Tofacitinib

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# Black Box Warning

# Overview
Tofacitinib is an anti rheumatic that is FDA approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include anemia, hepatic steatosis, pruritis, tendonitis, pyrexia.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Tofacitinib  is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).
- Tofacitinib should not be used in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine.
- The recommended dose of tofacitinib is 5 mg twice daily.
- Tofacitinib dosage should be reduced to 5 mg once daily in patients:
- With moderate or severe renal insufficiency
- With moderate hepatic impairment
- 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).
- Tofacitinib should not be used in patients with severe hepatic impairment.
- It is recommended that tofacitinib not be initiated in patients with a lymphocyte count less than 500 cells/mm3, an absolute neutrophil count (ANC) less than 1000 cells/mm3, or who have hemoglobin levels less than 9 g/dL.
- Coadministration of tofacitinib with potent inducers of CYP3A4 (e.g., rifampin) may result in loss of or reduced clinical response to tofacitinib.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tofacitinib in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Tofacitinib in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tofacitinib in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tofacitinib in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Tofacitinib in pediatric patients.

# Contraindications
There is limited information regarding Tofacitinib Contraindications in the drug label.

# Warnings
- Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving tofacitinib. The most common serious infections reported with tofacitinib included pneumonia, cellulitis, herpes zoster and urinary tract infection.
- Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcus, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus, and BK virus were reported with tofacitinib. 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., histoplasmosis, coccidioidomycosis, and listeriosis).
- Tofacitinib should not be initiated in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating tofacitinib in patients:
- with chronic or recurrent infection
- who have been exposed to tuberculosis
- with a history of a serious or an opportunistic infection
- who have resided or traveled 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 tofacitinib. Tofacitinib should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis.
- A patient who develops a new infection during treatment with tofacitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.
- Patients should be evaluated and tested for latent or active infection prior to administration of tofacitinib.
- Anti-tuberculosis therapy should also be considered prior to administration of tofacitinib 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 who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
- Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
- Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering tofacitinib.
- Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with tofacitinib. The impact of tofacitinib on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials.
- Consider the risks and benefits of tofacitinib treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing tofacitinib in patients who develop a malignancy. Malignancies were observed in clinical studies of tofacitinib.
- In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving tofacitinib with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure.
- Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with tofacitinib.
- 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, ]-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with tofacitinib (2.3%) compared to 0 out of 111 patients treated with cyclosporine.
- Events of gastrointestinal perforation have been reported in clinical studies with tofacitinib in rheumatoid arthritis patients, although the role of JAK inhibition in these events is not known.
- Tofacitinib should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.
- Treatment with tofacitinib 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 tofacitinib 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 treatment with tofacitinib is not recommended.
- Monitor lymphocyte counts at baseline and every 3 months thereafter. For recommended modifications based on lymphocyte counts
- Treatment with tofacitinib was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo.
- Avoid initiation of tofacitinib treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3). For patients who develop a persistent ANC of 5001000 cells/mm3, interrupt tofacitinib dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with tofacitinib is not recommended.
- Monitor neutrophil counts at baseline and after 48 weeks of treatment and every 3 months thereafter. For recommended modifications based on ANC results
- Avoid initiation of tofacitinib treatment in patients with a low hemoglobin level (i.e. less than 9 g/dL). Treatment with tofacitinib should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment.
- Monitor hemoglobin at baseline and after 48 weeks of treatment and every 3 months thereafter. For recommended modifications based on hemoglobin results.
- Treatment with tofacitinib was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.
- Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of tofacitinib should be interrupted until this diagnosis has been excluded.
- Treatment with tofacitinib was associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. 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 approximately 48 weeks following initiation of tofacitinib therapy.
- Manage patients according to clinical guidelines  for the management of hyperlipidemia.
- No data are available on the response to vaccination or on the secondary transmission of infection by live vaccines to patients receiving tofacitinib. Live vaccines should not be given concurrently with tofacitinib.
- Update immunizations in agreement with current immunization guidelines prior to initiating tofacitinib therapy.

# Adverse Reactions

## Clinical Trials Experience
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.
- The following data includes two Phase 2 and five Phase 3 double-blind, controlled, multicenter trials. In these trials, patients were randomized to doses of tofacitinib 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, tofacitinib 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven protocols included provisions for patients taking placebo to receive treatment with tofacitinib at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore some analyses that follow include patients who changed treatment by design or by patient response from placebo to tofacitinib in both the placebo and tofacitinib group of a given interval. Comparisons between placebo and tofacitinib were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and tofacitinib 10 mg twice daily were based on the first 12 months of exposure.
- The long-term safety population includes all patients who participated in a double-blind, controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modification of tofacitinib doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose.
- The most common serious adverse reactions were serious infections.
- The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking tofacitinib and 3% for placebo-treated patients.
- In the seven controlled trials, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group.
- The most commonly reported infections with tofacitinib were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).
- In the seven controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received tofacitinib 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily tofacitinib group minus placebo.
- In the seven controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received 5 mg twice daily of tofacitinib and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib.
- The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection.
- In the seven controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of tofacitinib, or 10 mg twice daily of tofacitinib.
- In the seven controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of tofacitinib and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib.
- Cases of disseminated tuberculosis were also reported. The median tofacitinib exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days)
- In the seven controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of tofacitinib, or 10 mg twice daily of tofacitinib.
- In the seven controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of tofacitinib and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib.
- The median tofacitinib exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days).
- In the seven controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either tofacitinib 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily tofacitinib group minus placebo.
- In the seven controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received 5 mg twice daily of tofacitinib and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with tofacitinib 10 mg twice daily.
- The most common types of malignancy, 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.
- In the controlled clinical trials, confirmed decreases in lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily tofacitinib groups combined during the first 3 months of exposure.
- Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.
- In the controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily tofacitinib groups combined during the first 3 months of exposure.
- There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group.
- There was no clear relationship between neutropenia and the occurrence of serious infections.
- In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the controlled clinical trials.
- Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3 ULN) were observed in patients treated with tofacitinib. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of tofacitinib, or reduction in tofacitinib dose, resulted in decrease or normalization of liver enzymes.
- In the controlled monotherapy trials (03 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and tofacitinib 5 mg, and 10 mg twice daily groups.
- In the controlled background DMARD trials (03 months), ALT elevations greater than 3 ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3 ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively.
- One case of drug-induced liver injury was reported in a patient treated with tofacitinib 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3 ULN and bilirubin elevations greater than 2 ULN, which required hospitalizations and a liver biopsy.
- In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the controlled clinical trials are summarized below:
- Mean LDL cholesterol increased by 15% in the tofacitinib 5 mg twice daily arm and 19% in the tofacitinib 10 mg twice daily arm.
- Mean HDL cholesterol increased by 10% in the tofacitinib 5 mg twice daily arm and 12% in the tofacitinib 10 mg twice daily arm.
- Mean LDL/HDL ratios were essentially unchanged in tofacitinib-treated patients.
- In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.
- In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the controlled clinical trials.
- In the controlled clinical trials, dose-related elevations in serum creatinine were observed with tofacitinib 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 extensions, up to 2% of patients were discontinued from tofacitinib 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.
- Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily tofacitinib and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in Table 4.

## Postmarketing Experience
- Blood and lymphatic system disorders
- Anemia
- Metabolism and nutrition disorders
- Dehydration
- Psychiatric disorders
- Insomnia
- Nervous system disorders
- Paresthesia
- Respiratory, thoracic and mediastinal disorders
- Dyspnea, cough, sinus congestion
- Gastrointestinal disorders
- Abdominal pain, dyspepsia, vomiting, gastritis, nausea
- Hepatobiliary disorders
- Hepatic steatosis
- Skin and subcutaneous tissue disorders
- Rash, erythema, pruritus
- Musculoskeletal, connective tissue and bone disorders
- Musculoskeletal pain, arthralgia, tendonitis, joint swelling
- General disorders and administration site conditions
- Pyrexia, fatigue, peripheral edema

# Drug Interactions
- Tofacitinib exposure is increased when tofacitinib is coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole).
- Tofacitinib exposure is increased when tofacitinib is coadministered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole).
- Tofacitinib exposure is decreased when tofacitinib is coadministered with potent CYP3A4 inducers (e.g., rifampin) .
- There is a risk of added immunosuppression when tofacitinib is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in rheumatoid arthritis.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies in pregnant women. Tofacitinib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Tofacitinib has been shown to be fetocidal and teratogenic in rats and rabbits when given at exposures 146 times and 13 times, respectively, the maximum recommended human dose (MRHD).
- In a rat embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 146 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively, and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum).
- In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day). In the rabbit embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 13 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day) in the absence of signs of maternal toxicity.
- Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).
- In a peri- and postnatal rat study, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the MRHD (on an AUC basis at oral doses of 50 mg/kg/day). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).
- Pregnancy registry has been established  to monitor the outcomes of pregnant women exposed to XELJAN
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tofacitinib in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Tofacitinib during labor and delivery.

### Nursing Mothers
- Tofacitinib was secreted in milk of lactating rats. It is not known whether tofacitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from tofacitinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug for the mother.

### Pediatric Use
- The safety and effectiveness of tofacitinib in pediatric patients have not been established.

### Geriatic Use
- Of the 3315 patients who enrolled in Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among tofacitinib-treated subjects 65 years of age and older was higher than among those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

### Gender
There is no FDA guidance on the use of Tofacitinib with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Tofacitinib with respect to specific racial populations.

### Renal Impairment
- No dose adjustment is required in patients with mild renal impairment. Tofacitinib dose should be reduced to 5 mg once daily in patients with moderate and severe renal impairment. In clinical trials, tofacitinib was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance values (estimated by the Cockroft-Gault equation) less than 40 mL/min.

### Hepatic Impairment
- Treatment with tofacitinib is not recommended in patients with severe hepatic impairment. No dose adjustment is required in patients with mild hepatic impairment. tofacitinib dose should be reduced to 5 mg once daily in patients with moderate hepatic impairment. The safety and efficacy of tofacitinib have not been studied in patients with severe hepatic impairment or in patients with positive hepatitis B virus or hepatitis C virus serology

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tofacitinib in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Tofacitinib in patients who are immunocompromised.

### Nonteratogenic effects:

# Administration and Monitoring

### Administration
- Oral

### Monitoring
- Laboratory monitoring Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids.
- Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib. Tofacitinib should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis.
- 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.
- Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury.

# IV Compatibility
There is limited information regarding IV Compatibility of Tofacitinib in the drug label.

# Overdosage
- Signs, Symptoms, and Laboratory Findings of Acute Overdosage in Humans
- There is no experience with overdose of tofacitinib.
- Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate that more than 95% of the administered dose is expected to be eliminated within 24 hours.
- There is no specific antidote for overdose with tofacitinib. 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.

# Pharmacology

## Mechanism of Action
- Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.

## Structure

## Pharmacodynamics
- Treatment with XELJANZ was associated with dose-dependent reductions of circulating CD16/56+ natural killer cells, with estimated maximum reductions occurring at approximately 810 weeks after initiation of therapy. These changes generally resolved within 26 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 (CD3+, CD4+ and CD8+) were small and inconsistent. The clinical significance of these changes is unknown.
Total serum IgG, IgM, and IgA levels after 6-month dosing in patients with rheumatoid arthritis were lower than placebo; however, changes were small and not dose-dependent.
After treatment with XELJANZ in patients with rheumatoid arthritis, 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 pharmacokinetic half-life.

## Pharmacokinetics
Following oral administration of XELJANZ, peak plasma concentrations are reached within 0.51 hour, elimination half-life is ~3 hours and a dose-proportional increase in systemic exposure was observed in the therapeutic dose range. Steady state concentrations are achieved in 2448 hours with negligible accumulation after twice daily administration.
Absorption
The absolute oral bioavailability of tofacitinib is 74%. 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 meals.
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 1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.
Metabolism and Elimination
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.
Pharmacokinetics in Rheumatoid Arthritis Patients
Population PK analysis in rheumatoid arthritis patients indicated no clinically relevant change in tofacitinib exposure, after accounting for differences in renal function (i.e., creatinine clearance) between patients, based on age, weight, gender and race (Figure 1). 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 tofacitinib is estimated to be approximately 27%.
Specific Populations
The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of tofacitinib is shown in Figure 1.
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.
Drug Interactions
Potential for XELJANZ to Influence the PK of Other Drugs
In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations exceeding 185 times the steady state Cmax of a 5 mg twice daily dose. These in vitro results were confirmed by a human drug interaction study showing no changes in the PK of midazolam, a highly sensitive CYP3A4 substrate, when coadministered with XELJANZ.
In rheumatoid arthritis patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in rheumatoid arthritis patients. Therefore, coadministration with XELJANZ is not expected to result in clinically relevant increases in the metabolism of CYP substrates in rheumatoid arthritis patients.
In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is low.
Dosing recommendations for coadministered drugs following administration with XELJANZ are shown in Figure 2.

## Nonclinical Toxicology
- In a 39-week toxicology study in monkeys, tofacitinib at exposure levels approximately 6 times the MRHD (on an AUC basis at oral doses of 5 mg/kg twice daily) produced lymphomas. No lymphomas were observed in this study at exposure levels 1 times the MRHD (on an AUC basis at oral doses of 1 mg/kg twice daily).
- The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib, at exposure levels approximately 34 times the MRHD (on an AUC basis at oral doses of 200 mg/kg/day) was not carcinogenic in mice.
- In the 24-month oral carcinogenicity study in Sprague-Dawley rats, tofacitinib caused benign Leydig cell tumors, hibernomas (malignancy of brown adipose tissue), and benign thymomas at doses greater than or equal to 30 mg/kg/day (approximately 42 times the exposure levels at the MRHD on an AUC basis). The relevance of benign Leydig cell tumors to human risk is not known.
- Tofacitinib was not mutagenic in the bacterial reverse mutation assay. It was positive for clastogenicity in the in vitro chromosome aberration assay with human lymphocytes in the presence of metabolic enzymes, but negative in the absence of metabolic enzymes. Tofacitinib was negative in the in vivo rat micronucleus assay and in the in vitro CHO-HGPRT assay and the in vivo rat hepatocyte unscheduled DNA synthesis assay.
- In rats, tofacitinib at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day) reduced female fertility due to increased post-implantation loss. There was no impairment of female rat fertility at exposure levels of tofacitinib equal to the MRHD (on an AUC basis at oral doses of 1 mg/kg/day). Tofacitinib exposure levels at approximately 133 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day) had no effect on male fertility, sperm motility, or sperm concentration.

# Clinical Studies
- The XELJANZ clinical development program included two dose-ranging trials and five confirmatory trials.
- Dose selection for XELJANZ was based on two pivotal dose-ranging trials.
- Dose-Ranging Study 1 was a 6-month monotherapy trial in 384 patients with active rheumatoid arthritis who had an inadequate response to a DMARD. Patients who previously received adalimumab therapy were excluded. Patients were randomized to 1 of 7 monotherapy treatments: XELJANZ 1, 3, 5, 10 or 15 mg twice daily, adalimumab 40 mg subcutaneously every other week for 10 weeks followed by XELJANZ 5 mg twice daily for 3 months, or placebo.
- Dose-Ranging Study 2 was a 6-month trial in which 507 patients with active rheumatoid arthritis who had an inadequate response to MTX alone received one of 6 dose regimens of XELJANZ (20 mg once daily; 1, 3, 5, 10 or 15 mg twice daily), or placebo added to background MTX.
- The results of XELJANZ-treated patients achieving ACR20 responses in Studies 1 and 2 are shown in Figure 4. Although a dose-response relationship was observed in Study 1, the proportion of patients with an ACR20 response did not clearly differ between the 10 mg and 15 mg doses. Furthermore, there was a smaller proportion of patients who responded to adalimumab monotherapy compared to those treated with XELJANZ doses 3 mg twice daily and greater. In Study 2, a smaller proportion of patients achieved an ACR20 response in the placebo and XELJANZ 1 mg groups compared to patients treated with the other XELJANZ doses. However, there was no difference in the proportion of responders among patients treated with XELJANZ 3, 5, 10, 15 mg twice daily or 20 mg once daily doses.
CONFIRMATORY TRIALS
Study I was a 6-month monotherapy trial in which 610 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a DMARD (nonbiologic or biologic) received XELJANZ 5 or 10 mg twice daily or placebo. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire  Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.
Study II was a 12-month trial in which 792 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a nonbiologic DMARD received XELJANZ 5 or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments such as azathioprine or cyclosporine). At the Month 3 visit, nonresponding patients were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. At the end of Month 6, all placebo patients were advanced to their second predetermined treatment in a blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3, and rates of DAS28-4(ESR) less than 2.6 at Month 6.
Study III was a 12-month trial in 717 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX. Patients received XELJANZ 5 or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX.
Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
Study IV is an ongoing 2-year trial with a planned analysis at 1 year in which 797 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
Study V was a 6-month trial in which 399 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to at least one approved TNF-inhibiting biologic agent received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) less than 2.6.
Clinical Response
The percentages of XELJANZ-treated patients achieving ACR20, ACR50, and ACR70 responses in Studies I, IV, and V are shown in Table 5. Similar results were observed with Studies II and III. In all trials, patients treated with either 5 or 10 mg twice daily XELJANZ had higher ACR20, ACR50, and ACR70 response rates versus placebo, with or without background DMARD treatment, at Month 3 and Month 6. Higher ACR20 response rates were observed within 2 weeks compared to placebo. In the 12-month trials, ACR response rates in XELJANZ-treated patients were consistent at 6 and 12 months.

# How Supplied
- XELJANZ is provided as 5 mg tofacitinib (equivalent to 8 mg tofacitinib citrate) tablets: White, round, immediate-release film-coated tablets, debossed with "Pfizer" on one side, and "JKI 5" on the other side, and available in:

## Storage
- Store at 20C to 25C (68F to 77F).
- Do not repackage.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking XELJANZ. Instruct patients to take XELJANZ only as prescribed.

# Precautions with Alcohol
- Alcohol-Tofacitinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- XELJANZ 

# Look-Alike Drug Names
There is limited information regarding Tofacitinib Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price