TRIJAN

Tofacitinib is an inhibitor of

Janus kinases, a group of intracellular enzymes involved in signalling pathways that affect hematopoiesis and immune cell function.

It is approved by the

FDA for treatment of moderate to severe rheumatoid arthritis that responds inadequately to methotrexate or in those who are intolerant to methotrexate.

Besides rheumatoid arthritis, tofacitinib has also been studied in clinical trials for the prevention of organ transplant rejection, and is currently under investigation for the treatment of psoriasis.

Known adverse effects include nausea and headache as well as more serious immunologic and hematological adverse effects.

Tofacitinib is marketed under the brand name Xeljanz by Pfizer.

Tofacitinib is indicated for the treatment of adult patients with moderately-to-severely active rheumatoid arthritis (RA), active psoriatic arthritis, active ankylosing spondylitis, or moderately-to-severely active ulcerative colitis who have had an inadequate response or intolerance to one or more TNF blockers.

It is also indicated as an oral solution in patients ≥2 years of age for the treatment of polyarticular course juvenile idiopathic arthritis who have had an inadequate response or intolerance to one or more TNF blockers.

Tofacitinib is not recommended to be used in combination with other biologic disease-modifying anti-rheumatic drugs (DMARDs) or potent immunosuppressive agents such as azathioprine or cyclosporine.

Tofacitinib targets inflammation present in rheumatoid arthritis by inhibiting the janus kinases involved in the inflammatory response pathway.

In placebo controlled trials of rheumatoid arthritis patients receiving 5 mg or 10 mg of tofacitinib twice daily, higher ACR20 responses were observed within 2 weeks in some patients (with ACR20 being defined as a minimum 20% reduction in joint pain or tenderness and 20% reduction in arthritis pain, patient disability, inflammatory markers, or global assessments of arthritis by patients or by doctors, according to the American College of Rheumatology (ACR) response criteria list), and improvements in physical functioning greater than placebo were also noted.

Common known adverse effects of tofacitinib include headaches, diarrhea, nausea, nasopharyngitis and upper respiratory tract infection.

More serious immunologic and hematological adverse effects have also been noted resulting in lymphopenia, neutropenia, anemia, and increased risk of cancer and infection.

Before initiations of tofacitinib patients should be tested for latent infections of tuberculosis, and should be closely monitored for signs and symptoms of infection (fungal, viral, bacterial, or mycobacterial) during therapy.

Therapy is not to be started in the presence of active infection, systemic or localized, and is to be interrupted if a serious infection occurs.

Tofacitinib has been associated with an increased risk of lymphomas, such as Epstein-Barr virus associated lymphomas, and other malignancies (including lung, breast, gastric, and colorectal cancers).

It is recommended to monitor lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids.

Tofacitinib use is associated with a rapid decrease in C-reactive protein (CRP), dose dependent decreases in natural killer cells, and dose dependent increases in B cells.

Depression in

C-reactive protein levels continue after 2 weeks of tofacitinib discontinuation and suggest that pharmacodynamic activity last longer than pharmacokinetic half life.

Tyrosine-protein kinase

JAK1 Inhibitor Tyrosine-protein kinase JAK2 Inhibitor Tyrosine-protein kinase JAK3 Inhibitor + 1 more target.

74% oral absorption (absolute bioavailability), with peak plasma concentrations (T max ) achieved in 0.5-1 hour.

Administration with fatty meals does not alter AUC but reduces Cmax by 32%.

Vd= 87 L after intravenous administration.

Distribution is equal between red blood cells and plasma.

Metabolized in the liver by

Metabolites produced are inactive.

70% metabolized in the liver by CYP3A4 (major) and CYP2C19 (minor).

Metabolites produced are inactive. 30% renally eliminated as unchanged drug.

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Minimum lethal dose in rat: 500 mg/kg. Maximum asymptomatic dose in non human primate: 40 mg/kg. Lymphatic, immune system, bone marrow and erythroid cell toxicity was seen in animal studies involving rate and monkeys.

Doses used in these studies ranged from 1 mg/kg/day to 10 mg/kg/day, over a duration of 6 weeks to 6 months.

Lymphopenia, neutropenia, and anemia is seen in human subjects and may call for an interruption or discontinuation of therapy if severe.

Reduced female fertility in rats was seen at exposures 17 times the maximum recommended human dose.

Fertility may be impaired in human females and harm may be caused to unborn child.

Carcinogenic potential is seen, however evidence for dose dependency is lacking.

Because the janus kinase pathway plays a role in stimulating the production of red blood cells and is involved in immune cell function, inhibition of this pathway leads to increased risk of anemia, neutropenia, lymphopenia, cancer and infection.

Lymphopenia, neutropenia, and anemia in human subjects may call for an interruption or discontinuation of therapy if severe.

Role of

JAK inhibition in the development of gastrointestinal perforation is not known.

Recommended Evaluations and Immunization Prior to Treatment Initiation Prior to initiating tofacitinib extended-release tablets, consider performing an active and latent TB evaluation, viral hepatitis screening, a complete blood count, and updating immunizations.

Avoid tofacitinib extended-release tablets initiation if absolute lymphocyte count < 500 cells/mm3, an absolute neutrophil count (ANC) < 1,000 cells/mm3 or hemoglobin < 9 g/dL.

Tofacitinib extended-release tablets is not substitutable with tofacitinib tablets and tofacitinib oral solution.

Switching between tofacitinib tablets and tofacitinib extended-release tablets should be made by the healthcare provider.

Recommended Dosage Adult Patients with

RA, PsA or AS Tofacitinib extended-release tablets 11 mg ones daily.

Tofacitinib extended-release tablets 22 mg once daily for 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response.

If needed, continue tofacitinib extended-release tablets 22 mg once daily for a maximum of 16 weeks.

Discontinue tofacitinib extended-release tablets 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved.

Tofacitinib extended-release tablets 11 mg once daily.

For patients with loss of response during maintenance treatment, tofacitinib extended-release tablets 22 mg once daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient.

Use the lowest effective dose needed to maintain response.

Dosage in Patients with Renal Impairment or Hepatic Impairment Use of tofacitinib extended-release tablets in patients with severe HI is not recommended.

See full prescribing information (FPI) for recommended dosage in patients with moderate or severe RI or moderate HI.

See the full prescribing information for dosage modification by indication for patients who concomitantly use CYP2C19 and/or CYP3A4 inhibitors and patients with lymphopenia, neutropenia, or anemia. 2.1 Recommended Evaluations and Immunization Prior to Treatment Initiation Prior to initiating tofacitinib extended-release tablets, consider performing the following: Active and latent tuberculosis (TB) infection evaluation: If the patient has latent TB, treat for TB prior to tofacitinib extended-release tablets treatment.

Viral hepatitis screening in accordance with clinical guidelines.

A complete blood count

Avoid initiation of tofacitinib extended-release tablets treatment in patients with a lymphocyte count less than 500 cells/mm 3, absolute neutrophil count less than 1,000 cells/mm 3, or hemoglobin level less than 9 g/dL.

Baseline hepatic function evaluation: tofacitinib extended-release tablets is not recommended for patients with severe hepatic impairment.

Update immunizations according to current immunization guidelines.

The interval between live vaccinations and initiation of tofacitinib extended-release tablets should be in accordance with current vaccination guidelines regarding immunosuppressive agents. 2.2 Important Administration Instructions Tofacitinib extended-release tablets is not substitutable with tofacitinib tablets and tofacitinib oral solution.

Dose interruption is recommended for management of lymphopenia, neutropenia, and anemia.

Interrupt use of tofacitinib extended-release tablets if a patient develops a serious infection until the infection is controlled.

Take tofacitinib extended-release tablets with or without food.

Swallow tofacitinib extended-release tablets whole and intact.

Do not crush, split, or chew the extended-release tablets. 2.3 Recommended Dosage in Adults with Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis Table 1 displays the recommended dosage of tofacitinib extended-release tablets for adults with RA, PsA, and AS with and without renal impairment (including those who are undergoing hemodialysis) or hepatic impairment.

The table also displays the recommended dosage modifications for patients concomitantly using CYP2C19 and/or CYP3A4 inhibitors, and patients with lymphopenia, neutropenia, or anemia.

Table 1 Recommended Dosage of Tofacitinib extended-release tablets in Adults with Rheumatoid Arthritis, Psoriatic Arthritis, or Ankylosing Spondylitis a Excludes patients who concomitantly use tofacitinib extended-release tablets with strong CYP3A4 inhibitor(s) or moderate CYP3A4 inhibitor(s) and strong CYP2C19 inhibitor(s), as well as patients with lymphocyte count less than 500 cells/mm 3, ANC < 1,000 cells/mm 3, or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. b Tofacitinib PK was evaluated in subjects with varying degrees of renal impairment, where the severity of renal impairment was defined based on creatinine clearance (CLcr) estimated using the Cockcroft-Gault equation: CLcr > 80 mL/min (normal renal function); > 50 and ≤ 80 mL/min (mild renal impairment); ≥ 30 and ≤ 50 mL/min (moderate renal impairment); < 30 mL/min (severe renal impairment).

Adults Tofacitinib extended-release tablets Patients with Normal Renal and Hepatic Function a 11 mg once daily Recommended Dosage in Patients with Renal Impairment (RI) b Mild RI (CLcr > 50 and ≤ 80 mL/min) 11 mg once daily Moderate RI (CLcr ≥ 30 and ≤ 50 mL/min) Tofacitinib tablets 5 mg once daily Severe RI (CLcr < 30 mL/min) Tofacitinib tablets 5 mg once daily For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days.

If a dose was taken before the dialysis procedure, supplemental doses are not recommended after dialysis.

Impairment (HI) Mild HI (Child-Pugh A) 11 mg once daily Moderate HI (Child-Pugh B) Tofacitinib tablets 5 mg once daily Severe HI (Child-Pugh C) Use of tofacitinib extended-release tablets is not recommended.

Dosage Modifications with Concomitant Use of

CYP3A4 and/or CYP2C19 Inhibitor(s) Strong CYP2C19 inhibitor(s) 11 mg once daily Moderate CYP2C19 inhibitor(s) Moderate CYP3A4 inhibitor(s) Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) Tofacitinib tablets 5 mg once daily Strong CYP3A4 inhibitor(s) Dosage Modifications for Lymphopenia, Neutropenia, or Anemia Patients with lymphocyte count less than 500 cells/mm 3, confirmed by repeat testing Discontinue dosing.

Patients with

ANC less than 500 cells/mm 3 Discontinue dosing.

ANC 500 cells/mm to 1,000 cells/mm 3 Interrupt dosing.

ANC is greater than 1000, resume 11 mg once daily.

Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL Interrupt dosing until hemoglobin values have normalized.

Switching from Tofacitinib Tablets to Tofacitinib Extended-Release Tablets Patients treated with tofacitinib tablets 5 mg twice daily may be switched to tofacitinib extended-release tablets 11 mg once daily the day following the last dose of tofacitinib tablets 5 mg. 2.5 Recommended Dosage in Adults with Ulcerative Colitis Table 3 displays the recommended dosage of tofacitinib extended-release tablets in adult patients with ulcerative colitis (UC) with and without renal impairment (including those who are undergoing hemodialysis) or hepatic impairment.

Table 4 displays the recommended dosage modification for patients concomitantly using CYP2C19 and/or CYP3A4 inhibitors, and patients with lymphopenia, neutropenia, or anemia.

Table 3 Recommended Dosage of tofacitinib extended-release tablets in Adults with Ulcerative Colitis With and Without Renal Impairment or Hepatic Impairment a Excludes patients who concomitantly use tofacitinib extended-release tablets with strong CYP3A4 inhibitor(s) or moderate CYP3A4 inhibitor(s) and strong CYP2C19 inhibitor(s), as well as patients with lymphocyte count less than 500 cells/mm 3, ANC < 1,000 cells/mm 3, or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. b Tofacitinib PK was evaluated in subjects with varying degrees of renal impairment, where the severity of renal impairment was defined based on creatinine clearance (CLcr) estimated using the Cockcroft-Gault equation: CLcr > 80 mL/min (normal renal function); CLcr > 50 and ≤ 80 mL/min (mild renal impairment); ≥ 30 and ≤ 50 mL/min (moderate renal impairment); < 30 mL/min (severe renal impairment).

Adults Tofacitinib extended-release tablets Patients with Normal Renal and Hepatic Function a Induction: 22 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response.

If needed continue 22 mg once daily for a maximum of 16 weeks.

Discontinue 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved.

Maintenance: 11 mg once daily.

For patients with loss of response during maintenance treatment, may consider a dosage of 22 mg once daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient.

Impairment (RI) b Mild RI (CLcr > 50 and ≤ 80 mL/min) Same as patients with normal renal function.

RI (CLcr ≥ 30 and ≤ 50 mL/min) Induction: 11 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response.

If needed continue 11 mg once daily for a maximum of 16 weeks.

Discontinue 11 mg once daily after 16 weeks if adequate therapeutic response is not achieved.

Tofacitinib extended-release tablets are not recommended.

For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days.

RI (CLcr < 30 mL/min) Recommended Dosage in Patients with Hepatic Impairment (HI) Mild HI (Child-Pugh A) Same as patients with normal hepatic function.

HI (Child-Pugh B) Induction: 11 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response.

HI (Child-Pugh C) Use of tofacitinib extended-release tablets is not recommended.

Table 4 Dosage Modifications of Tofacitinib extended-release tablets Due to Drug Interactions and for Lymphopenia, Neutropenia or Anemia in Adults with Ulcerative Colitis Adults Tofacitinib extended-release tablets Dosage Modifications with Concomitant Use of CYP3A4 and/or CYP2C19 Inhibitor(s) Strong CYP2C19 inhibitor(s) No dosage modification is recommended.

CYP2C19 inhibitor(s) Moderate CYP3A4 inhibitor(s) Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) Induction: 1.

Tofacitinib extended-release tablets, 11 mg (equivalent to 17.77 mg tofacitinib citrate) are light pink to pink, oval shaped, film-coated tablets, imprinted with '1353' in black ink on one side and plain on other side and are supplied as follows: NDC 70710-1353-3 in bottle of 30 tablets with child-resistant closure.

NDC 70710-1353-9 in bottle of 90 tablets with child-resistant closure.

Tofacitinib extended-release tablets, 22 mg (equivalent to 35.53 mg tofacitinib citrate) are white to off-white, oval shaped, film-coated tablets imprinted with "1727" in black ink on one side and plain on other side and are supplied as follows: NDC 70710-1727-3 in bottle of 30 tablets with child-resistant closure.

NDC 70710-1727-9 in bottle of 90 tablets with child-resistant closure.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) .

Tofacitinib extended-release tablets

Do not repackage.

The available data with tofacitinib extended-release tablet from a pregnancy exposure registry that enrolled 11 exposed pregnant females, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

There are risks to the mother and the fetus associated with RA and UC in pregnancy.

In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively.

Further, in a peri.

• and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dosage of 5 mg twice daily and approximately 36 times the maximum recommended dosage of 10 mg twice daily, respectively.

The background risks of major birth defects and miscarriage for the indicated populations are unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

The background risks in the

U.S. general population of major birth defects and miscarriages are 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively.

Maternal and/or Embryo/Fetal Risk: Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with RA or UC.

Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 grams) infants, and small for gestational age at birth.

In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily, and approximately 73 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats).

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 recommended dose of 5 mg twice daily, and approximately 29 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats).

In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily, and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) 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 recommended dose of 5 mg twice daily, and approximately 1.5 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits).

In a peri.

• and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the recommended dose of 5 mg twice daily, and approximately 36 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats).

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 recommended dose of 5 mg twice daily, and approximately 8.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats).

The safety and effectiveness of tofacitinib extended-release tablets in pediatric patients for indications, other than in patients with PsA, have not been established.

The safety and effectiveness of tofacitinib extended-release tablets in pediatric patients have not been established.

Of the 3,315 adults who were enrolled in clinical trials with RA (Studies RA-I to V), a total of 505 patients were 65 years of age and older, including 71 patients 75 years and older.

The frequency of serious infection among tofacitinib tablets -treated patients 65 years of age and older was higher than among those adults under the age of 65.

Of the 1,156 tofacitinib tablet-treated patients in clinical trials of patients with UC, a total of 77 patients (7%) were 65 years of age or older.

Clinical studies of tofacitinib in patients with UC did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger adult patients.

Of the 783 tofacitinib tablet-treated patients in clinical trials of patients with PsA, a total of 72 (9.2%) patients were 65 years of age and older, including 2 (0.3%) patients 75 years and older.

These clinical studies did not include sufficient numbers of patients aged 65 years and older with PsA to determine if they respond differently from younger adult patients.

Of the 420 tofacitinib tablet-treated patients in clinical trials of patients with AS, a total of 12 (2.9%) patients were 65 years of age and older, including 1 (0.2%) patient 75 years and older.

These clinical studies did not include sufficient numbers of patients aged 65 years and older with AS to determine if they respond differently from younger adult patients.