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Tofacitinib is a brand name for Tofacitinib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE Tofacitinib extended-release tablets are Janus kinase (JAK) inhibitors. Tofacitinib extended-release tablets are indicated for the treatment of adult patients with: Moderately to severely active rheumatoid arthritis (RA), who have had an inadequate response or intolerance to one or more TNF…
Verbatim from this product's FDA label. Tap a section to expand.
2 DOSAGE AND ADMINISTRATION 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. 1 ) Important Administration Instructions Tofacitinib extended-release tablets is not substitutable with tofacitinib tablets and tofacitinib oral solution.
2 ) Switching between tofacitinib tablets and tofacitinib extended-release tablets should be made by the healthcare provider. 2 ) Recommended Dosage Adult Patients with RA, PsA or AS Tofacitinib extended-release tablets 11 mg ones daily.
3 ) Adult Patients with UC Induction: 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. 5 ) Maintenance: 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. 5 ) Dosage in Patients with Renal Impairment or Hepatic Impairment Use of tofacitinib extended-release tablets in patients with severe HI is not recommended. 7 ) See full prescribing information (FPI) for recommended dosage in patients with moderate or severe RI or moderate HI.
7 ) Dosage Modification 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. 1 )]. 1 )].
8 )]. 3 )]. Update immunizations according to current immunization guidelines. 9 )]. 2 Important Administration Instructions Tofacitinib extended-release tablets is not substitutable with tofacitinib tablets and tofacitinib oral solution.
8 )] Most common adverse reactions are: RA, PsA and AS : Reported in ≥ 2% of adult patients treated with tofacitinib extended-release tablets monotherapy or in combination with DMARDs: upper respiratory tract infection (URI), nasopharyngitis, diarrhea, and headache.
1 ) UC : Reported in ≥ 5% of adult patients treated with either tofacitinib extended-release tablets and ≥ 1% greater than reported in patients treated with placebo: nasopharyngitis, elevated cholesterol levels, headache, URI, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.
1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. gov/medwatch . 1 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 clinical studies described in this subsection were conducted using tofacitinib tablets (referred to as "tofacitinib" in this subsection of labeling). 6 )] . 3 ) and Warnings and Precautions ( 5 )]. 1 )] , the recommended dosage of tofacitinib is 5 mg twice daily and the recommended dosage for tofacitinib extended-release tablets is 11 mg once daily .
The safety of tofacitinib was also evaluated in two Phase 2 and five Phase 3 double-blind, placebo-controlled, multicenter trials in patients with RA.
In these trials, adults were randomized to receive:
Tofacitinib (monotherapy) 5 mg twice daily (292 patients) or 10 mg twice daily (306 patients), In combination with DMARDs (including methotrexate), tofacitinib 5 mg twice daily (1,044 patients) or 10 mg twice daily (1,043 patients) and Placebo (809 patients).
5 WARNINGS AND PRECAUTIONS Serious Infections : Avoid use of tofacitinib extended-release tablets during an active serious infection, including localized infections. 1 ) Gastrointestinal Perforations : Promptly evaluate patients at increased risk for gastrointestinal perforation who present with new onset abdominal symptoms.
6 ) Laboratory Monitoring : Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. 8 ) Vaccinations : Avoid use of live vaccines concurrently with tofacitinib extended-release tablets .
1 Serious Infections Serious and sometimes fatal infections may occur with tofacitinib extended-release tablets. Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib.
The most common serious infections reported with tofacitinib included pneumonia, urinary tract infection, cellulitis, herpes zoster, bronchitis, septic shock, diverticulitis, gastroenteritis, appendicitis, and sepsis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multi−dermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis 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. In the UC population, treatment with tofacitinib tablets 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily.
Additionally, opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with tofacitinib tablets 10 mg twice daily. , coccidioidomycosis).
4 CONTRAINDICATIONS None. None. ( 4 )
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Switching between tofacitinib tablets and tofacitinib extended-release tablets should be made by the healthcare provider. 1 )] . 1 )] . 3 )] . Swallow tofacitinib extended-release tablets whole and intact. 3 )]. 7 )]. 3 )], 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. Recommended Dosage in Patients with Hepatic 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.
, 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. Patients with ANC 500 cells/mm 3 to 1,000 cells/mm 3 Interrupt dosing. When 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.
7 )]. 3 )] , 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.
Use the lowest effective dose needed to maintain response . Recommended Dosage in Patients with Renal Impairment (RI) b Mild RI (CLcr > 50 and ≤ 80 mL/min) Same as patients with normal renal function. Moderate 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.
Maintenance:
Tofacitinib extended-release tablets are not recommended. 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.
Severe 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. Moderate 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.
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.
Maintenance:
Tofacitinib extended-release tablets are not recommended. Severe 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.
, fluconazole) 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.
Strong CYP3A4 inhibitor(s) Maintenance:
Tofacitinib extended-release tablets are not recommended. Dosage Modifications for Lymphopenia, Neutropenia, or Anemia Lymphocyte count less than 500 cells/mm 3 , confirmed by repeat testing Discontinue dosing. ANC less than 500 cells/mm 3 Discontinue dosing.
ANC 500 to 1,000 cells/mm 3 If taking: ●22 mg once daily, reduce to 11 mg once daily. When ANC is greater than 1,000, increase to 22 mg once daily based on clinical response. ●11 mg once daily, interrupt dosing. When ANC is greater than 1000, resume 11 mg once daily.
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.
10 mg twice daily may be switched to tofacitinib extended-release tablets 22 mg once daily the day following the last dose of tofacitinib extended-release tablets 10 mg.
All seven trials 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 groups were based on the first 3 months of exposure, and comparisons between tofacitinib 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 adults with RA who participated in a double-blind, placebo-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. 1 )] . The proportion of patients who discontinued treatment due to any adverse reaction during the 0 month to 3 months exposure in the double-blind, placebo-controlled trials was 4% for tofacitinib-treated patients and 3% for placebo-treated patients.
Overall Infections In the seven placebo-controlled trials in patients with RA, during the 0 month to 3 months exposure, the overall frequency of infections was 20% and 22% in the tofacitinib 5 mg twice daily and tofacitinib 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). 7 events per 100 patient-years) who received tofacitinib 5 mg or 10 mg twice daily.
5) events per 100 patient-years for the combined tofacitinib 5 mg twice daily and 10 mg twice daily group minus placebo. 7 events per 100 patient-years) who received tofacitinib 10 mg twice daily. 2) events per 100 patient-years for tofacitinib 10 mg twice daily minus tofacitinib 5 mg twice daily.
1 )] .
Tuberculosis:
In the seven placebo-controlled trials in patients with RA, during the 0 month to 3 months exposure, tuberculosis (TB) was not reported in patients who received placebo, tofacitinib 5 mg twice daily, or tofacitinib 10 mg twice daily.
5 events per 100 patient-years) who received tofacitinib 10 mg twice daily. 9) events per 100 patient-years for tofacitinib 10 mg twice daily minus tofacitinib 5 mg twice daily. Cases of disseminated TB were also reported. 1 )].
Opportunistic Infections (excluding tuberculosis):
In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, tofacitinib 5 mg twice daily, or tofacitinib 10 mg twice daily.
3 events per 100 patient-years) who received tofacitinib 10 mg twice daily. 5) events per 100 patient-years for tofacitinib 10 mg twice daily minus tofacitinib 5 mg twice daily. 1 )]. 3 events per 100 patient-years) who received either tofacitinib 5 mg or 10 mg twice daily.
7) events per 100 patient-years for the combined tofacitinib 5 mg and 10 mg twice daily group minus placebo. 6 events per 100 patient-years) who received tofacitinib 10 mg twice daily. 7) events per 100 patient-years for tofacitinib 10 mg twice daily minus tofacitinib 5 mg twice daily.
One of these malignancies was a case of lymphoma that occurred during the 0- month to 12-month period in a patient treated with tofacitinib 10 mg twice daily. 3 )]. 04% of patients for the tofacitinib 5 mg twice daily and 10 mg twice daily groups combined during the first 3 months of exposure.
8 )]. 07% of patients for the tofacitinib 5 mg twice daily and 10 mg twice daily groups combined during the first 3 months of exposure. There were no confirmed decreases in ANC below 500 cells/mm 3 observed in any treatment group. There was no clear relationship between neutropenia and the occurrence of serious infections.
8 )].
Liver Enzyme Elevations:
Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were observed in patients with RA 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 placebo-controlled monotherapy trials (0 month to 3 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. 2% of patients who received placebo, tofacitinib 5 mg, and 10 mg twice daily, respectively.
4% of patients who received placebo, tofacitinib 5 mg, and 10 mg twice daily, respectively. 5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and a liver biopsy.
Lipid Elevations:
In the placebo-controlled clinical trials in patients with RA, 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 placebo-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 placebo-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 placebo-controlled clinical trials.
Serum Creatinine Elevations:
In the placebo-controlled clinical trials in patients with RA, dose-related elevations in serum creatinine were observed with tofacitinib treatment. 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. Common Adverse Reactions Table 5 displays adverse reactions that occurred in 2% or more of patients on tofacitinib 5 mg or 10 mg twice daily and at least 1% greater than in tofacitinib-treated patients that observed in placebo-treated patients with or without DMARD in the RA trials.
Table 5 Common Adverse Reactions* in Clinical Trials of Tofacitinib for the Treatment of Rheumatoid Arthritis in Adults With or Without Concomitant DMARDs (0Month to 3 Months) N reflects randomized and treated patients from the seven placebo-controlled clinical trials.
* reported in ≥ 2% of patients treated with either dose of tofacitinib and ≥ 1% greater than that reported for placebo. ** The recommended dose of tofacitinib for the treatment of RA is 5 mg twice daily [see Dosage and Administration ( 2 )] .
Preferred Term Placebo Tofacitinib 5 mg Twice Daily Tofacitinib 10 mg Twice Daily** N = 809 (%) N = 1,336 (%) N = 1,349 (%) Upper respiratory tract infection 3 4 4 Nasopharyngitis 3 4 3 Diarrhea 2 4 3 Headache 2 4 3 Hypertension 1 2 2 Other adverse reactions that occurred in placebo-controlled and open-label extension studies in patients with RA included: Blood and lymphatic system disorders: Anemia Infections and infestations: Diverticulitis Metabolism and nutrition disorders: Dehydration Psychiatric disorders: Insomnia Nervous system disorders: Paresthesia Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with RA and some were fatal) 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 Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema Clinical Experience in Methotrexate-Naïve Patients Study RA-VI was an active-controlled clinical trial in methotrexate-naïve patients [see Clinical Studies ( 14 )] .
The safety experience in these patients was consistent with Studies RA-I through V. Adverse Reactions in Adults with Psoriatic Arthritis The safety of tofacitinib was evaluated in 2 double-blind Phase 3 clinical trials in adults with active psoriatic arthritis (PsA): Study PsA-I (NCT01877668) had a duration of 12 months and enrolled adults who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF blocker.
Study PsA-I included a 3-month placebo-controlled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months. Study PsA-II (NCT01882439) had a duration of 6 months and enrolled adults who had an inadequate response to at least one approved TNF blocker.
This clinical trial included a 3-month placebo-controlled period. In these combined Phase 3 clinical trials, 238 patients were randomized and treated with tofacitinib 5 mg twice daily and 236 patients were randomized and treated with tofacitinib 10 mg twice daily.
A dosage of tofacitinib 10 mg twice daily is not recommended for the treatment of PsA. 3 )]. All patients in the clinical trials in patients with PsA were required to receive treatment with a stable dose of a nonbiologic DMARD [the majority (79%) received methotrexate].
The study population randomized and treated with tofacitinib (474 patients) included 45 (10%) patients aged 65 years or older and 66 (14%) patients with diabetes at baseline. During the 2 PsA controlled clinical trials, there were: 3 malignancies (excluding NMSC) in 474 patients who received tofacitinib plus non-biologic DMARD (6 to 12 months exposure) 0 malignancies in 236 patients who received placebo plus non-biologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in patients who received adalimumab plus non-biologic DMARD group (12 months exposure).
No lymphomas were reported. Malignancies have also been observed in the long-term extension study in patients with PsA treated with tofacitinib. The safety profile observed in adults with active PsA treated with tofacitinib was consistent with the safety profile observed in adults with RA.
Adverse Reactions in Adults with Ankylosing Spondylitis The safety of tofacitinib was evaluated in adults with active ankylosing spondylitis (AS) in a double-blind placebo-controlled Phase 3 clinical trial (Study AS-I) and in a dose-ranging Phase 2 clinical trial (Study AS-II).
Study AS-I (NCT03502616) had a duration of 48 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. Study AS-I included a 16-week double-blind period in which patients received tofacitinib 5 mg or placebo twice daily and a 32-week open-label treatment period in which all patients received tofacitinib 5 mg twice daily.
Study AS-II (NCT01786668) had a duration of 16 weeks and enrolled adults who had an inadequate response to at least 2 NSAIDs. This clinical trial included a 12-week treatment period in which patients received either tofacitinib 2 mg (40% of the recommended dose), 5 mg, 10 mg, or placebo twice daily.
A dosage of tofacitinib 10 mg twice daily is not recommended for the treatment of AS . 3 )]. In the combined Phase 2 and Phase 3 clinical trials, a total of 420 patients were treated with either tofacitinib 2 mg, 5 mg, or 10 mg twice daily.
Of these, 316 patients were treated with tofacitinib 5 mg twice daily for up to 48 weeks. In the combined double-blind period, 185 patients were randomized to and treated with tofacitinib 5 mg twice daily and 187 to placebo for up to 16 weeks.
Concomitant treatment with stable doses of nonbiologic DMARDs, NSAIDs, or corticosteroids (≤ 10 mg/day) was permitted. The study population randomized and treated with tofacitinib included 13 (3%) patients aged 65 years or older and 18 (4%) patients with diabetes at baseline.
The safety profile observed in adults with AS treated with tofacitinib was consistent with the safety profile observed in adults with RA and PsA. 5 )] . Adverse reactions reported in ≥ 5% of patients treated with either tofacitinib 5 mg or 10 mg twice daily and ≥ 1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials of patients with UC were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.
Induction Trials in Adults with UC Common adverse reactions reported in ≥ 2% of patients treated with tofacitinib 10 mg twice daily and ≥ 1% greater in tofacitinib-treated patients than placebo-treated patients in the 3 induction trials of patients with UC (Studies UC-I, UC-II, and UC-V) were: headache, nasopharyngitis, elevated cholesterol levels, acne, increased blood creatine phosphokinase, and pyrexia.
Maintenance Trial in Adults with UC Common adverse reactions reported in ≥ 4% of patients treated with either dosage of tofacitinib and ≥ 1% greater than reported in patients treated with placebo in the maintenance trial of patients with UC (Study UC-III) are shown in Table 6.
Table 6 Common Adverse Reactions* in Adults with UC During the 52-Week Maintenance Trial (Study UC-III) * Reported in ≥ 4% of patients treated with either tofacitinib dosage and ≥ 1% greater in tofacitinib-treated patients than placebo-treated patients.
** Includes hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low-density lipoprotein increased, low-density lipoprotein abnormal, or lipids increased. 3 )]. During the UC controlled clinical studies (8-week induction and 52-week maintenance studies), which included 1,220 patients, 0 cases of solid cancer or lymphoma were observed in tofacitinib-treated patients.
3 )] . 5 )] . 2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of tofacitinib extended-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune system disorders:
Drug hypersensitivity (events such as angioedema and urticaria have been observed) Skin and subcutaneous tissue disorders: Acne
Avoid use of tofacitinib extended-release tablets in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating tofacitinib extended-release tablets 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.
Closely monitor patients for the development of signs and symptoms of infection during and after treatment with tofacitinib extended-release tablets. Interrupt tofacitinib extended-release tablets if a patient develops a serious infection, an opportunistic infection, or sepsis.
In patients who develop a new infection during treatment with tofacitinib extended-release tablets, promptly complete diagnostic testing appropriate for an immunocompromised patient; initiate appropriate antimicrobial therapy and monitor the patients closely.
Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections. 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.
5 )]. Tuberculosis Evaluate and test patients for latent or active tuberculosis (TB) infection prior to and per applicable guidelines during administration of tofacitinib extended-release tablets. Consider anti-TB therapy prior to administration of tofacitinib extended-release tablets in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection.
Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient. Monitor patients closely for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.
Treat patients with latent TB with standard antimycobacterial therapy before administering tofacitinib extended-release tablets. , herpes zoster), were observed in clinical studies with tofacitinib. Postmarketing cases of hepatitis B reactivation have been reported in patients treated with tofacitinib.
The impact of tofacitinib extended-release tablets on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Perform screening for viral hepatitis in accordance with clinical guidelines before starting therapy with tofacitinib extended-release tablets.
The risk of herpes zoster is increased in patients treated with tofacitinib extended-release tablets and appears to be higher in patients treated with tofacitinib in Japan and Korea. 2 Increased Risk of Mortality Increased risk of mortality may occur with tofacitinib extended-release tablets.
Adult patients with rheumatoid arthritis (RA), 50 years of age and older, with at least one cardiovascular risk factor treated with tofacitinib tablets 5 mg or 10 mg twice a day had a higher observed rate of all-cause mortality, including sudden cardiovascular death, compared to those treated with TNF blockers in a large, randomized, postmarketing safety study (RA Safety Study 1).
6 )] . Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with tofacitinib extended-release tablets. 3 )] . 5 )] . 3 Malignancy and Lymphoproliferative Disorders Malignancies and lymphoproliferative disorders may occur with tofacitinib extended-release tablets.
1 )]. Other malignancies were observed in tofacitinib clinical studies and the postmarketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. In RA Safety Study 1, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with tofacitinib tablets 5 mg or 10 mg twice a day compared with TNF blockers.
77 for TNF blockers. 6 )]. Lymphomas and lung cancers, which are a subset of all malignancies in RA Safety Study 1, were observed at a higher rate in patients treated with tofacitinib tablets 5 mg twice a day and tofacitinib tablets 10 mg twice a day compared to those treated with TNF blockers.
02 for TNF blockers. 6 )] . Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with tofacitinib extended-release tablets , particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy while on treatment, and patients who are current or past smokers.
3 )] . Non-Melanoma Skin Cancer Non-melanoma skin cancers (NMSCs) have been reported in patients treated with tofacitinib tablets. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with tofacitinib tablets 10 mg twice daily was associated with greater risk of NMSC than treatment with placebo.
4 Major Adverse Cardiovascular Events Major adverse cardiovascular events may occur with tofacitinib extended-release tablets. In RA Safety Study 1, patients with RA who were 50 years of age and older with at least one cardiovascular risk factor and treated with tofacitinib tablets 5 mg or 10 mg twice daily had a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke, compared to those treated with TNF blockers.
79 for TNF blockers. 6 )] . Patients who are current or past smokers are at additional increased risk. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with tofacitinib extended-release tablets, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors.
Inform patients about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue tofacitinib extended-release tablets in patients that have experienced a MI or stroke. 3 )] . 5 Thrombosis Thrombosis may occur with tofacitinib extended-release tablets.
Thrombosis, including pulmonary embolism (PE), deep venous thrombosis (DVT), and arterial thrombosis, have occurred in patients treated with tofacitinib and other Janus kinase ( JAK) inhibitors used to treat inflammatory conditions.
2 )] . Patients with RA 50 years of age and older with at least one cardiovascular risk factor treated with tofacitinib tablets 5 mg or 10 mg twice daily compared to TNF blockers in RA Safety Study 1 had an observed increase in incidence of these thrombotic events.
16 for TNF blockers. 6 )] . 3 )] . In a long-term extension study in patients with UC, five cases of pulmonary embolism were reported in patients taking tofacitinib 10 mg twice daily, including one death in a patient with advanced cancer.
Promptly evaluate patients with symptoms of thrombosis and discontinue tofacitinib extended-release tablets in patients with symptoms of thrombosis. Avoid tofacitinib extended-release tablets in patients that may be at increased risk of thrombosis.
5 )] . 6 Gastrointestinal Perforations Gastrointestinal perforations may occur with tofacitinib extended-release tablets . Events of gastrointestinal perforation have been reported in clinical studies with tofacitinib tablets, although the role of JAK inhibition in these events is not known.
In these studies, many patients with RA received background therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the tofacitinib tablets treatment groups in clinical trials of patients with UC, and many of them were receiving background corticosteroids.
1 )] . 7 Hypersensitivity Reactions Hypersensitivity reactions may occur with tofacitinib extended-release tablets. Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving tofacitinib extended-release tablets .
Some events were serious. 2 )] . 8 Laboratory Abnormalities Laboratory abnormalities may occur with tofacitinib extended-release tablets . Lymphocyte Abnormalities Treatment with tofacitinib tablets was associated with initial lymphocytosis at one month of tofacitinib tablets treatment followed by a gradual decrease in mean absolute lymphocyte counts below the baseline of approximately 10% during 12 months of therapy.
Lymphocyte counts less than 500 cells/mm 3 in these patients were associated with an increased incidence of treated and serious infections. Monitor lymphocyte counts at baseline and every 3 months thereafter. , less than 500 cells/mm 3 ).
In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm 3 , treatment with tofacitinib extended-release tablets is not recommended. Neutropenia Treatment with tofacitinib tablets was associated with an increased incidence of neutropenia (less than 2,000 cells/mm 3 ) compared to treatment with placebo.
Monitor neutrophil counts at baseline and after 4 weeks to 8 weeks of treatment and every 3 months thereafter. , ANC less than 1,000 cells/mm 3 ). For patients who develop a persistent ANC of 500 cells/mm 3 to 1,000 cells/mm 3 , interrupt dosing until ANC is greater than or equal to 1,000 cells/mm 3 .
In patients who develop an ANC less than 500 cells/mm 3 , treatment with tofacitinib extended-release tablets is not recommended. Anemia Monitor hemoglobin at baseline and after 4 weeks to 8 weeks of treatment and every 3 months thereafter.
, less than 9 g/dL). Interrupt treatment with tofacitinib extended-release tablets in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment until hemoglobin values have normalized.
Liver Enzyme Elevations Treatment with tofacitinib tablets was associated with an increased incidence of liver enzyme elevation compared to treatment with placebo. Most of these abnormalities occurred in studies with background DMARD therapy (primarily methotrexate).
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, interrupt the administration of tofacitinib extended-release tablets until this diagnosis has been excluded.
Lipid Elevations Treatment with tofacitinib tablets was associated with dose-dependent increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol.
Maximum changes in these lipid parameters were generally observed within 6 weeks. There were no clinically relevant changes in LDL/HDL cholesterol ratios. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.
Perform assessment of lipid parameters approximately 4 weeks to 8 weeks following initiation of tofacitinib extended-release tablets therapy. , National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia. 9 Vaccinations Avoid use of live vaccines concurrently with tofacitinib extended-release tablets.
Prior to initiating tofacitinib therapy, update immunizations in agreement with current immunization guidelines. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.