tofacitinib solution
tofacitinib · Solution · Oral
• Active 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…
Uses
Tofacitinib is a Janus kinase (JAK) inhibitor. Tofacitinib oral solution is indicated for the treatment of pediatric patients 2 years of age and older with:
• Active psoriatic arthritis (PsA), who have had an inadequate response or intolerance to one or more TNF blockers.
• Active polyarticular course juvenile idiopathic arthritis (pcJIA), who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use :
• Use of tofacitinib oral solution for PsA or pcJIA in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended ( 1.2 , 1.4 ) 1.2 Psoriatic Arthritis Tofacitinib oral solution is indicated for the treatment of adult and pediatric patients 2 years of age and older with active psoriatic arthritis (PsA), who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use Use of tofacitinib in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended. 1.4 Polyarticular Course Juvenile Idiopathic Arthritis Tofacitinib oral solution is indicated for the treatment of pediatric patients 2 years of age and older with active polyarticular course juvenile idiopathic arthritis (pcJIA), who have had an inadequate response or intolerance to one or more TNF blockers. Limitations of Use Use of tofacitinib in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Dosage and administration
Recommended Evaluations and Immunization Prior to Treatment Initiation
• Prior to initiating tofacitinib oral solution, consider performing an active and latent TB evaluation, viral hepatitis screening, a complete blood count, and updating immunizations. Avoid tofacitinib initiation if absolute lymphocyte count <500 cells/mm 3 , an absolute neutrophil count (ANC) <1,000 cells/mm 3 or hemoglobin <9 g/dL. ( 2.1 ) Important Administration Instructions
• Tofacitinib extended-release tablets are not substitutable with tofacitinib tablets and tofacitinib oral solution. ( 2.2 )
• Switching between tofacitinib oral solution and tofacitinib extended-release tablets should be made by the healthcare provider. ( 2.2 ) Recommended Dosage Pediatric Patients 2 Years of Age and Older with PsA or pcJIA Who Weigh At Least 10 kg
• Tofacitinib oral solution 5 mg twice daily for those ≥40 kg or weight-based equivalent twice daily for those <40 kg. ( 2.4 ) Dosage in Patients with Renal Impairment or Hepatic Impairment
• Use of tofacitinib in patients with severe HI is not recommended. ( 2.4 , 8.7 )
• See full prescribing information (FPI) for recommended dosage in patients with moderate or severe RI or moderate HI. ( 2.4 , 8.6 , 8.7 ) 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. ( 2.4 , 7 ) 2.1 Recommended Evaluations and Immunization Prior to Treatment Initiation Prior to initiating tofacitinib oral solution, consider performing the following:
• Active and latent tuberculosis (TB) infection evaluation: If the patient has latent TB, treat for TB prior to tofacitinib treatment [see Warnings and Precautions ( 5.1 )] .
• Viral hepatitis screening in accordance with clinical guidelines [see Warnings and Precautions ( 5.1 )] .
• A complete blood count: Avoid initiation of tofacitinib treatment in patients with a lymphocyte count less than 500 cells/mm 3 , absolute neutrophil count less than 1,000 cells/mm 3 , or hemoglobin level less than 9 g/dL [see Warnings and Precautions ( 5.9 )] .
• Baseline hepatic function evaluation: tofacitinib is not recommended for patients with severe hepatic impairment [see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] .
• Update immunizations according to current immunization guidelines. The interval between live vaccinations and initiation of tofacitinib should be in accordance with current vaccination guidelines regarding immunosuppressive agents [see Warnings and Precautions ( 5.10 )] . 2.2 Important Administration Instructions
• Tofacitinib extended-release tablets are not substitutable with tofacitinib oral solution. Switching between tofacitinib oral solution and tofacitinib extended-release tablets should be made by the healthcare provider.
• Dose interruption is recommended for management of lymphopenia, neutropenia, and anemia [see Warnings and Precautions ( 5.9 ) and Adverse Reactions ( 6.1 )] .
• Interrupt use of tofacitinib oral solution if a patient develops a serious infection until the infection is controlled [see Warnings and Precautions ( 5.1 )] .
• Take tofacitinib oral solution with or without food [see Clinical Pharmacology ( 12.3 )] . 2.4 Recommended Dosage in Pediatric Patients 2 Years of Age and Older with Psoriatic Arthritis or Polyarticular Course Juvenile Idiopathic Arthritis Table 2 displays the recommended body weight-based dosages for tofacitinib oral solution in pediatric patients 2 years of age and older with PsA or pcJIA [see Indication and Usage ( 1.2 , 1.4 )] with and without renal impairment (including those who are undergoing hemodialysis) or hepatic impairment [see Use in Specific Populations ( 8.6 , 8.7 )] . The table also includes recommended dosage modification for pediatric patients concomitantly using CYP2C19 and/or CYP3A4 inhibitors [see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )] , and pediatric patients with lymphoma, neutropenia, or anemia. Administer tofacitinib oral solution using the included press-in bottle adapter and oral dosing syringe [see Instructions for Use] . Table 2: Recommended Dosage of Tofacitinib Oral Solution in Pediatric Patients 2 Years of Age and Older with PsA or pcJIA Pediatric Patients 2 Years of Age and Older Tofacitinib Oral Solution Patients with Normal Renal and Hepatic Function Excludes patients who concomitantly use tofacitinib tablets and tofacitinib oral solution 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.
• 10 kg ≤ body weight <20 kg: 3.2 mg (3.2 mL oral solution) twice daily
• 20 kg ≤ body weight <40 kg: 4 mg (4 mL oral solution) twice daily
• Body weight ≥40 kg: 5 mg (one 5 mg tablet or 5 mL oral solution) twice daily Patients treated with tofacitinib oral solution 5 mL may be switched to tofacitinib tablets 5 mg. Recommended Dosage in Patients with Renal Impairment (RI) Mild RI Same as patients with normal renal function. Moderate RI
• 10 kg ≤ body weight <20 kg: 3.2 mg once daily
• 20 kg ≤ body weight <40 kg: 4 mg once daily
• Body weight ≥40 kg: 5 mg once daily Severe RI
• 10 kg ≤ body weight <20 kg: 3.2 mg once daily
• 20 kg ≤ body weight <40 kg: 4 mg once daily
• Body weight ≥40 kg: 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 Same as patients with normal hepatic function.
Dosage forms and strengths
Tofacitinib oral solution: 1 mg/mL of tofacitinib: Clear, colorless oral solution.
• Tofacitinib oral solution: 1 mg/mL ( 3 )
Contraindications
None. None. ( 4 )
Warnings and precautions
• Serious Infections : Avoid use of tofacitinib during an active serious infection, including localized infections. ( 5.1 )
• Gastrointestinal Perforations : Promptly evaluate patients at increased risk for gastrointestinal perforation who present with new onset abdominal symptoms. ( 5.6 )
• Hypoglycemia in Patients with Diabetes : Consider increased monitoring of blood glucose; advise patients with diabetes to notify their healthcare provider if they develop signs or symptoms of hypoglycemia. ( 5.8 )
• Laboratory Monitoring : Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. ( 5.9 )
• Vaccinations : Avoid use of live vaccines concurrently with tofacitinib. ( 5.10 ) 5.1 Serious Infections Serious and sometimes fatal infections may occur with tofacitinib. 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. Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis). Avoid use of tofacitinib in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating tofacitinib in patients:
• with chronic or recurrent infection
• who have been exposed to tuberculosis
• with a history of a serious or an opportunistic infection
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
• with underlying conditions that may predispose them to infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with tofacitinib. Interrupt tofacitinib if a patient develops a serious infection, an opportunistic infection, or sepsis. In patients who develop a new infection during treatment with tofacitinib, 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. Discontinuation and monitoring criteria for lymphopenia are recommended [see Dosage and Administration ( 2.4 )] . Tuberculosis Evaluate and test patients for latent or active tuberculosis (TB) infection prior to and per applicable guidelines during administration of tofacitinib. Consider anti-TB therapy prior to administration of tofacitinib 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. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., 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 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. The risk of herpes zoster is increased in patients treated with tofacitinib and appears to be higher in patients treated with tofacitinib in Japan and Korea. 5.2 Increased Risk of Mortality Increased risk of mortality may occur with tofacitinib. 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). The incidence rate of all-cause mortality per 100 patient-years was 1.23 for tofacitinib tablets 10 mg twice a day, 0.88 for tofacitinib tablets 5 mg twice a day, and 0.69 for TNF blockers [see Clinical Studies ( 14.6 )] .
Side effects
The following clinically significant adverse reactions are described elsewhere in the labeling:
• Serious Infections [see Warnings and Precautions ( 5.1 )]
• Increased Risk of Mortality [see Warnings and Precautions ( 5.2 )]
• Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions ( 5.3 )]
• Major Adverse Cardiovascular Events [see Warnings and Precautions ( 5.4 )]
• Thrombosis [see Warnings and Precautions ( 5.5 )]
• Gastrointestinal Perforations [see Warnings and Precautions ( 5.6 )]
• Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )]
• Hypoglycemia in Patients with Diabetes [see Warnings and Precautions ( 5.8 )]
• Laboratory Abnormalities [see Warnings and Precautions ( 5.9 )] Most common adverse reactions are:
• RA, PsA, and AS : Reported in ≥2% of adult patients treated with tofacitinib tablets monotherapy or in combination with DMARDs: upper respiratory tract infection (URI), nasopharyngitis, diarrhea, and headache. ( 6.1 )
• PcJIA : Consistent with common adverse reactions reported in adult patients with RA. ( 6.1 )
• UC : Reported in ≥5% of adult patients treated with either tofacitinib 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 and/or tofacitinib oral solution. Adverse Reactions in Adults with Rheumatoid Arthritis In RA Safety Study 1, 1,455 adults were treated with tofacitinib tablets 5 mg twice daily, 1,456 adults were treated with 10 mg twice daily, and 1,451 adults were treated with a TNF blocker for a median of 4 years [see Clinical Studies ( 14.6 )] . A dosage of tofacitinib tablets 10 mg twice daily is not recommended for the treatment of RA because of increased risks [see Warnings and Precautions ( 5 )] . For the treatment of adults with moderately to severely active RA, the recommended dosage of tofacitinib tablets 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 tablets (monotherapy) 5 mg twice daily (292 patients) or 10 mg twice daily (306 patients),
• In combination with DMARDs (including methotrexate), tofacitinib tablets 5 mg twice daily (1,044 patients) or 10 mg twice daily (1,043 patients and
• Placebo (809 patients). All seven trials included provisions for patients taking placebo to receive treatment with tofacitinib tablets 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 tablets 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 tablets 5 mg twice daily and tofacitinib tablets 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. The most common serious adverse reactions were serious infections [see Warnings and Precautions ( 5.1 )] . The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for tofacitinib tablets-treated patients and 3% for placebo-treated patients. Overall Infections In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the tofacitinib tablets 5 mg twice daily and tofacitinib tablets 10 mg twice daily groups, respectively, and 18% in the placebo group. The most commonly reported infections with tofacitinib tablets were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively). Serious Infections In the seven placebo-controlled trials in patients with RA, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received tofacitinib tablets 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined tofacitinib tablets 5 mg twice daily and 10 mg twice daily group minus placebo.
Drug interactions
Table 7 includes drugs with clinically important drug interactions when administered concomitantly with tofacitinib and instructions for preventing or managing them. Table 7: Clinically Significant Interactions Affecting Tofacitinib When Concomitantly Used with Other Drugs Strong CYP3A4 Inhibitors (e.g., ketoconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage modification of tofacitinib is recommended [see Dosage and Administration ( 2 ), Clinical Pharmacology, Figure 3 ( 12.3 )] Moderate CYP3A4 Inhibitors Concomitantly Used with Strong CYP2C19 Inhibitors (e.g., fluconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage modification of tofacitinib is recommended [see Dosage and Administration ( 2 ), Clinical Pharmacology, Figure 3 ( 12.3 )] Strong CYP3A4 Inducers (e.g., rifampin) Clinical Impact Decreased exposure to tofacitinib and may result in loss of or reduced clinical response Intervention Concomitant use with tofacitinib is not recommended [see Clinical Pharmacology, Figure 3 ( 12.3 )] Immunosuppressive Drugs (e.g., azathioprine, tacrolimus, cyclosporine) Clinical Impact Risk of added immunosuppression; concomitant use of tofacitinib with biologic DMARDs or potent immunosuppressants has not been studied in patients with RA, PsA, AS, UC, or pcJIA. Intervention Concomitant use with tofacitinib is not recommended [see Indications and Usage ( 1 ), Clinical Pharmacology, Figure 3 ( 12.3 )] See FPI for clinically significant drug interactions. ( 2 , 7 )
Use in specific populations
Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary The available data with tofacitinib from a pregnancy exposure registry that enrolled 11 exposed pregnant females, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with RA and UC in pregnancy (see Clinical Considerations) . In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively. Further, in a peri- and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dosage of 5 mg twice daily and approximately 36 times the maximum recommended dosage of 10 mg twice daily, respectively (see Data) . The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with RA or UC. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 grams) infants, and small for gestational age at birth. Data Animal Data In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily, and approximately 73 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the recommended dose of 5 mg twice daily, and approximately 29 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats). In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily, and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the recommended dose of 5 mg twice daily, and approximately 1.5 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits). In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the recommended dose of 5 mg twice daily, and approximately 36 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the recommended dose of 5 mg twice daily, and approximately 8.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats). 8.2 Lactation Risk Summary Based on published data, tofacitinib is present in human milk. Data on the effects of tofacitinib on the breastfed infant is limited to a small number of cases with no reported adverse effects. There are no data on the effects on milk production. Given the serious adverse reactions seen in patients treated with tofacitinib, such as increased risk of serious infections, advise patients that breastfeeding is not recommended during treatment and for at least 18 hours after the last dose of tofacitinib tablets/tofacitinib oral solution or 36 hours after the last dose of tofacitinib extended-release tablets (approximately 6 elimination half-lives). Data Following administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum, and were approximately 2 times higher in milk relative to maternal serum at all time points measured.
Pregnancy
8.1 Pregnancy Risk Summary The available data with tofacitinib from a pregnancy exposure registry that enrolled 11 exposed pregnant females, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with RA and UC in pregnancy (see Clinical Considerations) . In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively. Further, in a peri- and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dosage of 5 mg twice daily and approximately 36 times the maximum recommended dosage of 10 mg twice daily, respectively (see Data) . The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with RA or UC. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 grams) infants, and small for gestational age at birth. Data Animal Data In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily, and approximately 73 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the recommended dose of 5 mg twice daily, and approximately 29 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats). In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily, and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the recommended dose of 5 mg twice daily, and approximately 1.5 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits). In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the recommended dose of 5 mg twice daily, and approximately 36 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the recommended dose of 5 mg twice daily, and approximately 8.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats).
Pediatric use
8.4 Pediatric Use The safety and effectiveness of tofacitinib in pediatric patients for indications other than in patients with active pcJIA and PsA, have not been established. The safety and effectiveness of tofacitinib have not been established in pediatric patients less than 2 years of age. The safety and effectiveness of tofacitinib extended-release tablets in pediatric patients have not been established. Polyarticular Course Juvenile Idiopathic Arthritis (pcJIA) The safety and effectiveness of tofacitinib tablets/tofacitinib oral solution for the treatment of active pcJIA have been established in pediatric patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers. Use of tofacitinib for this indication is supported by evidence from adequate and well-controlled studies of tofacitinib in adults with RA, pharmacokinetic (PK) data from adult patients with RA, and with additional safety, efficacy, and PK data from a clinical trial of tofacitinib in pediatric patients 2 years and older with active pcJIA (Study pcJIA-I) [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14.1 , 14.4 )] . Adverse reactions observed in pediatric patients with pcJIA who received tofacitinib were consistent with those reported in adults with RA [see Adverse Reactions ( 6.1 )] . Psoriatic Arthritis The safety and effectiveness of tofacitinib tablets/tofacitinib oral solution for the treatment of active PsA have been established in pediatric patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers. Use of tofacitinib for this indication is supported by evidence from well-controlled studies of tofacitinib tablets in adults with PsA, PK data from adults with PsA, and PK data from a clinical trial of tofacitinib in 225 pediatric patients with JIA, and safety data from 280 pediatric patients 2 years of age and older with JIA [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14.2 )] . Following administration of the recommended tofacitinib dosage in pediatric patients 2 years of age and older with PsA, tofacitinib plasma exposures are predicted to be comparable to those observed in adults with PsA based on population PK modeling and simulation [see Clinical Pharmacology ( 12.3 )] . Systemic Juvenile Idiopathic Arthritis The safety and effectiveness of tofacitinib for the treatment of pediatric patients with systemic juvenile idiopathic arthritis (sJIA) have not been established. Additional pediatric information describing a clinical study in which efficacy was not demonstrated is approved for Pfizer Inc.’s Xeljanz (tofacitinib) tablets and oral solution. However, due to Pfizer Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.
Geriatric use
8.5 Geriatric Use Of the 3,315 adults who were enrolled in clinical trials with RA (Studies RA-I to V), a total of 505 patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among tofacitinib tablets-treated patients 65 years of age and older was higher than among those adults under the age of 65. Of the 1,156 tofacitinib tablet-treated patients in clinical trials of patients with UC, a total of 77 patients (7%) were 65 years of age or older. Clinical studies of tofacitinib tablets in patients with UC did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger adult patients. Of the 783 tofacitinib tablet-treated patients in clinical trials of patients with PsA, a total of 72 (9.2%) patients were 65 years of age and older, including 2 (0.3%) patients 75 years and older. These clinical studies did not include sufficient numbers of patients aged 65 years and older with PsA to determine if they respond differently from younger adult patients. Of the 420 tofacitinib tablet-treated patients in clinical trials of patients with AS, a total of 12 (2.9%) patients were 65 years of age and older, including 1 (0.2%) patient 75 years and older. These clinical studies did not include sufficient numbers of patients aged 65 years and older with AS to determine if they respond differently from younger adult patients.
Overdosage
There is no specific antidote for overdose with tofacitinib. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. In a study in patients with end-stage renal disease (ESRD) undergoing hemodialysis, plasma tofacitinib concentrations declined more rapidly during the period of hemodialysis and dialyzer efficiency, calculated as dialyzer clearance/blood flow entering the dialyzer, was high [mean (SD) = 0.73 (0.15)]. However, due to the significant non-renal clearance of tofacitinib, the fraction of total elimination occurring by hemodialysis was small, and thus, limits the value of hemodialysis for treatment of overdose with tofacitinib. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
Description
Tofacitinib oral solution is formulated with the citrate salt of tofacitinib, a JAK inhibitor. Tofacitinib citrate is a white to off-white powder with the following chemical name: (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino)-ß-oxo-1- piperidinepropanenitrile, 2-hydroxy-1,2,3-propanetricarboxylate (1:1). The solubility of tofacitinib citrate in water is 2.9 mg/mL. Tofacitinib citrate has a molecular weight of 504.5 Daltons (or 312.4 Daltons as the tofacitinib free base) and a molecular formula of C 16 H 20 N 6 O
• C 6 H 8 O 7 . The chemical structure of tofacitinib citrate is: Tofacitinib oral solution is supplied for oral administration as a 1 mg/mL clear, colorless solution. Each 1 mL contains 1 mg of tofacitinib (equivalent to 1.62 mg of tofacitinib citrate) and the following inactive ingredients: grape flavor (natural & artificial), hydrochloric acid, purified water, sodium acetate trihydrate, sodium benzoate, sodium hydroxide, sucralose and tartaric acid. structure-formula.jpg
Mechanism of action
12.1 Mechanism of Action Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.
How supplied
How supplied information for tofacitinib oral solution is shown in Table 23. Table 23: How Supplied Information for Tofacitinib Oral Solution Bottle Fill (volume mL) NDC Number Tofacitinib Oral Solution 1 mg/mL Clear, colorless solution 240 mL NDC 0054-0821-58 Tofacitinib 1 mg/ mL oral solution is a clear, colorless solution that contains 1 mg of tofacitinib. It is packaged in HDPE bottles as follows: Each bottle is packaged with one press-in bottle adapter and one 5 mL oral dosing syringe with 3.2 mL, 4 mL, and 5 mL gradations. The press-in bottle adapter and oral dosing syringe are not made with natural rubber latex. Storage and Handling for Tofacitinib Oral Solution Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (between 59°F and 86°F). [See USP Controlled Room Temperature]. Store in the original bottle and carton to protect from light. Use contents of bottle within 60 days of opening. Discard unused oral solution after 60 days.
Patient information
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Serious Infections Inform patients that tofacitinib may lower the ability of their immune system to fight infections. Advise patients not to start taking tofacitinib if they have an active infection. Instruct patients to contact their healthcare provider immediately during treatment if symptoms suggesting infection appear to ensure rapid evaluation and appropriate treatment [see Warnings and Precautions ( 5.1 )] . Advise patients that the risk of herpes zoster, some cases of which can be serious, is increased in patients treated with tofacitinib [see Warnings and Precautions ( 5.1 )] . Malignancies and Lymphoproliferative Disorders Inform patients that tofacitinib may increase their risk of certain cancers, and that lymphoma and other cancers have been observed in patients taking tofacitinib. Instruct patients to inform their healthcare provider if they have ever had any type of cancer [see Warnings and Precautions ( 5.3 )] . Major Adverse Cardiovascular Events Inform patients that tofacitinib may increase their risk of major adverse cardiovascular events (MACE) defined as myocardial infarction, stroke, and cardiovascular death. Instruct all patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events [see Warnings and Precautions ( 5.4 )] . Thrombosis Advise patients to stop taking tofacitinib and to call their healthcare provider right away if they experience any symptoms of thrombosis (sudden shortness of breath, chest pain worsened with breathing, swelling of leg or arm, leg pain or tenderness, red or discolored skin in the affected leg or arm) [see Warnings and Precautions ( 5.5 )] . Hypersensitivity Advise patients to stop taking tofacitinib and to call their healthcare provider right away if they experience any symptoms of allergic reactions while taking tofacitinib [see Warnings and Precautions ( 5.7 )] . Hypoglycemia in Patients with Diabetes Consider advising patients with diabetes to increase monitoring of blood glucose since hypoglycemia, including severe hypoglycemia, has been reported after starting tofacitinib. Advise patients with diabetes to notify their healthcare provider if they develop signs or symptoms of hypoglycemia [see Warnings and Precautions ( 5.8 )] . Important Information on Laboratory Abnormalities Inform patients that tofacitinib may affect certain lab test results, and that blood tests are required before and during tofacitinib treatment [see Warnings and Precautions ( 5.9 )] . Pregnancy Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise females to inform their prescriber of a known or suspected pregnancy [see Use in Specific Populations ( 8.1 )] . Lactation Advise women not to breastfeed during treatment with tofacitinib and for at least 18 hours after the last dose of tofacitinib or 36 hours after the last dose of tofacitinib extended-release tablets [see Use in Specific Populations ( 8.2 )] . Infertility Advise females of reproductive potential that tofacitinib may impair fertility [see Use in Specific Populations ( 8.3 ), Nonclinical Toxicology ( 13.1 )] . It is not known if this effect is reversible. Residual Tablet Shell Patients receiving tofacitinib extended-release tablets may notice an inert tablet shell passing in the stool or via colostomy. Patients should be informed that the active medication has already been absorbed by the time the patient sees the inert tablet shell. Manufactured by: Aphena Pharma Solutions Easton, Maryland (MD) 21601, United States (USA) Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 C50001592/02 Revised: July 2026
Label text from the FDA structured product label by Hikma Pharmaceuticals USA Inc. (revised Jul 1, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Tofacitinib Citrate in 1 product
tofacitinib solution NDC products (1)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0054-0821 | Tofacitinib Citrate 1 mg/mL Solution | Hikma Pharmaceuticals USA Inc. | ANDA |
Frequently asked questions
What is tofacitinib solution used for?
Tofacitinib is a Janus kinase (JAK) inhibitor. Tofacitinib oral solution is indicated for the treatment of pediatric patients 2 years of age and older with: • Active psoriatic arthritis (PsA), who have had an inadequate response or intolerance to one or more TNF blockers. • Active polyarticular course juvenile idiopathic arthritis (pcJIA), who have had an inadequate response or intolerance to one…
What are the side effects of tofacitinib solution?
The following clinically significant adverse reactions are described elsewhere in the labeling: • Serious Infections [see Warnings and Precautions ( 5.1 )] • Increased Risk of Mortality [see Warnings and Precautions ( 5.2 )] • Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions ( 5.3 )] • Major Adverse Cardiovascular Events [see Warnings and Precautions ( 5.4 )] •… See the full label for the complete list.
Who makes tofacitinib solution?
tofacitinib solution is listed by 1 labeler in the FDA NDC directory, including Hikma Pharmaceuticals USA Inc..