANZ 5 mg once daily. In UC patients the recommended dose is half the total daily dose indicated for patients with normal renal and hepatic function, i.e, the recommended dose is XELJANZ 5 mg twice daily when the indicated dose in the presence of normal renal and hepatic function is XELJANZ 10 mg twice daily, and the recommended dose is XELJANZ 5 mg once daily when the indicated dose in the presence of normal renal and hepatic function is XELJANZ 5 mg twice daily.
b
Supplemental doses are not necessary in patients after dialysis.

Psoriatic Arthritis

Results from population PK analysis in patients with active PsA were consistent with those in patients with RA.

Storage And Stability

Store between 15°C and 30°C.

Dosage Forms, Composition And Packaging

XELJANZ

Tablet: 5 mg tofacitinib (as tofacitinib citrate) (White round film coated tablet with Pfizer on one side and JKI 5 on the other side)
HDPE bottles with desiccant and child-resistant caps containing 60 film-coated tablets.
Foil / foil blisters containing 56 film-coated tablets.

The tablet core contains Croscarmellose Sodium, Lactose Monohydrate, Magnesium Stearate, Microcrystalline Cellulose.  The film coat contains HPMC 2910/Hypromellose 6 cP, Lactose Monohydrate, Macrogol/PEG 3350, Titanium dioxide, Triacetin (Glycerol Triacetate)

Tablet: 10 mg (Blue round film coated tablet with Pfizer on one side and JKI 10 on the other side)
HDPE bottles with desiccant and child-resistant caps containing 60 film-coated tablets.
Foil / foil blisters containing 56 film-coated tablets.

The tablet core contains: Microcrystalline Cellulose, Lactose Monohydrate, croscarmellose Sodium, Magnesium Stearate. The film coat contains: HPMC 2910/Hypromellose 6cP, lactose monohydrate, macrogol/PEG3350, titanium dioxide, triacetin (glycerol triacetate), FD&C blue #2/indigo carmine aluminum lake, FD&C blue #1/brilliant blue FCF aluminum lake.

XELJANZ XR
Tablets: 11 mg tofacitinib (as tofacitinib citrate) (Pink oval extended-release-coated tablets)
HDPE bottles with desiccant and child-resistant caps containing 14 or 30 extended release film-coated tablets.

The tablet core contains: sorbitol, hydroxyethyl cellulose, copovidone, magnesium stearate. The Film Coat contains cellulose acetate, hydroxypropyl cellulose, HPMC 2910/hypromellose, titanium dioxide, triacetin, red iron oxide. The Printing ink contains shellac glaze, ammonium hydroxide, propylene glycol, ferrosoferric oxide/black iron oxide.



Control #: 230976
October 24, 2019

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