Version May 2024
Patients treated with tofacitinib are at increased risk of developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.
If a serious infection develops, interrupt tofacitinib until the infection is controlled.
Reported infections include:
• Active tuberculosis (TB), which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent TB before tofacitinib use and during therapy. Treatment for latent infection should be initiated prior to tofacitinib use.
• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated rather than localized disease.
• Bacterial, viral (including herpes zoster), and other infections due to opportunistic pathogens.
The risks and benefits of treatment with tofacitinib should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.
In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients ≥50 years of age with ≥1 cardiovascular risk factor comparing tofacitinib 5 mg twice a day or tofacitinib 10 mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with tofacitinib 5 mg twice a day or tofacitinib 10 mg twice a day. Tofacitinib 10 mg twice daily (or tofacitinib XR 22 mg once daily) dosage is not recommended for the treatment of RA or psoriatic arthritis (PsA).
Malignancies, including lymphomas and solid tumors, have occurred in patients treated with tofacitinib and other Janus kinase inhibitors used to treat inflammatory conditions. In RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]) was observed in patients treated with tofacitinib 5 mg twice a day or tofacitinib 10 mg twice a day compared TNF blockers.
Lymphomas and lung cancers were observed at a higher rate in patients treated with tofacitinib 5 mg twice a day or tofacitinib 10 mg twice a day in RA patients compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.
Epstein-Barr virus-associated posttransplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with tofacitinib and concomitant immunosuppressive medications.
RA patients ≥50 years of age with ≥1 cardiovascular risk factor, treated with tofacitinib 5 mg twice daily or tofacitinib 10 mg twice daily, had a higher rate of major adverse cardiovascular events (defined as cardiovascular death, myocardial infarction, and stroke), compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue tofacitinib in patients that have experienced a myocardial infarction or stroke.
Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, have occurred in patients treated with tofacitinib and other Janus kinase inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death. RA patients ≥50 years of age with ≥1 cardiovascular risk factor treated with tofacitinib 5 mg twice daily or tofacitinib 10 mg twice daily compared to TNF blockers had an observed increase in incidence of these events. Avoid tofacitinib in patients at risk. Discontinue tofacitinib and promptly evaluate patients with symptoms of thrombosis.
Note: ER tablets and oral solution are not interchangeable or substitutable. When transitioning from IR tablet to ER tablet, begin ER tablet the day following the last dose of IR tablet. Do not initiate therapy in patients with an absolute lymphocyte count <500 cells/mm3, ANC <1,000 cells/mm3, or hemoglobin <9 g/dL.
Ankylosing spondylitis: Oral:
IR tablet: 5 mg twice daily.
ER tablet: 11 mg once daily.
COVID-19, hospitalized patients (alternative agent) (off-label use):
Note: For use only as an alternative to baricitinib, for hospitalized patients with significant oxygen requirements (eg, high-flow oxygen, noninvasive ventilation, mechanical ventilation, extracorporeal membrane oxygenation) and those with lower but increasing oxygen requirements and evidence of systemic inflammation (Ref).
Oral: IR tablet: 10 mg twice daily, as part of an appropriate combination regimen, for 14 days or until hospital discharge, whichever is earlier (Ref).
Psoriasis (off-label): Oral: IR tablet: 5 to 10 mg twice daily (Ref).
Psoriatic arthritis (use in combination with nonbiologic disease-modifying antirheumatic drugs): Oral:
IR tablet: 5 mg twice daily.
ER tablet: 11 mg once daily.
Rheumatoid arthritis:
Note: For use as adjunctive therapy with nonbiologic disease-modifying antirheumatic drugs (DMARDs) in patients who have not met treatment goals despite maximally tolerated methotrexate therapy; may also be used off label as an alternative to methotrexate in DMARD-naive patients with moderate to high disease activity (Ref).
Oral:
IR tablet: 5 mg twice daily.
ER tablet: 11 mg once daily.
Ulcerative colitis (alternative agent): Oral:
IR tablet:
Induction: 10 mg twice daily for at least 8 weeks; based on therapeutic response, may continue 10 mg twice daily for a maximum of 16 weeks or transition to maintenance dose. Discontinue therapy if inadequate response achieved after 16 weeks using 10 mg twice daily.
Maintenance: 5 mg twice daily; if patient experiences loss of response on 5 mg twice daily, then use 10 mg twice daily after assessing the benefits and risks and use for the shortest duration; use lowest effective dose to maintain response.
ER tablet:
Induction: 22 mg once daily for at least 8 weeks; based on therapeutic response, may continue 22 mg once daily for a maximum of 16 weeks or transition to maintenance dose. Discontinue therapy if inadequate response achieved after 16 weeks using 22 mg once daily.
Maintenance: 11 mg once daily; if patient experiences loss of response on 11 mg once daily, then use 22 mg once daily after assessing the benefits and risks and use for the shortest duration; use lowest effective dose to maintain response.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Mild impairment: No dosage adjustment necessary.
Moderate to severe impairment:
IR tablet: Reduce dose to 5 mg twice daily (if taking 10 mg twice daily) or 5 mg once daily (if taking 5 mg twice daily).
ER tablet: Reduce dose to 11 mg once daily (if taking 22 mg once daily) or transition to immediate release 5 mg once daily (if taking 11 mg once daily).
End-stage renal disease requiring hemodialysis: Note: Administer after dialysis session on dialysis days; if dose given prior to dialysis, supplemental dose is not recommended after dialysis session.
IR tablet: Reduce dose to 5 mg twice daily (if taking 10 mg twice daily) or 5 mg once daily (if taking 5 mg twice daily).
ER tablet: Reduce dose to 11 mg once daily (if taking 22 mg once daily) or transition to immediate release 5 mg once daily (if taking 11 mg once daily).
Mild impairment: No dosage adjustment necessary.
Moderate impairment:
IR tablet: Reduce dose to 5 mg twice daily (if taking 10 mg twice daily) or 5 mg once daily (if taking 5 mg twice daily).
ER tablet: Reduce dose to 11 mg once daily (if taking 22 mg once daily) or transition to immediate release 5 mg once daily (if taking 11 mg once daily).
Severe impairment: Use is not recommended (has not been studied in patients with severe hepatic impairment or in patients with hepatitis B or hepatitis C viruses).
Infection: If a patient develops a serious infection, interrupt treatment until the infection is controlled.
Lymphopenia (lymphocytes ≥500 cells/mm3): Maintain dose.
Lymphopenia (lymphocytes <500 cells/mm3) confirmed by repeat evaluation: Discontinue therapy.
Neutropenia (ANC >1,000 cells/mm3): Maintain dose.
Neutropenia (ANC persistently between 500 to 1,000 cells/mm3):
IR tablet: If taking 5 mg twice daily, interrupt therapy; may resume 5 mg twice daily when ANC >1,000 cells/mm3. If taking 10 mg twice daily, reduce dose to 5 mg twice daily; may resume 10 mg twice daily when ANC >1,000 cells/mm3 based on clinical response.
ER tablet: If taking 11 mg once daily, interrupt therapy; may resume 11 mg once daily when ANC >1,000 cells/mm3. If taking 22 mg once daily, reduce dose to 11 mg once daily; may resume 22 mg once daily when ANC >1,000 cells/mm3.
Neutropenia (ANC <500 cells/mm3): Discontinue therapy.
Anemia (hemoglobin ≥8 g/dL and decrease ≤2 g/dL): Maintain dose.
Anemia (hemoglobin <8 g/dL or decrease >2 g/dL): Interrupt therapy until hemoglobin values have normalized.
Refer to adult dosing.
(For additional information see "Tofacitinib: Pediatric drug information")
Note: Oral solution and extended-release tablets are not bioequivalent and should not be substituted on a mg:mg basis; oral solution and immediate-release tablet may be converted mg:mg (5 mg oral solution may be switched to 5 mg immediate-release tablet). Assess baseline CBC; do not initiate therapy in patients with an absolute lymphocyte count <500 cells/mm3, ANC <1,000 cells/mm3, or hemoglobin <9 g/dL.
Juvenile idiopathic arthritis, polyarticular course: Children ≥2 years weighing ≥10 kg and Adolescents: Oral:
10 to <20 kg: Oral solution (1 mg/mL): 3.2 mg twice daily.
20 to <40 kg: Oral solution (1 mg/mL): 4 mg twice daily.
≥40 kg: Oral solution (1 mg/mL) or immediate-release tablet: 5 mg twice daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosage adjustment for toxicity: Children ≥2 years and Adolescents: Oral: Oral solution, immediate-release tablets:
Infection: If a patient develops a serious infection, interrupt treatment until the infection is controlled.
Anemia (hemoglobin <8 g/dL or decrease >2 g/dL): Interrupt therapy until hemoglobin values have normalized.
Lymphopenia (lymphocytes <500 cells/mm3) confirmed by repeat evaluation: Discontinue therapy.
Neutropenia:
ANC between 500 to 1,000 cells/mm3: Interrupt therapy until ANC >1,000 cells/mm3.
ANC <500 cells/mm3: Discontinue therapy.
Children ≥2 years and Adolescents: Oral: Oral solution, immediate-release tablets:
Mild kidney impairment: No adjustment necessary.
Moderate to severe kidney impairment: Reduce dose frequency to once daily.
Hemodialysis: Administer dose after dialysis session on dialysis days; if dose administered before session, a supplemental dose post-dialysis is not recommended.
Children ≥2 years and Adolescents: Oral: Oral solution, immediate-release tablet:
Mild hepatic impairment: No adjustment necessary.
Moderate hepatic impairment: Reduce dose frequency to once daily.
Severe hepatic impairment: Use is not recommended.
Lymphocytopenia (after an initial lymphocytosis), neutropenia, and anemia have been observed with tofacitinib therapy. Thrombocytopenia has also been reported (Ref). In an open-label long-term extension study over 9.5 years, potentially life-threatening lymphocytopenia (<500 cells/mm3) occurred in ~1% of patients; <1% of these patients developed serious infections. Moderate to severe neutropenia occurred in ~1% and <1% of patients, respectively; no patients developed serious infections (Ref). In another study, <1% of patients experienced a clinically significant decrease in hemoglobin (defined as a ≥3 g/dL decrease from baseline or hemoglobin ≤7 g/dL) (Ref). Cell counts typically stabilize with continued treatment; for cases requiring discontinuation, partial or complete resolution usually occurred (Ref).
Mechanism: Dose-related; may impair pro-growth signaling in bone marrow stem cells (Ref).
Onset: Delayed. Lymphocytopenia: Increases in lymphocyte counts in the first 3 months, followed by decreases for up to 48 months. Neutropenia: Decreases in the first 24 months (Ref).
Risk factors:
• Higher doses (Ref)
Data regarding risk of major cardiovascular events (MACE) with tofacitinib are unclear. In a long-term open-label extension study over 9.5 years, the rate of cardiovascular events was low (Ref). Another study over a median follow-up of 4 years found an increased risk of MACE (including acute myocardial infarction and cerebrovascular accident) in patients ≥50 years of age with rheumatoid arthritis (RA) receiving tofacitinib compared to patients receiving tumor necrosis factor inhibitors (Ref). Furthermore, a study using a simulated clinical trial cohort with real world data found a small but statistically insignificant increase in cardiovascular outcomes (Ref). However, in a large registry of patients with RA, the rate of MACE was similar to patients receiving biological disease-modifying drugs (Ref), and a World Health Organization database also failed to find an association (Ref).
Mechanism: Unknown; although, tofacitinib increases lipid levels by reducing cholesterol ester metabolism (Ref).
Risk factors:
• Age ≥65 years (Ref)
• Cardiovascular risk factors (eg, current or former smokers)
Gastrointestinal (GI) perforation has been reported, typically secondary to diverticulitis, and may be life-threatening. Most perforations have occurred in the lower GI tract (Ref). Incidence was rare in patients with rheumatoid arthritis in long-term studies; lower incidence than tocilizumab but higher incidence than tumor necrosis factor inhibitors (Ref).
Onset: Varied; may occur weeks to years after initiation (Ref).
Risk factors:
• Older age (Ref)
• Concurrent glucocorticoids (ie, prednisone ≥7.5 mg/day) or nonsteroidal anti-inflammatory drugs (Ref)
• History of diverticulitis/other GI conditions (Ref)
Increased liver enzymes may occur, which are usually mild and transient and rarely result in dose adjustment or discontinuation (Ref). Hepatotoxicity is rare (Ref).
Mechanism: Unknown, dose-related; metabolized in the liver through the CYP 3A4 pathway. Hepatotoxicity may be related to the production of a toxic or immunogenic intermediate (Ref).
Risk factors:
• Higher doses (Ref)
• Concurrent use of conventional synthetic disease modifying antirheumatic drugs (Ref)
Patients receiving tofacitinib are at increased risk for infection (including serious infection), which may result in hospitalization and/or fatality. Infections may present as disseminated (rather than local) disease. Active tuberculosis (including disseminated), invasive fungal infection (including cryptococcosis and pneumocystosis), bacterial infection, viral infection, or other opportunistic infection have been reported. Nasopharyngitis, upper respiratory tract infections, and urinary tract infections are the most common infections (Ref). Other infections, including appendicitis, cellulitis, diverticulitis of the gastrointestinal tract, herpes zoster infections (including disseminated cutaneous, meningoencephalitis, ophthalmologic) and reactivation of hepatitis B virus have also been reported. One study over a median follow-up of 4 years found an increased risk of infections in patients ≥50 years of age with rheumatoid arthritis (RA) receiving tofacitinib compared to patients receiving tumor necrosis factor inhibitors (Ref). In additional studies in patients with RA, the incidence of herpes zoster in patients receiving tofacitinib was more than twice that in patients receiving biological disease modifying drugs (DMARDs) (Ref).
Mechanism: Dose-related; may impair lymphocyte function, leading to suppression of immune response and increased risk of infection (Ref).
Onset: Delayed; median exposure prior to diagnosis of an opportunistic infection was 8 months (range: ~40 days to ~2 years).
Risk factors:
• Higher doses (Ref)
• Older age (Ref)
• Concurrent immunosuppressants (eg, corticosteroids, conventional synthetic DMARDS (Ref)
• Asian ethnicity (for herpes zoster) (Ref)
• Females (Ref)
• Lymphocytopenia (<500 cells/mm3) (Ref)
• History of an opportunistic infection
• Chronic or recurrent infection
• Conditions that predispose to infections (eg, advanced or poorly controlled diabetes)
• Residence/travel in areas of endemic tuberculosis or mycoses (blastomycosis, coccidioidomycosis, histoplasmosis)
Malignant neoplasm, including malignant lymphoma and malignant solid tumor, have occurred in patients treated with tofacitinib and other Janus kinase inhibitors for the treatment of inflammatory conditions. The most common types of malignancy observed were lung carcinoma, malignant neoplasm of the breast, gastric carcinoma, malignant neoplasm of colon or rectum, renal cell carcinoma, prostate carcinoma, malignant lymphoma, pancreatic adenocarcinoma, and malignant melanoma. One study over a median follow-up of 4 years found an increased risk of malignancies in patients ≥50 years of age with rheumatoid arthritis (RA) receiving tofacitinib compared to patients receiving tumor necrosis factor inhibitors (TNFi) (Ref). In contrast, no increase in risk of malignancies in general or of any specific type was detected compared to patients with RA receiving conventional synthetic disease modifying drugs (DMARDs) or with TNFi in earlier meta-analyses of randomized clinical trials (Ref). In two large registries of patients with RA, the rate of malignancy in patients receiving tofacitinib was similar to patients receiving biological DMARDs or with TNFi (Ref).
Mechanism: Not clearly established; may inhibit immunosurveillance to malignancy (Ref).
Risk factors:
• Age ≥65 years (Ref)
• Current or former smoker
Thrombosis, including arterial thrombosis, deep vein thrombosis, and pulmonary embolism, have occurred in patients treated with tofacitinib and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions. One study over a median follow-up of 4 years found an increased risk of venous thrombosis and pulmonary embolism in patients ≥50 years of age with rheumatoid arthritis (RA) receiving tofacitinib compared to patients receiving tumor necrosis factor inhibitors (TNFi) (Ref). However, in multiple large registries of patients with RA and other patients, the rate of thrombotic events with tofacitinib was low and similar to patients who used biological disease modifying drugs or TNFi (Ref).
Mechanism: Dose-related; JAK inhibition may affect a variety of pathways affecting endothelial activation and platelet aggregation (Kotyla 2021). Tofacitinib may also have off-target effects not related to JAK inhibition (Ref).
Risk factors:
• Higher doses (Ref)
• Cardiovascular or venous thromboembolic risk factors (Ref)
Active tuberculosis (TB), which may present with pulmonary or extrapulmonary disease, has been reported. One study over a median follow-up of 4 years found an increased risk of TB in patients ≥50 years of age with rheumatoid arthritis (RA) receiving tofacitinib compared to patients receiving tumor necrosis factor inhibitors (Ref). In a meta-analysis of randomized clinical trials, the risk of TB in patients receiving tofacitinib at any dose was higher versus placebo but not statistically significant (Ref).
Mechanism: Dose-related; may impair lymphocyte function, leading to suppression of immune response and increased risk of infection (Ref).
Risk factors:
• Higher dose (Ref)
• Residence in an area with high TB prevalence
• Known TB exposure or ongoing risk factors for TB exposure (eg, travel to areas with high TB prevalence)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reaction incidence reported in adults. Incidences of adverse reactions may include unapproved dosing regimens and combination therapy.
>10%:
Endocrine & metabolic: Hyperlipidemia (including increased HDL cholesterol [10% to 12%], increased LDL cholesterol [15% to 19%], increased serum cholesterol [total: ≤9%], and increased serum triglycerides [≤9%]).
Infection: Infection (20% to 22%; including bacterial infection, BK virus, cryptococcosis, cytomegalovirus disease, fungal infection, histoplasmosis, listeriosis, mycobacterium infection, opportunistic infection, reactivation of HBV, serious infection, tuberculosis [including disseminated], viral infection [and reactivation]) (table 1)
|
Drug (Tofacitinib) |
Placebo |
Dose |
Indication |
Number of Patients (Tofacitinib) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
22% |
18% |
10 mg twice daily |
Rheumatoid arthritis |
1,349 |
809 |
|
20% |
18% |
5 mg twice daily |
Rheumatoid arthritis |
1,336 |
809 |
Respiratory: Nasopharyngitis (3% to 14%) (table 2)
|
Drug (Tofacitinib) |
Placebo |
Dose |
Indication |
Number of Patients (Tofacitinib) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
4% |
3% |
5 mg twice daily |
Rheumatoid arthritis |
1,336 |
809 |
|
3% |
3% |
10 mg twice daily |
Rheumatoid arthritis |
1,349 |
809 |
|
14% |
6% |
10 mg twice daily |
Ulcerative colitis |
196 |
198 |
|
10% |
6% |
5 mg twice daily |
Ulcerative colitis |
198 |
198 |
1% to 10%:
Cardiovascular: Hypertension (2%)
Dermatologic: Acne vulgaris (≥2%), skin rash (6%)
Gastrointestinal: Diarrhea (3% to 5%), gastroenteritis (4%), nausea (4%)
Genitourinary: Urinary tract infection (2%)
Hematologic & oncologic: Anemia (2% to 4%) (table 3)
|
Drug (Tofacitinib) |
Placebo |
Dose |
Indication |
Number of Patients (Tofacitinib) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
4% |
2% |
5 mg twice daily |
Ulcerative colitis |
198 |
198 |
|
2% |
2% |
10 mg twice daily |
Ulcerative colitis |
196 |
198 |
Infection: Herpes zoster infection (1% to 5%; including disseminated cutaneous, meningoencephalitis, ophthalmologic) (table 4)
|
Drug (Tofacitinib) |
Placebo |
Dose |
Indication |
Number of Patients (Tofacitinib) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
5% |
1% |
10 mg twice daily |
Ulcerative colitis |
196 |
198 |
|
1% |
1% |
5 mg twice daily |
Ulcerative colitis |
198 |
198 |
Nervous system: Headache (3% to 9%)
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (3% to 7%)
Respiratory: Upper respiratory tract infection (4% to 7%) (table 5)
|
Drug (Tofacitinib) |
Placebo |
Dose |
Indication |
Number of Patients (Tofacitinib) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
4% |
3% |
5 mg twice daily |
Rheumatoid arthritis |
1,336 |
809 |
|
4% |
3% |
10 mg twice daily |
Rheumatoid arthritis |
1,349 |
809 |
|
7% |
4% |
5 mg twice daily |
Ulcerative colitis |
198 |
198 |
|
6% |
4% |
10 mg twice daily |
Ulcerative colitis |
196 |
198 |
Miscellaneous: Fever (≥2%)
<1%: Hematologic & oncologic: Lymphocytopenia (Wallenhaupt 2019), neutropenia (Wallenhaupt 2019)
Frequency not defined:
Cardiovascular: Peripheral edema
Dermatologic: Cellulitis, erythema of skin, pruritus
Endocrine & metabolic: Dehydration
Gastrointestinal: Abdominal pain, appendicitis, diverticulitis of the gastrointestinal tract, dyspepsia, esophageal candidiasis, gastritis, vomiting
Hepatic: Liver steatosis
Nervous system: Fatigue, insomnia, paresthesia
Neuromuscular & skeletal: Arthralgia, joint swelling, musculoskeletal pain, tendinopathy
Renal: Increased serum creatinine
Respiratory: Cough, dyspnea, infection due to an organism in genus Pneumocystis, interstitial lung disease, paranasal sinus congestion
Postmarketing:
Cardiovascular: Acute myocardial infarction (FDA 2021), arterial thrombosis (Mease 2020), deep vein thrombosis (Mease 2020), pulmonary embolism (Mease 2020), thrombosis (FDA 2019), venous thrombosis (Mease 2020)
Dermatologic: Malignant melanoma, skin carcinoma (nonmelanoma) (Ytterberg 2022)
Gastrointestinal: Gastrointestinal perforation (Xie 2016), malignant neoplasm of colon or rectum, pancreatic adenocarcinoma
Genitourinary: Malignant neoplasm of breast, prostate carcinoma
Hematologic & oncologic: Gastric carcinoma, lymphocytosis (Wollenhaupt 2019), malignant lymphoma (Ytterberg 2022), malignant neoplasm (Ytterberg 2022), malignant solid tumor (Ytterberg 2022), thrombocytopenia (Kadoba 2020)
Hepatic: Hepatotoxicity (Magri 2021), increased liver enzymes (Magri 2021)
Hypersensitivity: Angioedema, hypersensitivity reaction
Nervous system: Cerebrovascular accident (FDA 2021)
Renal: Renal cell carcinoma
Respiratory: Lung carcinoma, pneumonia (Wollenhaupt 2019)
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to tofacitinib or any component of the formulation; severe hepatic impairment; pregnancy; breastfeeding.
Concerns related to adverse effects:
• Hypersensitivity: Hypersensitivity reactions, including angioedema and urticaria, have occurred; discontinue therapy and evaluate cause for serious reactions.
• Interstitial lung disease: Interstitial lung disease (ILD) has been reported; patients developing ILD were receiving concomitant therapy associated with ILD (eg, methotrexate). Use with caution in patients with risk/history of ILD (Xeljanz Canadian product monograph).
Disease-related concerns:
• Active infections: Do not initiate tofacitinib in patients with active infections, including localized infections.
• Hepatic impairment: Use with caution in patients with hepatic impairment; see "Dosing: Hepatic Impairment" for additional information.
• Lung disease: Patients with a history of chronic lung disease or those who develop interstitial lung disease may be more prone to infections; use with caution.
• Renal impairment: Use with caution in patients with renal impairment; see "Dosing: Altered Kidney Function" for additional information.
Concurrent drug therapy issues:
• Immunosuppressant medications: Tofacitinib should not be administered in combination with strong immunosuppressive medications (eg, azathioprine, tacrolimus, cyclosporine) due to the risk of additive immunosuppression; such combinations have not been studied in RA.
• Biologic disease-modifying antirheumatic drugs: Tofacitinib should not be administered in combination with biologic disease-modifying antirheumatic drugs.
Special populations:
• Asian patients: Use with caution in Asian patients; an increased incidence of adverse reactions (eg, herpes zoster, opportunistic infections, decreased WBC, interstitial lung disease, increased transaminases) has been observed (Wollenhaupt 2014; Xeljanz Canadian product monograph).
• Patients with rheumatic musculoskeletal disease undergoing hip or knee replacement surgery: Hold tofacitinib for at least 3 days prior to surgery to reduce infection risk; therapy can be restarted once surgical wound shows evidence of healing (eg, no swelling, erythema, or drainage), sutures/staples are removed, and no ongoing nonsurgical site infections (typically ~14 days to reduce infection risk) (ACR/AAHKS [Goodman 2022]).
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol and/or sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol. Large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates. The "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982). Some data suggest that benzoate displaces bilirubin from protein-binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol and/or benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.
• Extended release: Use caution when administering the ER formulation to patients with preexisting severe GI narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures following ingestion of other medications that also utilize a nondeformable ER formulation. The inert tablet shell of the ER tablet may be noticeable in the stool (or colostomy); the active medication will have been already absorbed.
• Non-interchangeability of dosage forms: ER tablets are not interchangeable or substitutable with the oral solution.
Other warnings/precautions:
• Immunizations: Immunization status should be current before initiating therapy. Live vaccines should not be given concomitantly with tofacitinib; recommended interval between receipt of live vaccines and initiation of immunosuppressive agents, such as tofacitinib, should follow current vaccination clinical guidelines. Dissemination of the vaccine strain of varicella zoster virus has been reported in a varicella virus-naive patient 16 days following vaccination with Zostavax (live attenuated zoster) and 2 days after the initiation of tofacitinib.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Oral, as citrate [strength expressed as base]:
Xeljanz: 1 mg/mL (240 mL) [contains sodium benzoate]
Tablet, Oral, as citrate [strength expressed as base]:
Xeljanz: 5 mg
Xeljanz: 10 mg [contains fd&c blue #1 (brill blue) aluminum lake, fd&c blue #2 (indigotine,indigo carmine)]
Tablet Extended Release 24 Hour, Oral, as citrate [strength expressed as base]:
Xeljanz XR: 11 mg
Xeljanz XR: 22 mg [contains fd&c blue #2 (indigo carm) aluminum lake]
No
Solution (Xeljanz Oral)
1 mg/mL (per mL): $23.14
Tablet, 24-hour (Xeljanz XR Oral)
11 mg (per each): $231.36
22 mg (per each): $231.36
Tablets (Xeljanz Oral)
5 mg (per each): $115.68
10 mg (per each): $115.68
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as citrate [strength expressed as base]:
Xeljanz: 5 mg
Xeljanz: 10 mg [contains fd&c blue #1 (brill blue) aluminum lake, fd&c blue #2 (indigo carm) aluminum lake]
Generic: 5 mg, 10 mg
Tablet Extended Release 24 Hour, Oral, as citrate [strength expressed as base]:
Xeljanz XR: 11 mg
Available through specialty/network pharmacies. Further information may be obtained from the manufacturer, Pfizer Inc, at 1-855-493-5526 or at http://www.xeljanz.com/.
Oral: May be taken with or without food.
Extended release: Swallow tablet whole and intact; do not crush, split, or chew.
Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR tablet formulation is available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery.
Oral: Oral solution, immediate-release tablets: May be taken with or without food.
Oral solution: Use provided bottle adapter to attach oral syringe. After each use store bottle in carton to protect from light, rinse oral syringe with water, and allow to air dry. Discard any remaining oral solution 60 days after opening bottle.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Xeljanz, Xeljanz XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203214s028,208246s013,213082s003lbl.pdf#page=66
Ankylosing spondylitis: Treatment of active ankylosing spondylitis in adults who have had an inadequate response or intolerance to 1 or more tumor necrosis factor (TNF) blockers.
Polyarticular course juvenile idiopathic arthritis: Treatment of active polyarticular course juvenile idiopathic arthritis in patients ≥2 years of age who have had an inadequate response or intolerance to 1 or more TNF blockers.
Psoriatic arthritis: Treatment of active psoriatic arthritis (in combination with nonbiologic disease-modifying antirheumatic drugs [DMARDs]) in adults who have had an inadequate response or intolerance to 1 or more TNF blockers.
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 or intolerance to 1 or more TNF blockers.
Ulcerative colitis: Treatment of moderately to severely active ulcerative colitis in adults who have had an inadequate response or intolerance to 1 or more TNF blockers.
Limitations of use: For the above indications, the use of tofacitinib in combination with biologic DMARDs, biologic therapies (for ulcerative colitis), or with potent immunosuppressants (eg, azathioprine, cyclosporine) is not recommended.
COVID-19, hospitalized patients; Psoriasis
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP2C19 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Anifrolumab: Biologic Disease-Modifying Antirheumatic Drugs (DMARDs) may enhance the immunosuppressive effect of Anifrolumab. Risk X: Avoid combination
Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Bradycardia-Causing Agents: Tofacitinib may enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Chikungunya Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
Corticosteroids (Systemic): May enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Doses equivalent to more than 2 mg/kg or 20 mg/day of prednisone (for persons over 10 kg) administered for 2 or more weeks are considered immunosuppressive. Risk D: Consider therapy modification
COVID-19 Vaccines: Tofacitinib may diminish the therapeutic effect of COVID-19 Vaccines. Management: Rheumatology guidelines recommend holding baricitinib, tofactinib, or upadacitinib for 1 to 2 weeks after vaccine administration as permitted by the underlying disease. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Tofacitinib. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Tofacitinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Tofacitinib. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Tofacitinib. Management: Tofacitinib dose reductions are recommended when combined with strong CYP3A4 inhibitors. Recommended dose adjustments vary by tofacitinib formulation and therapeutic indication. See full Lexi Interact monograph for details. Risk D: Consider therapy modification
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Fluconazole: May increase the serum concentration of Tofacitinib. Management: Tofacitinib dose reductions are recommended when combined with fluconazole. Recommended dose adjustments vary by tofacitinib formulation and therapeutic indication. See full Lexi Interact monograph for details. Risk D: Consider therapy modification
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Immunosuppressants (Cytotoxic Chemotherapy): May enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Immunosuppressants (Miscellaneous Oncologic Agents): May enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Immunosuppressants (Therapeutic Immunosuppressant Agents): May enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combination
Influenza Virus Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate 2 to 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Methotrexate: May enhance the immunosuppressive effect of Tofacitinib. Management: Concomitant use of tofacitinib with high-dose or IV methotrexate is not recommended. Use with antirheumatic doses of methotrexate is permitted, and if combined, patients should be monitored for infection. Risk D: Consider therapy modification
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Nadofaragene Firadenovec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Ritlecitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Recommendations for use of tofacitinib to treat rheumatic and musculoskeletal diseases in patients planning to become pregnant or who are planning to father a child are not available due to lack of data (ACR [Sammaritano 2020]).
Agents other than tofacitinib are preferred to treat inflammatory bowel disease in patients planning to become pregnant. Disease management should be optimized prior to pregnancy. Tofacitinib should be avoided or used with caution prior to a planned pregnancy; discontinue 1 week prior to conception to limit first trimester fetal exposure (Mahadevan 2019).
Outcome data following tofacitinib exposure during pregnancy are limited (Clowse 2016; Fernández-Sánchez 2021; Mahadevan 2018).
Recommendations for use of tofacitinib in pregnant patients with rheumatic and musculoskeletal diseases are not available due to lack of data. Placental transfer may be expected based on molecular weight (ACR [Sammaritano 2020]).
Inflammatory bowel disease is associated with adverse pregnancy outcomes, including an increased risk of miscarriage, premature delivery, delivery of a low-birth-weight infant, and poor maternal weight gain. Management of maternal disease should be optimized prior to pregnancy. Treatment decreases disease flares, disease activity, and the incidence of adverse pregnancy outcomes. When treatment for inflammatory bowel disease is needed in pregnant patients, use of tofacitinib should be avoided at least during the first trimester (Mahadevan 2019).
Tofacitinib is under study for the treatment of COVID-19 (NIH 2023). The risk of severe morbidity and mortality from COVID-19 infection is increased in pregnant patients compared to nonpregnant patients. Pregnant and recently pregnant patients with moderate or severe infection are at increased risk of complications such as hypertensive disorders of pregnancy, postpartum hemorrhage, or other infections compared to pregnant patients without COVID-19. Pregnant patients with symptoms may require ICU admission, mechanical ventilation, or ventilatory support (extracorporeal membrane oxygenation). Other adverse pregnancy outcomes include preterm birth and stillbirth. The risk of coagulopathy, cesarean delivery, and maternal death may be increased; neonates have an increased risk for NICU admission. Maternal age and comorbidities such as diabetes, hypertension, lung disease, and obesity may also increase the risk of severe illness in pregnant and recently pregnant patients (ACOG 2023; NIH 2023).
In general, the treatment of COVID-19 infection during pregnancy is the same as in nonpregnant patients. However, because data for most therapeutic agents in pregnant patients are limited, treatment options should be evaluated as part of a shared decision-making process. Use of an agent other than tofacitinib may be preferred (NIH 2023). Information related to the treatment of COVID-19 during pregnancy continues to emerge; refer to current guidelines for the treatment of pregnant patients.
Tofacitinib is present in breast milk.
Data related to the presence of tofacitinib in breast milk are available from a lactating patient treated for ulcerative proctitis. Tofacitinib 10 mg twice daily was initiated at 30 months postpartum. Breastfeeding was discontinued once treatment started; however, 37 breast milk samples were collected over 25 days while milk continued to be produced. Tofacitinib breast milk concentrations ranged from 2 ng/mL (14 hours after the maternal dose) to 54.5 ng/mL (4 hours after dosing; median 9.9 ng/mL). Breast milk concentrations at 5 and 8 hours after the maternal dose were 21.4% and 54.4% higher than those in the maternal plasma, respectively. Using the highest breast milk concentration, authors of the study calculated the estimated daily infant dose of tofacitinib via breast milk to be 0.0082 mg/kg/day providing a relative infant dose (RID) of 3.4% compared to the weight adjusted maternal dose (Julsgaard 2023). In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000; Julsgaard 2023). However, due to the high oral absorption of tofacitinib, authors of this study suggest the immune system of a breastfeeding infant could be affected; breastfeeding should be avoided (Julsgaard 2023).
Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer does not recommend breastfeeding during treatment and for at least 18 hours after the last dose of IR tofacitinib or 36 hours (~6 half-lives) after the last dose of tofacitinib extended release.
Recommendations for use of tofacitinib in breastfeeding patients with rheumatic and musculoskeletal diseases are not available (ACR [Sammaritano 2020]). Tofacitinib is not recommended to treat inflammatory bowel disease in patients who are breastfeeding (Mahadevan 2019).
Lymphocyte count (baseline and every 3 months thereafter); neutrophil/platelet counts (baseline, after 4 to 8 weeks, and every 3 months thereafter); hemoglobin (baseline, after 4 to 8 weeks, and every 3 months thereafter); lipids (4 to 8 weeks after therapy initiation and periodically); LFTs; viral hepatitis (prior to initiating therapy in accordance with clinical guidelines); signs/symptoms of infections (including tuberculosis) during and after therapy; abdominal symptoms; skin examinations (periodically, in patients at increased risk for skin cancer); heart rate and blood pressure at baseline and periodically thereafter.
Tofacitinib inhibits Janus kinase (JAK) enzymes, which are intracellular enzymes involved in stimulating hematopoiesis and immune cell function through a signaling pathway. In response to extracellular cytokine or growth factor signaling, JAKs activate signal transducers and activators of transcription (STATs), which regulate gene expression and intracellular activity. Inhibition of JAKs prevents cytokine- or growth factor-mediated gene expression and intracellular activity of immune cells, reduces circulating CD16/56+ natural killer cells, serum IgG, IgM, IgA, and C-reactive protein, and increases B cells.
Absorption: Oral:
IR tablet: Rapid (74%); Cmax is reduced by 32% when administered with high-fat meal, but AUC remains unchanged.
Extended release: When administered with high-fat meal, Cmax,following an 11 mg and 22 mg dose, increased by 27% and 19%, respectively, and Tmax was extended by ~1 hour, but AUC remains unchanged.
Distribution: Vd: 87 L.
Bioavailability: The AUC and Cmax of 11 mg extended release once daily are equivalent to 5 mg IR tablet administered twice daily.
Protein binding: ~40% (predominantly to albumin).
Metabolism: Hepatic (70%): CYP3A4 and CYP2C19 to inactive metabolites.
Half-life elimination: ~3 hours (IR solution, tablet); ~6 to 8 hours (extended release).
Time to peak: 0.5 to 1 hour (IR solution, tablet); 4 hours (extended release).
Excretion: Primarily urine (30%) as unchanged drug.
Altered kidney function: AUC increased ~1.75- to 2.5-fold in moderate and severe renal impairment.
Hepatic function impairment: AUC and Cmax increased ~1.5-fold in moderate hepatic impairment.
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