Tofacitinib

For the treatment of moderate to severe rheumatoid arthritis which is resistant or intolerant to methotrexate therapy. It may also be used as an adjunct to methotrexate therapy, or other non-biologic disease-modifying antirheumatic drugs (DMARDS), when methotrexate alone is not sufficient. Tofacitinib has also been investigated as a preventative therapy for kidney transplant rejections, and as a treatment for psoriasis, ulcerative colitis, and ankylosing spondylitis. It is not to be initiated in patients with a history of chronic or recurrent infections, or in the presence of active infection, even if localized, due to reports of serious and sometimes fatal infections (commonly pneumonia, herpes zoster and urinary tract infections). Use of Tofacitinib is also discouraged in those who have been, or are likely to be, exposed to TB. An increased likelihood of exposure may be encountered by traveling to certain areas. In addition, Tofacitinib is not to be used in patients with severe hepatic impairment, or low hemoglobin (less than 9g/dL). Cautioned is advised when using Tofacitinib in patients at risk of gastrointestinal perforation, and in the elderly who are more susceptible to infection. (moderate Rheumatoid arthritis; severe Rheumatoid arthritis;)

Tofacitinib works by blocking certain enzymes in the body that affect immune system function.

Tofacitinib is used to treat moderate to severe rheumatoid arthritis in adults who have tried methotrexate without successful treatment of symptoms. Tofacitinib is sometimes given in combination with methotrexate or other arthritis medicines.

Tofacitinib may also be used for purposes not listed in this medication guide.

Dosage In Rheumatoid Arthritis

• Tofacitinib/Tofacitinib XR may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). The recommended dose of Tofacitinib is 5 mg twice daily and the recommended dose of Tofacitinib XR is 11 mg once daily.
• Tofacitinib/Tofacitinib XR is given orally with or without food.
• Swallow Tofacitinib XR tablets whole and intact. Do not crush, split, or chew.

Switching From Tofacitinib Tablets To Tofacitinib XR Tablets

Patients treated with Tofacitinib 5 mg twice daily may be switched to Tofacitinib XR 11 mg once daily the day following the last dose of Tofacitinib 5 mg.

Dosage Modifications Due To Serious Infections And Cytopenias

• It is recommended that Tofacitinib/Tofacitinib XR not be initiated in patients with an absolute 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.
• Dose interruption is recommended for management of lymphopenia, neutropenia and anemia.
• Avoid use of Tofacitinib/Tofacitinib XR if a patient develops a serious infection until the infection is controlled.

Dosage Modifications Due To Drug Interactions

• 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), the recommended dose is Tofacitinib 5 mg once daily.
• Coadministration of potent inducers of CYP3A4 (e.g., rifampin) with Tofacitinib/Tofacitinib XR may result in loss of or reduced clinical response to Tofacitinib/Tofacitinib XR.
• Coadministration of potent inducers of CYP3A4 with Tofacitinib/Tofacitinib XR is not recommended.

Dosage Modifications In Patients With Renal Or Hepatic Impairment

• In patients with:
  • moderate or severe renal insufficiency, or
  • moderate hepatic impairment, the recommended dose is Tofacitinib 5 mg once daily.

Use of Tofacitinib/Tofacitinib XR in patients with severe hepatic impairment is not recommended.

Table 1: Dose Adjustments for Lymphopenia

Table 2: Dose Adjustments for Neutropenia

Table 3: Dose Adjustments for Anemia

How supplied

Dosage Forms And Strengths

Tofacitinib 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.

Tofacitinib XR is provided as 11 mg Tofacitinib (equivalent to 17.77 mg Tofacitinib citrate) tablets: Pink, oval, extended release film-coated tablets with a drilled hole at one end of the tablet band and “JKI 11” printed on one side of the tablet.

Tofacitinib 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:

Tofacitinib

Bottles of 28: NDC 0069-1001-03

Bottles of 60: NDC 0069-1001-01

Bottles of 180: NDC 0069-1001-02

Tofacitinib XR is provided as 11 mg Tofacitinib (equivalent to 17.77 mg Tofacitinib citrate) tablets: Pink, oval, extended release tablet with a drilled hole at one end of the tablet band and “JKI 11” printed on one side of the tablet:

Tofacitinib XR

Bottles of 14: NDC 0069-0501-14

Bottles of 30: NDC 0069-0501-30

Storage And Handling

Store Tofacitinib/Tofacitinib XR at 20°C to 25°C (68°F to 77°F)..

Do not repackage.

Distributed by : Pfizer Labs, Division of Pfizer Inc., NY, NY 10017. Revised: February 2016

See also:
What is the most important information I should know about Tofacitinib?

Tofacitinib is used to treat moderate to severe rheumatoid arthritis in adults who have tried methotrexate without successful treatment of symptoms.

You should not use Tofacitinib if you have severe liver disease.

Stop using this medicine and call your doctor right away if you have signs of infection such as: fever, chills, sore throat, flu symptoms, sores or white patches in your mouth or throat, night sweats, stomach pain, diarrhea, weight loss, skin redness and swelling, or cough and chest pain.

If you have hepatitis B or C you may develop liver symptoms while taking this medication. Your doctor may want to check your liver function before and during your treatment with Tofacitinib.

Do not receive a "live" vaccine while using Tofacitinib, and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you.

Use Tofacitinib as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Tofacitinib comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Tofacitinib refilled.
• Take Tofacitinib by mouth with or without food.
• Talk with your doctor before including grapefruit or grapefruit juice in your diet.
• Continue to take Tofacitinib even if you feel well. Do not miss any doses.
• If you miss a dose of Tofacitinib, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Tofacitinib.

Use: Labeled Indications

Psoriatic arthritis: Treatment of active psoriatic arthritis in adults who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs)

Rheumatoid arthritis: Treatment of moderately to severely active rheumatoid arthritis (as monotherapy or in combination with methotrexate or other nonbiologic DMARDs) in adults who have had an inadequate response to, or are intolerant of, methotrexate

Ulcerative colitis: Treatment of moderately to severely active ulcerative colitis in adults who have had an inadequate response or intolerance to tumor necrosis factor blockers

Limitations of use: The use of Tofacitinib in combination with biologic DMARDs or with potent immunosuppressants (eg, azathioprine, cyclosporine) is not recommended.

See also:
What other drugs will affect Tofacitinib?

Interactions Affecting the Use of Tofacitinib: Since Tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce CYP3A4 is likely. Tofacitinib exposure is increased when co-administered with potent inhibitors of cytochrome P450 (CYP) 3A4 (eg, ketoconazole) or when administration of one or more 1 concomitant medications results in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (eg, fluconazole).

Tofacitinib exposure is decreased when co-administered with potent CYP inducers (eg, rifampin). Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to significantly alter the PK of Tofacitinib.

Concomitant administration with methotrexate (MTX) 15-25 mg once weekly had no effect on the pharmacokinetics of Tofacitinib. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, with a single dose of Tofacitinib increased the AUC and C_max by 103% and 16%, respectively. Co-administration of fluconazole, a moderate inhibitor of CYP3A4 and a strong inhibitor of CYP2C19, increased the AUC and C_max of Tofacitinib by 79% and 27%, respectively. Co-administration of tacrolimus (Tac), a mild inhibitor of CYP3A4, increased the AUC of Tofacitinib by 21% and decreased the C_max of Tofacitinib by 9%. Co-administration of cyclosporine (CsA), a moderate inhibitor of CYP3A4, increased the AUC of Tofacitinib by 73% and decreased C_max of Tofacitinib by 17%. The combined use of multiple-dose Tofacitinib with these potent immunosuppressives has not been studied in patients with rheumatoid arthritis (RA). Co-administration of rifampin, a strong CYP3A4 inducer, decreased the AUC and C_max of Tofacitinib by 84% and 74%, respectively.

Potential for Tofacitinib 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 130 times the steady state free C_max of a 10 mg twice daily dose. These in vitro results were confirmed by a human drug interaction study showing no changes in the pharmacokinetics of midazolam, a highly sensitive CYP3A4 substrate, when co-administered with Tofacitinib. In vitro data indicate that the potential for Tofacitinib to inhibit transporters eg, P-glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is also low.

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

Co-administration of Tofacitinib with methotrexate 15-25 mg once weekly decreased the AUC and C_max of MTX by 10% and 13% respectively. The extent of decrease in methotrexate exposure does not warrant modifications to the individualized dosing of methotrexate.

Co-administration of Tofacitinib did not have an effect on the pharmacokinetics of metformin, indicating that Tofacitinib does not interfere with the organic cationic transporter (OCT2) in healthy volunteers.

In rheumatoid patients, the oral clearance of Tofacitinib does not vary with time, indicating that Tofacitinib does not normalize CYP enzyme activity in RA patients. Therefore, co-administration with Tofacitinib is not expected to result in clinically relevant increases in the metabolism of CYP substrates in RA patients.

Pediatric Population: Studies have only been performed in adults.

See also:
What are the possible side effects of Tofacitinib?

The following data includes 5 double-blind, controlled, multicenter studies. In these studies, patients were randomized and treated to doses of Tofacitinib 5 mg twice daily (243 patients) or 10 mg twice daily (245 patients) monotherapy and Tofacitinib 5 mg twice daily (973 patients) or 10 mg twice daily (969 patients) in combination with DMARDs (including methotrexate).

Of the 3030 patients who received Tofacitinib in these 5 clinical studies, including those who advanced from placebo to Tofacitinib, 1871 received treatment for at least 6 months and 580 for at least one year.

The long-term safety population includes all patients who participated in a double-blind, controlled study (including earlier development phase studies) and then participated in one of two long-term safety studies.

Of the 3227 patients who received Tofacitinib in the long-term studies, 1689 received open-label treatment for at least 6 months, 970 for at least one year, 659 received treatment for at least 2 years, and 62 for at least 3 years.

All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 54 years and 84% were female.

Clinical Trials Experience: The most common serious adverse reactions in rheumatoid arthritis were serious infections.

Rheumatoid Arthritis: In rheumatoid arthritis, the most commonly reported adverse reactions during the first 3 months in controlled clinical trials (occurring in ≥2% of patients treated with Tofacitinib citrate (Tofacitinib) monotherapy or in combination with DMARDs) were upper respiratory tract infections, headache, nasopharyngitis, and diarrhea.

The proportion of patients who discontinued treatment due to any adverse reactions during first 3 months of the double-blind, placebo-controlled studies was 4.2% for patients taking Tofacitinib citrate (Tofacitinib) and 3.2% for placebo-treated patients. The most common infections resulting in discontinuation of therapy were herpes zoster and pneumonia.

The Adverse Drug Reactions (ADRs) listed in the table below are presented by System Organ Class (SOC) and frequency categories, defined using the following convention: Very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) or rare (≥1/10,000 to <1/1,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Overall Infections: Rheumatoid Arthritis: In the 6-month, controlled clinical study the rates of infections in the 5 mg twice daily and 10 mg twice daily Tofacitinib monotherapy group were 16.5% and 19.2%, respectively, compared to 18.9% in the placebo group. In studies of 6- or 12- month duration without background DMARDs, the rates of infections in the 5 mg twice daily and 10 mg twice daily Tofacitinib plus DMARD group were 20.9% and 21.7%, respectively, compared to 18.2% in the placebo plus DMARD group.

The most commonly reported infections were upper respiratory tract infections and nasopharyngitis (4.1% and 3.4%, respectively).

The overall rate of infections with Tofacitinib citrate (Tofacitinib) in the long-term safety all exposure population was 41.5 events per 100 patient-years (31.5 and 66.9 events for 5 mg and 10 mg twice daily, respectively). For patients on monotherapy, the rates were 35.5 and 55.8 events per 100 patient-years for 5 mg and 10 mg twice daily, respectively. For patients on background DMARDs, the rates were 28.8 and 78.4 events per 100 patient years for 5 mg and 10 mg twice daily, respectively.

Serious Infections: Rheumatoid Arthritis: In the 6-month, controlled clinical study, the rate of serious infections in the 5 mg twice daily Tofacitinib monotherapy group was 0.85 events per 100 patient years. In the 10 mg twice daily Tofacitinib monotherapy group, the rate was 3.5 events per 100 patient-years, and the rate was 0 events per 100 patient-years for the placebo group.

In studies of 6- or 12-months duration, the rates of serious infections in the 5 mg twice daily and 10 mg twice daily Tofacitinib plus DMARD groups were 3.6 and 2.9 events per 100 patient-years, respectively, compared to 1.7 events per 100 patient-years in the placebo plus DMARD group.

In the long-term safety all exposure population, the overall rates of serious infections were 2.3 and 4.9 events per 100 patient-years for 5 mg and 10 mg twice daily Tofacitinib, respectively. The most common serious infections reported with Tofacitinib included pneumonia, herpes zoster, urinary tract infection, and diverticulitis. Cases of opportunistic infections have been reported.

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 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.

Clinical Experience in Methotrexate-Naive Rheumatoid Arthritis Patients: Study VI was an active-controlled clinical trial in methotrexate-naive RA patients. The safety experience in these patients was consistent with Studies I-V.

Laboratory Tests: Lymphocytes: In the controlled clinical studies in rheumatoid arthritis, confirmed decreases in lymphocyte counts below 500 cells/mm³ occurred in 0.21% of patients for the 5 mg twice daily and 10 mg twice daily doses combined.

In the long-term safety population in rheumatoid arthritis, confirmed decreases in lymphocyte counts below 500 cells/mm³ occurred in 0.31% of patients for the 5 mg twice daily and 10 mg twice daily doses combined.

Confirmed lymphocyte counts <500 cells/mm³ were associated with an increased incidence of treated and serious infections.

Neutrophils: In the controlled clinical studies in rheumatoid arthritis, confirmed decreases in ANC below 1000 cells/mm³ occurred in 0.08% of patients for the 5 mg twice daily and 10 mg twice daily doses combined. There were no confirmed decreases in ANC below 500 cells/mm³ observed in any treatment group. There was no clear relationship between neutropenia and the occurrence of serious infections.

In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the controlled clinical studies.

Liver Enzyme Tests: Rheumatoid Arthritis: Confirmed increases in liver enzymes >3 times the upper limit of normal (3 x ULN) were uncommonly observed. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of Tofacitinib, or reduction in Tofacitinib dose, resulted in decrease or normalization of liver enzymes.

In the controlled portion of the phase 3 monotherapy study (0-3 months), ALT elevations >3 x ULN were observed in 1.65%, 0.41%, and 0% of patients receiving placebo, 5 mg and 10 mg twice daily, respectively. In this study, AST elevations >3 x ULN were observed in 1.65%, 0.41% and 0% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively.

In the controlled portion of the phase 3 studies on background DMARDs (0-3 months), ALT elevations >3 x ULN were observed in 0.9%, 1.24% and 1.25% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these studies, AST elevations >3 x ULN were observed in 0.72%, 0.5% and 0.42% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively.

Lipids: Elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were first assessed at one month following initiation of Tofacitinib citrate (Tofacitinib) in the controlled double-blind clinical trials. Increases were observed at this time point and remained stable thereafter.

Rheumatoid Arthritis: Changes in lipid parameters from baseline through the end of the study (6-12 months) in the controlled clinical studies in rheumatoid arthritis are summarized as follows: Mean LDL cholesterol increased by 14% in the Tofacitinib 5 mg twice daily arm and 20% in the Tofacitinib 10 mg twice daily arm; mean HDL cholesterol increased by 16% in the Tofacitinib 5 mg twice daily arm and 18% in the Tofacitinib 10 mg twice daily arm.

Upon withdrawal of Tofacitinib treatment, lipid levels returned to baseline.

In both rheumatoid arthritis, Mean LDL cholesterol/HDL cholesterol ratios and Apolipoprotein B (ApoB)/ApoA1 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 populations, elevations in the lipid parameters remained consistent with what was seen in the controlled clinical studies.

Each 5 mg of film-coated tablet contains 8.078 mg of Tofacitinib citrate equivalent to Tofacitinib 5 mg free base active pharmaceutical ingredient. Each 5 mg tablet also contains 62.567 mg lactose monohydrate.

Tofacitinib citrate (CP-690,550-10) has a molecular weight of 504.5 Daltons, or 312.4 Daltons, for Tofacitinib free base (CP-690,550). The molecular formula of Tofacitinib citrate is C₁₆H₂₀N₆O·C₆H₈O₇.

Excipients/Inactive Ingredients: Microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate. Film Coat for 5 mg Tablets: Opadry II White (33G28523) Containing: HPMC 2910/Hypromellose 6cP, titanium dioxide, lactose monohydrate, macrogol/PEG3350 and triacetin (glycerol triacetate).