Xeljanz

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT XELJANZ® (XELJANZ)

Composition:

Active substance: tofacitinib;

One prolonged-release tablet contains 11 mg of tofacitinib citrate equivalent to 11 mg of tofacitinib;

Excipients: sorbitol (E 420), hydroxyethylcellulose, copovidone, magnesium stearate, cellulose acetate, hydroxypropylcellulose, Opadry Pink 03K140024, Opacode Black.

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties: pink, oval-shaped tablets with a drilled hole on one end of the tablet's side and printed with "JKI 11" on one side.

Pharmacotherapeutic group.

Immunosuppressants. Janus kinase (JAK) inhibitors. ATC code L04AF01.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Tofacitinib is a potent, selective inhibitor of the Janus kinase (JAK) family. In enzyme assays, tofacitinib was shown to inhibit JAK1, JAK2, JAK3, and to a lesser extent TyK2. Unlike other agents, tofacitinib demonstrates high selectivity towards other kinases in the human genome. In human cells, tofacitinib predominantly suppresses signal transduction through heterodimeric cytokine receptors associated with JAK3 and/or JAK1, with functional selectivity over cytokine receptors that signal through JAK2 kinase pairs. Inhibition of JAK1 and JAK3 by tofacitinib attenuates signaling of interleukins (IL-2, -4, -6, -7, -9, -15, -21) and type I and II interferons, resulting in modulation of immune and inflammatory responses.

Pharmacodynamic effects

In patients with rheumatoid arthritis (RA), treatment with tofacitinib for up to 6 months was associated with a dose-dependent reduction in circulating CD16/56+ natural killer (NK) cells, with an expected maximum decrease in the number of these cells approximately 8–10 weeks after initiation of therapy. These changes typically resolved within 2–6 weeks after discontinuation of therapy. Tofacitinib therapy was associated with a dose-dependent increase in B-cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte subsets (CD3+, CD4+, and CD8+) were small and inconsistent.

Following long-term therapy (mean duration of tofacitinib treatment approximately 5 years), CD4+ and CD8+ cell counts were shown to decrease from baseline by an average of 28% and 27%, respectively. In contrast to the reduction observed after short-term dosing, the number of CD16/56+ NK cells increased on average by 73% from baseline. No further increase in CD19+ B-cell counts was observed after long-term tofacitinib treatment. All these lymphocyte subset parameters returned to baseline levels after temporary interruption of therapy. There is no evidence of a causal relationship between lymphocyte subset counts and the occurrence of serious or opportunistic infections or herpes zoster (for information on monitoring absolute lymphocyte count, see section "Dosage and administration").

Changes in total serum levels of immunoglobulins IgG, IgM, and IgA during 6 months of tofacitinib use in patients with RA were small, dose-independent, and similar to those observed with placebo, indicating absence of systemic suppression of humoral immunity.

In patients with RA, rapid reduction in serum C-reactive protein (CRP) levels was observed following tofacitinib administration, which was sustained throughout the treatment period. CRP levels, which decreased during tofacitinib therapy, did not return fully to baseline within 2 weeks after therapy discontinuation, indicating a longer duration of pharmacodynamic activity compared to the elimination half-life.

Pharmacokinetics.

Following oral administration of tofacitinib in the form of 11 mg extended-release tablets, peak plasma concentration is reached within 4 hours, and the elimination half-life is approximately 6 hours. Steady-state concentrations are achieved within 48 hours, with minimal drug accumulation after once-daily dosing. At steady state, the AUC and Cmax values of tofacitinib administered once daily as 11 mg extended-release tablets are equivalent to those observed with tofacitinib administered as 5 mg film-coated tablets twice daily.

Absorption and distribution

Administration of tofacitinib 11 mg extended-release tablets with a high-fat meal did not alter AUC values, while Cmax values increased by 27%.

After intravenous administration, the volume of distribution is 87 L. Approximately 40% of circulating tofacitinib is protein-bound. Tofacitinib binds predominantly to albumin and likely does not bind to α1-acid glycoprotein. Tofacitinib distributes evenly between red blood cells and plasma.

Biotransformation and elimination

The clearance mechanisms of tofacitinib are as follows: approximately 70% of the administered dose is metabolized in the liver, and 30% is excreted unchanged by the kidneys. Tofacitinib metabolism is primarily mediated by the CYP3A4 isoenzyme, with minor contribution from CYP2C19. In a human study with radiolabeled tofacitinib, more than 65% of total circulating radioactivity was attributed to unchanged active substance, while the remaining 35% was accounted for by 8 metabolites, each representing less than 8% of total radioactivity. All metabolites were observed in animals and are predicted to have less than 10-fold potency compared to unchanged tofacitinib in inhibiting JAK1/3. No evidence of stereoinversion was observed in human samples. The pharmacological activity of tofacitinib is associated with the parent molecule. In vitro, tofacitinib is a substrate for the multidrug resistance gene-1 (MDR1), but not for the breast cancer resistance protein, organic anion transporting polypeptides (OATP1B1/1B3), or organic cation transporters (OCT1/2).

Pharmacokinetics in patients

The enzymatic activity of CYP isoenzymes in patients with rheumatoid arthritis (RA) is reduced due to chronic inflammation. In patients with RA, oral clearance of tofacitinib does not change over time, indicating that tofacitinib therapy does not normalize CYP isoenzyme activity.

Population pharmacokinetic analysis in patients with RA shows that systemic exposure (AUC) of tofacitinib at the extremes of patient body weight range (40 kg; 140 kg) was similar (within 5% deviation) to that in a patient weighing 70 kg. It is estimated that AUC values in elderly patients aged 80 years are less than 5% higher than in patients with a mean age of 55 years. In women, estimated AUC values were 7% lower than in men. Available data also indicate no significant differences in AUC values of tofacitinib between Caucasian, African, and Asian patients. A nearly linear relationship between patient body weight and volume of distribution of tofacitinib was observed, resulting in higher maximum concentration (Cmax) values and lower trough concentrations (Cmin) in patients with lower body weight. However, this difference is not considered clinically significant. Inter-individual variability (coefficient of variation in percent) for tofacitinib AUC values was approximately 27%.

Results of population pharmacokinetic analysis in patients with active PsA or ankylosing spondylitis (AS) were consistent with those in patients with RA.

Renal impairment

In patients with mild (creatinine clearance 50–80 ml/min), moderate (creatinine clearance 30–49 ml/min), and severe (creatinine clearance < 30 ml/min) renal impairment, AUC values were 37%, 43%, and 123% higher, respectively, compared to patients with normal renal function (see section "Dosage and administration"). In patients with end-stage renal disease (ESRD), the contribution of dialysis to total tofacitinib clearance was relatively small. After a single 10 mg dose, mean AUC in patients with ESRD, based on concentrations measured on a non-dialysis day, was approximately 40% higher (90% CI: 1.5–95%) compared to patients with normal renal function. Tofacitinib has not been evaluated in clinical studies in patients with baseline creatinine clearance (calculated by the Cockcroft-Gault formula) less than 40 ml/min (see section "Dosage and administration").

Hepatic impairment

In patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment, AUC values increased by 3% and 65%, respectively, compared to patients with normal hepatic function. Tofacitinib has not been evaluated in clinical studies in patients with severe hepatic impairment (Child-Pugh class C) (see sections "Dosage and administration" and "Special precautions") or in patients with positive test results for hepatitis B or hepatitis C at screening.

Interactions

Tofacitinib is not an inhibitor or inducer of CYP isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and is not an inhibitor of uridine diphosphate-glucuronosyltransferase (UGT) isoforms (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7). Tofacitinib is not an inhibitor of MDR1, OATP1B1/1B3, OCT2, OAT1/3, or multidrug resistance-associated protein (MRP) at clinically relevant concentrations.

Comparison of pharmacokinetics of tofacitinib in extended-release tablets and film-coated tablets

Pharmacokinetic equivalence (based on AUC and Cmax values) of tofacitinib 11 mg extended-release tablets administered once daily and tofacitinib 5 mg film-coated tablets administered twice daily has been demonstrated.

Clinical characteristics.

Indications.

Rheumatoid arthritis

Tofacitinib in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to therapy with one or more disease-modifying antirheumatic drugs (DMARDs) or who are intolerant to such drugs. Tofacitinib may be prescribed as monotherapy in cases of methotrexate intolerance or when methotrexate treatment is inappropriate (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Psoriatic arthritis

Tofacitinib in combination with methotrexate is indicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have responded inadequately to prior therapy with disease-modifying antirheumatic drugs or who are intolerant to these agents.

Ankylosing spondylitis

Tofacitinib is indicated for the treatment of adult patients with active ankylosing spondylitis (AS) who have not responded adequately to standard therapy.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".

Active tuberculosis, serious infections including sepsis, or opportunistic infections (see section "Special warnings and precautions for use").

Severe hepatic impairment (see section "Dosage and administration").

Pregnancy and lactation (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other types of interactions.

Potential of other medicinal products to affect the pharmacokinetics (PK) of tofacitinib

Since tofacitinib is metabolized by the CYP3A4 isoenzyme, interactions are likely with medicinal products that inhibit or induce CYP3A4. Exposure to tofacitinib increases when administered concomitantly with strong CYP3A4 inhibitors (e.g., ketoconazole) or when concomitant administration of one or more medicinal products (e.g., fluconazole) results in both moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (see section "Dosage and administration").

Exposure to tofacitinib decreases when administered concomitantly with strong inducers of CYP enzyme system (e.g., rifampicin). It is unlikely that inhibitors of CYP2C19 or P-glycoprotein alone will significantly alter the PK of tofacitinib.

Concomitant administration with ketoconazole (a strong CYP3A4 inhibitor), fluconazole (a moderate CYP3A4 inhibitor and strong CYP2C19 inhibitor), tacrolimus (a mild CYP3A4 inhibitor), and cyclosporine (a moderate CYP3A4 inhibitor) increased AUC values of tofacitinib, whereas rifampicin (a strong inducer of CYP enzymes) decreased AUC values of tofacitinib. Concomitant administration of tofacitinib with strong inducers of CYP enzymes (e.g., rifampicin) may result in loss or reduction of clinical response (see figure). Concomitant use of strong CYP enzyme inducers with tofacitinib is not recommended. Concomitant administration with ketoconazole and fluconazole increased Cmax values of tofacitinib, whereas tacrolimus, cyclosporine, and rifampicin decreased Cmax values of tofacitinib. Concomitant administration with methotrexate at a dose of 15–25 mg once weekly did not affect the PK of tofacitinib in patients with RA (see figure).

Note. The control group refers to patients who received tofacitinib only.

a The dose of tofacitinib should be reduced to 5 mg (as film-coated tablets) once daily in patients who are receiving 11 mg (as extended-release tablets) once daily (see section "Dosage and administration").

Fig. Effect of other medicinal products on the pharmacokinetics of tofacitinib

Potential of tofacitinib to influence the PK of other medicinal products

Concomitant administration of tofacitinib did not affect the PK of oral contraceptives—levonorgestrel and ethinylestradiol—in healthy female volunteers.

In patients with RA, concomitant administration of tofacitinib with methotrexate at doses of 15–25 mg once weekly reduced the AUC and Cmax of methotrexate by 10% and 13%, respectively. The extent of reduction in methotrexate exposure does not require adjustment of the individually optimized methotrexate dose.

Special precautions for use.

The following patient groups should only receive tofacitinib if there are no suitable alternative treatment options:

• patients aged 65 years and older;
• patients with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors (e.g., current smoking or a history of prolonged smoking);
• patients with risk factors for malignancy (e.g., current or past history of malignancy).

Use in patients aged 65 years and older

Due to the increased risk of serious infections, myocardial infarction, malignancies, and all-cause mortality associated with tofacitinib use in patients aged 65 years and older, tofacitinib should only be used in these patients if there are no suitable alternative treatment options (see additional information below).

Use in combination with other medicinal products

The use of tofacitinib in combination with biological agents such as TNF antagonists, IL-1R antagonists, IL-6R antagonists, CD20 monoclonal antibodies, IL-17 antagonists, IL-12/IL-23 antagonists, integrin antagonists, selective costimulation modulators, and potent immunosuppressants such as azathioprine, 6-mercaptopurine, cyclosporine, and tacrolimus has not been studied. Therefore, such combinations should be avoided due to the potential for enhanced immunosuppression and an increased risk of infections.

In clinical trials of RA, a higher incidence of adverse reactions was observed when tofacitinib was used in combination with methotrexate compared to tofacitinib monotherapy.

The use of tofacitinib in combination with phosphodiesterase 4 inhibitors has not been studied in clinical trials.

Venous thromboembolism (VTE)

Serious VTE complications, including pulmonary embolism (PE), some of which were fatal, and deep vein thrombosis (DVT), have been reported in patients receiving tofacitinib. In a randomized, post-marketing safety study involving RA patients aged 50 years and older with at least one additional cardiovascular risk factor, a dose-dependent increased risk of VTE was observed with tofacitinib compared to TNF inhibitors (see sections "Adverse reactions" and "Pharmacological properties").

In a post hoc exploratory analysis of this study involving patients with known VTE risk factors, VTE events occurred more frequently in patients receiving tofacitinib who had D-dimer levels ≥ 2 × upper limit of normal (ULN) at 12 months of therapy compared to those with D-dimer levels < 2 × ULN; this trend was not observed in patients receiving TNF inhibitors. Interpretation is limited by the low number of VTE events and limited D-dimer testing (assessed only at baseline, 12 months, and end of study). In patients without VTE during the study, mean D-dimer levels were significantly reduced at 12 months compared to baseline across all treatment groups. However, D-dimer levels ≥ 2 × ULN at 12 months were observed in approximately 30% of patients without subsequent VTE events, indicating limited specificity of the D-dimer test in this study.

Tofacitinib should only be used in patients with serious adverse cardiovascular events or malignancy risk factors (see also below "Serious adverse cardiovascular events (including myocardial infarction)" and "Malignancies and lymphoproliferative disorders") if there are no suitable alternative treatment options.

Tofacitinib should be used with caution in patients with VTE risk factors other than serious adverse cardiovascular events or malignancy risk factors.

VTE risk factors other than serious adverse cardiovascular events or malignancy risk factors include prior VTE events; high-risk groups include patients who have undergone major surgery or are immobilized; patients using combined hormonal contraceptives or hormone replacement therapy; and patients with inherited coagulation disorders. During tofacitinib therapy, patients should be periodically re-evaluated for VTE risk.

RA patients with known VTE risk factors should undergo D-dimer testing approximately 12 months after initiation of therapy. If the D-dimer test result is ≥ 2 × ULN, the decision to continue tofacitinib therapy should only be made after confirming that the clinical benefit outweighs the associated risks.

Patients presenting with signs and symptoms suggestive of VTE should undergo immediate evaluation, and tofacitinib should be discontinued regardless of dose or indication if VTE is suspected.

Retinal vein thrombosis

Retinal vein thrombosis has been reported in patients receiving tofacitinib (see section "Adverse reactions"). Patients should be advised to seek immediate medical attention if symptoms suggestive of retinal vein thrombosis occur.

Serious infections

Serious and sometimes fatal infections caused by bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib therapy (see section "Adverse reactions"). The risk of opportunistic infections is higher in the Asian geographical region (see section "Adverse reactions"). RA patients receiving corticosteroids may be more susceptible to infections.

Tofacitinib therapy should not be initiated in patients with active infections, including localized infections.

Before initiating therapy, the risks and benefits of tofacitinib should be carefully considered in patients:

• with recurrent infections;
• with a history of serious or opportunistic infections;
• who have lived in or traveled to endemic fungal areas;
• with comorbidities that may predispose them to infections.

Patients should be closely monitored during and after tofacitinib therapy for early signs and symptoms of infection. If a patient develops a serious infection, opportunistic infection, or sepsis, therapy with this drug should be temporarily suspended. Any patient who develops a new infection during tofacitinib therapy should undergo immediate comprehensive diagnostic evaluation appropriate for immunocompromised patients, initiate appropriate antimicrobial therapy, and be closely monitored.

Since the incidence of infections is generally increased in elderly patients and in patients with diabetes, tofacitinib should be used cautiously in the treatment of elderly patients and patients with diabetes (see section "Adverse reactions"). The use of tofacitinib in patients aged 65 years and older should only be considered if no suitable alternative treatment options are available.

The risk of infection may increase with the degree of lymphopenia; therefore, lymphocyte counts should be considered when assessing individual infection risk. Criteria for treatment interruption and monitoring in lymphopenia are provided in the section "Dosage and administration".

Tuberculosis

Before initiating therapy, the risks and benefits of tofacitinib should be carefully considered in patients:

• who have been in contact with individuals with tuberculosis;
• who have lived in or traveled to areas with endemic tuberculosis.

Before starting and during treatment with tofacitinib, patients should be evaluated for latent or active tuberculosis infection.

Patients with latent tuberculosis who test positive should receive a course of standard anti-mycobacterial therapy before initiating tofacitinib.

Prophylactic anti-tuberculosis therapy should also be considered for patients with a negative tuberculosis test but with a history of latent or active tuberculosis without documented adequate treatment, or for patients with a negative test but with risk factors for tuberculosis infection. It is recommended to consult a healthcare provider experienced in the treatment of tuberculosis to assist in determining the need for prophylactic anti-tuberculosis therapy for each individual patient. Patients should be closely monitored for signs and symptoms of tuberculosis, particularly those who tested negative for latent tuberculosis infection before starting therapy.

Reactivation of viral infection

Cases of viral infection reactivation, including herpes zoster (shingles), have been reported in patients receiving tofacitinib (see section "Adverse reactions"). The incidence of herpes zoster is increased in the following subgroups of patients receiving tofacitinib:

• patients from Japan or Korea;
• patients with an absolute leukocyte count below 1000 cells/mm³ (see section "Dosage and administration");
• patients with long-standing RA who have previously received two or more biologic disease-modifying antirheumatic drugs (bDMARDs);
• patients receiving tofacitinib at a dose of 10 mg twice daily.

The effect of tofacitinib on reactivation of chronic viral hepatitis is unknown. Patients with positive screening tests for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed before and during tofacitinib therapy according to clinical guidelines.

At least one confirmed case of progressive multifocal leukoencephalopathy (PML) has been reported in RA patients receiving tofacitinib in the post-marketing period. PML can be fatal and should be considered in the differential diagnosis of immunosuppressed patients presenting with new or worsening neurological symptoms.

Serious adverse cardiovascular events (including myocardial infarction)

Serious adverse cardiovascular events have been observed in patients receiving tofacitinib.

In a randomized, post-marketing safety study involving RA patients aged 50 years and older with at least one additional cardiovascular risk factor, an increased incidence of myocardial infarction was observed with tofacitinib compared to TNF inhibitors (see section "Adverse reactions"). Tofacitinib should only be used in patients aged 65 years and older, current or past smokers, and patients with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors if there are no suitable alternative treatment options.

Malignancies and lymphoproliferative disorders

Tofacitinib may affect the body's ability to prevent the development of malignancies.

In a randomized, post-marketing safety study involving RA patients aged 50 years and older with at least one additional cardiovascular risk factor, an increased incidence of malignancies, particularly non-melanoma skin cancer (NMSC), lung cancer, and lymphoma, was observed with tofacitinib compared to TNF inhibitors (see section "Adverse reactions").

NMSC, lung cancer, and lymphoma have also been observed in other clinical trials and in the post-marketing period in patients receiving tofacitinib.

Other malignancies have been reported in clinical trials and in the post-marketing period in patients receiving tofacitinib, including breast cancer, melanoma, prostate cancer, and pancreatic cancer.

Tofacitinib should only be used in patients aged 65 years and older, current or past smokers, and patients with other malignancy risk factors (e.g., current or past history of malignancy, except successfully treated non-melanoma skin cancer) if there are no suitable alternative treatment options. All patients, particularly those at increased risk of skin cancer, should undergo periodic skin examinations (see section "Adverse reactions").

Interstitial lung disease

This medicinal product should be used with caution in patients with a history of chronic lung disease, as they may be more susceptible to infections. Cases of interstitial lung disease (some fatal) have been reported in patients receiving tofacitinib in clinical trials for RA and in the post-marketing period, although the role of JAK inhibition in these cases is unknown. Patients of Asian origin with RA are known to have a higher risk of interstitial lung disease; therefore, this drug should be used with caution in such patients.

Gastrointestinal perforation

Cases of gastrointestinal perforation have been reported in clinical trials, although the role of JAK inhibition in these cases is unknown. Tofacitinib should be used with caution in patients who may have an increased risk of gastrointestinal perforation (e.g., patients with a history of diverticulitis; patients receiving concomitant corticosteroids and/or nonsteroidal anti-inflammatory drugs). Patients who develop new gastrointestinal signs and symptoms should undergo immediate evaluation for early detection of gastrointestinal perforation.

Fractions

Fractures have been observed in patients receiving tofacitinib. Tofacitinib should be used with caution in patients with known risk factors for fractures, such as elderly patients, women, and patients receiving corticosteroids, regardless of indication and dose.

Liver enzymes

Tofacitinib therapy has been associated with an increased frequency of elevated liver enzymes in some patients (see section "Adverse reactions"). The initiation of tofacitinib therapy should be carefully considered in patients with elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, especially when used concomitantly with potentially hepatotoxic drugs such as methotrexate. Routine monitoring of liver function biochemical parameters is recommended after starting therapy, and any observed increase in liver enzymes should be promptly investigated to identify possible drug-induced liver injury. If drug-induced liver injury is suspected, tofacitinib should be discontinued until this diagnosis is ruled out.

Hypersensitivity

Hypersensitivity reactions have been reported in the post-marketing period associated with tofacitinib use. Allergic reactions included angioedema and urticaria; serious reactions occurred. Tofacitinib should be immediately discontinued in the event of any serious allergic or anaphylactic reaction.

Laboratory parameters

Lymphocytes

Tofacitinib therapy has been associated with an increased frequency of lymphopenia compared to placebo. Lymphocyte counts below 750 cells/mm³ were associated with an increased incidence of serious infections. It is recommended not to initiate or continue tofacitinib therapy in patients with confirmed absolute lymphocyte counts below 750 cells/mm³. Lymphocyte counts should be monitored at baseline and every 3 months thereafter. Dose adjustment recommendations based on lymphocyte count are provided in the section "Dosage and administration".

Neutrophils

Tofacitinib therapy has been associated with an increased frequency of neutropenia (neutrophil count below 2000 cells/mm³) compared to placebo. Tofacitinib therapy should not be initiated in patients with an absolute neutrophil count (ANC) below 1000 cells/mm³. ANC should be monitored at baseline, after 4–8 weeks of therapy, and every 3 months thereafter. Dose adjustment recommendations based on ANC are provided in the section "Dosage and administration".

Hemoglobin

Tofacitinib therapy has been associated with decreased hemoglobin levels. Tofacitinib therapy should not be initiated in patients with hemoglobin levels below 9 g/dL. Hemoglobin levels should be monitored at baseline, after 4–8 weeks of therapy, and every 3 months thereafter. Dose adjustment recommendations based on hemoglobin levels are provided in the section "Dosage and administration".

Lipid monitoring

Tofacitinib therapy has been associated with increased lipid levels, such as total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). The maximum effect is usually observed within 6 weeks of starting therapy. Lipid profile assessment should be performed 8 weeks after initiating tofacitinib therapy. Treatment of hyperlipidemia should be managed according to clinical guidelines. Elevated total cholesterol and LDL-C levels associated with tofacitinib can be reduced to pre-treatment levels with statin therapy.

Hypoglycemia in patients receiving diabetes treatment

Cases of hypoglycemia have been reported after initiating tofacitinib therapy in patients receiving antidiabetic medications. Dose adjustment of antidiabetic agents may be necessary if hypoglycemia occurs.

Vaccination

All patients should be up to date with all vaccinations according to current immunization guidelines before starting tofacitinib therapy. Live vaccines should not be administered concurrently with tofacitinib. The decision to administer live vaccines before starting tofacitinib therapy should consider prior immunosuppression in the patient.

Prophylactic vaccination against herpes zoster should be considered according to vaccination recommendations. Particular attention should be given to patients with long-standing RA who have previously received two or more bDMARDs. If a decision is made to administer a live herpes zoster vaccine, it should only be given to patients with a documented history of varicella or those who are seropositive for varicella-zoster virus. If the history of varicella is uncertain or unreliable, testing for varicella-zoster virus antibodies is recommended.

Live vaccines should be administered at least 2 weeks, but preferably 4 weeks, before starting tofacitinib therapy, or according to current vaccination guidelines and vaccine compatibility with immunomodulatory drugs. There are currently no data on secondary transmission of infection from live vaccines to patients receiving tofacitinib.

Gastrointestinal obstruction with the use of non-deformable extended-release formulation

Tofacitinib in the form of extended-release tablets should be used with caution in patients with known severe gastrointestinal narrowing (due to disease or iatrogenic causes). Isolated reports of obstructive symptoms have been received in patients with known strictures associated with the use of other extended-release non-deformable oral medications.

Excipients

This medicinal product contains sorbitol. The additive effect of concomitant use of medicinal products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be considered.

The sorbitol content in oral medicinal products may affect the bioavailability of other concurrently administered oral medicinal products.

Each extended-release tablet contains 152.23 mg of sorbitol. If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

Standard, well-controlled studies of tofacitinib use in pregnant women have not been conducted. Tofacitinib has been shown to cause teratogenic effects in rats and rabbits and to affect parturition and peri/postnatal development of offspring.

As a precautionary measure, tofacitinib is contraindicated during pregnancy (see section "Contraindications").

Women of reproductive potential / contraception in women

Women of reproductive potential should be advised to use effective contraception during tofacitinib therapy and for at least 4 weeks after the last dose.

Breastfeeding

It is unknown whether tofacitinib is excreted in human breast milk. A risk to the breastfed infant cannot be excluded. Tofacitinib was excreted in milk in rats during lactation. As a precautionary measure, tofacitinib is contraindicated during breastfeeding (see section "Contraindications").

Reproductive function

Formal studies on the effect of this medicinal product on human fertility have not been conducted. In rats, tofacitinib caused impaired fertility in females but not in males.

Ability to affect reaction speed when driving vehicles or operating machinery.

Tofacitinib has no effect or a negligible effect on the ability to drive vehicles or operate machinery.

Method of administration and dosing.

Treatment should be initiated and managed under the supervision of a healthcare professional experienced in the diagnosis and treatment of diseases requiring tofacitinib therapy.

Dosing

Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS)

The recommended dose is one 11 mg prolonged-release tablet taken once daily; this dose must not be exceeded.

No dose adjustment is required when used in combination with methotrexate.

Switching from tofacitinib 5 mg tablets coated with a film layer administered twice daily to tofacitinib 11 mg prolonged-release tablets administered once daily, and vice versa, is permitted starting the day after the last dose of either medicinal product. For comparison of pharmacokinetics between tofacitinib prolonged-release tablets and film-coated tablets, see section "Pharmacological properties".

Temporary interruption and permanent discontinuation of treatment

If a patient develops a serious infection, tofacitinib therapy should be temporarily interrupted until control of the infection is achieved.

Temporary interruption of tofacitinib may be required to manage dose-dependent laboratory abnormalities, such as lymphopenia, neutropenia, and anemia. As shown in Tables 1, 2, and 3 below, recommendations for temporary interruption or permanent discontinuation of treatment depend on the severity of laboratory abnormalities (see section "Special precautions for use").

Initiating treatment with the drug is not recommended in patients with an absolute lymphocyte count (ALC) below 750 cells/mm³.

Table 1

Low absolute lymphocyte count (see section "Special precautions for use")

It is recommended not to initiate therapy in patients with an absolute neutrophil count (ANC) of less than 1,000 cells/mm³.

Table 2

Low absolute neutrophil count (see section "Special precautions")

It is recommended not to initiate therapy in patients with hemoglobin levels below 9 g/dL.

Table 3

Low hemoglobin level (section "Special precautions")

Interactions

The total daily dose of tofacitinib should be reduced by half in patients receiving strong inhibitors of cytochrome P450 (CYP) 3A4 isoenzyme (e.g., ketoconazole), as well as in patients receiving concomitantly one or more medicinal products causing both moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (e.g., fluconazole) (see section "Interaction with other medicinal products and other forms of interaction"), namely:

• the dose of tofacitinib should be reduced to one 5 mg film-coated tablet once daily in patients who are receiving the 11 mg extended-release tablet once daily.

Discontinuation of therapy in AS

Available data indicate that clinical improvement in AS occurs within 16 weeks after initiation of tofacitinib therapy. For patients who do not exhibit clinical improvement during this period, the continuation of therapy should be reconsidered.

Special patient groups

Elderly patients

Dose adjustment is not required in patients aged 65 years and older. Data on use in patients over 75 years of age are currently limited. Recommendations for use in patients aged 65 years and older are provided in section "Special instructions".

Hepatic impairment

No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh class A).

In patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to one 5 mg film-coated tablet once daily if the recommended dose with normal hepatic function is one 11 mg extended-release tablet once daily (see section "Pharmacological properties").

Tofacitinib is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) (see section "Contraindications").

Renal impairment

No dose adjustment is required in patients with mild (creatinine clearance 50–80 mL/min) or moderate (creatinine clearance 30–49 mL/min) renal impairment.

In patients with severe renal impairment (creatinine clearance < 30 mL/min) (including patients on hemodialysis), the dose should be reduced to one 5 mg film-coated tablet once daily if the recommended dose with normal renal function is one 11 mg extended-release tablet once daily (see section "Pharmacological properties"). Patients with severe renal impairment should receive the reduced dose even after completion of hemodialysis (see section "Pharmacological properties").

Administration method

For oral use.

Tofacitinib may be administered orally with or without food.

Tofacitinib 11 mg extended-release tablets should be swallowed whole to ensure proper delivery of the full dose. Tablets must not be crushed, split, or chewed.

Children

The safety and efficacy of tofacitinib in the form of extended-release tablets in children (aged 0 to 18 years) have not been established. Data are lacking.

Overdose.

In case of overdose, patients should be monitored for signs and symptoms of adverse reactions. There is no specific antidote for tofacitinib overdose. Symptomatic and supportive treatment is indicated.

Pharmacokinetic data following single doses up to 100 mg in healthy volunteers indicate that more than 95% of the administered dose is expected to be eliminated within 24 hours.

Adverse Reactions

Summary of Safety Profile

Rheumatoid Arthritis

The most common serious adverse reactions were serious infections (see section "Special Warnings and Precautions for Use"). In a long-term safety study across the entire population of patients indicated for this drug, the most frequently reported serious infections during treatment with tofacitinib were pneumonia (1.7%), herpes zoster (0.6%), urinary tract infections (0.4%), cellulitis (0.4%), diverticulitis (0.3%), and appendicitis (0.2%). Opportunistic infections observed during tofacitinib treatment included tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infections, and listeriosis. Some patients had disseminated rather than localized forms of disease. Other serious infections not reported in clinical trials may also occur (e.g., coccidioidomycosis).

The most common adverse reactions reported during the first 3 months of therapy in placebo- or methotrexate-controlled double-blind studies were headache (3.9%), upper respiratory tract infections (3.8%), viral upper respiratory tract infections (3.3%), diarrhea (2.9%), nausea (2.7%), and hypertension (2.2%).

The proportion of patients who discontinued tofacitinib due to adverse reactions within the first 3 months in placebo- or methotrexate-controlled double-blind studies was 3.8%. The most common infections leading to discontinuation within the first 3 months in controlled clinical trials were herpes zoster (0.19%) and pneumonia (0.15%).

Psoriatic Arthritis

Overall, the safety profile observed in patients with active PsA receiving tofacitinib was consistent with the safety profile observed in patients with RA receiving tofacitinib.

Ankylosing Spondylitis

Overall, the safety profile observed in patients with active AS receiving tofacitinib was consistent with the safety profile observed in patients with RA receiving tofacitinib.

List of Adverse Reactions

The adverse reactions listed below were observed in clinical trials in patients with RA, PsA, AS, and ulcerative colitis (UC). Reactions are classified by system organ classes and the following standard frequency categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), or frequency not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

Infections and infestations: common: pneumonia, influenza, herpes zoster, urinary tract infections, sinusitis, bronchitis, nasopharyngitis, pharyngitis; uncommon: tuberculosis, diverticulitis, pyelonephritis, cellulitis, herpes simplex, viral gastroenteritis, viral infection; rare: sepsis, urosepsis, disseminated tuberculosis, bacteremia, Pneumocystis jirovecii-induced pneumonia, pneumococcal pneumonia, bacterial pneumonia, cytomegalovirus infection, bacterial arthritis; very rare: central nervous system tuberculosis, cryptococcal meningitis, necrotizing fasciitis, encephalitis, staphylococcal bacteremia, infection due to Mycobacterium avium complex, atypical mycobacterial infection.

Benign, malignant and unspecified neoplasms (including cysts and polyps): uncommon: lung cancer, non-melanoma skin cancer; rare: lymphoma.

Disorders of the blood and lymphatic system: common: lymphopenia, anemia; uncommon: leukopenia, neutropenia.

Immune system disorders: frequency not known: hypersensitivity*, angioedema*, urticaria*.

Metabolism and nutrition disorders: uncommon: dyslipidemia, hyperlipidemia, dehydration.

Psychiatric disorders: uncommon: insomnia.

Nervous system disorders: common: headache; uncommon: paresthesia.

Cardiac disorders: uncommon: myocardial infarction.

Vascular disorders: common: hypertension; uncommon: venous thromboembolism**.

Respiratory, thoracic and mediastinal disorders: common: cough; uncommon: dyspnea, nasal sinus edema.

Gastrointestinal disorders: common: abdominal pain, vomiting, diarrhea, nausea, gastritis, dyspepsia.

Hepatobiliary disorders: uncommon: hepatic steatosis, increased levels of liver enzymes, increased transaminase levels, increased gamma-glutamyl transferase levels; rare: abnormal liver function test results.

Skin and subcutaneous tissue disorders: common: rash, acne; uncommon: erythema, pruritus.

Musculoskeletal and connective tissue disorders: common: arthralgia; uncommon: joint swelling, tendinitis; rare: musculoskeletal pain.

General disorders and administration site conditions: common: peripheral edema; uncommon: fever, fatigue.

Investigations: common: increased blood creatine phosphokinase level; uncommon: increased blood creatinine level, increased blood cholesterol level, increased low-density lipoprotein cholesterol level, increased body weight.

Injury, poisoning and procedural complications: uncommon: ligament sprain, muscle strain.

* Data from spontaneous reports.

** The term "venous thromboembolism" includes pulmonary embolism (PE), deep vein thrombosis (DVT), and retinal vein thrombosis.

Description of Selected Adverse Reactions

Venous Thromboembolism (VTE)

Rheumatoid Arthritis

In a large (N = 4,362) randomized post-marketing safety study involving RA patients aged 50 years or older with at least one additional cardiovascular risk factor, VTE occurred at a higher frequency and in a dose-dependent manner in patients receiving tofacitinib compared to those receiving TNF inhibitors. Most of these events were serious, and some were fatal. The incidence rate (95% CI) of PE in the groups receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors was 0.17 (0.08–0.33), 0.50 (0.32–0.74), and 0.06 (0.01–0.17) events per 100 patient-years, respectively. Compared to TNF inhibitors, the hazard ratio (HR) for PE was 2.93 (0.79–10.83) and 8.26 (2.49–27.43) for tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily, respectively. Most (97%) patients who developed PE during tofacitinib treatment had VTE risk factors.

Ankylosing Spondylitis

According to combined data from phase 2 and phase 3 randomized controlled clinical trials, no cases of VTE were observed in 420 patients (233 patient-years of observation) receiving tofacitinib for up to 48 weeks.

Infections in General

Rheumatoid Arthritis

In phase 3 controlled clinical trials, the incidence of infections within 0–3 months after treatment initiation in the monotherapy groups receiving tofacitinib 5 mg twice daily (total 616 patients) and 10 mg twice daily (total 642 patients) was 16.2% (100 patients) and 17.9% (115 patients), respectively, compared to 18.9% (23 patients) in the placebo group (total 122 patients). In phase 3 controlled clinical trials with concomitant disease-modifying antirheumatic drugs (DMARDs), the incidence of infections within 0–3 months after treatment initiation in the tofacitinib 5 mg twice daily (total 973 patients) or 10 mg twice daily (total 969 patients) plus DMARDs group was 21.3% (207 patients) and 21.8% (211 patients), respectively, compared to 18.4% (103 patients) in the placebo plus DMARDs group (total 559 patients).

The most common infections were upper respiratory tract infections and nasopharyngitis (3.7% and 3.2%, respectively).

The overall incidence of infections in the long-term safety evaluation population, which included patients receiving tofacitinib for all approved indications (total 4,867 patients), was 46.1 patients with corresponding adverse reactions per 100 patient-years (43.8 and 47.2 patients with corresponding adverse reactions for 5 mg and 10 mg twice daily dosing regimens, respectively). In patients (total 1,750) receiving the drug as monotherapy, the incidence rates of infections were 48.9 and 41.9 patients with corresponding reactions per 100 patient-years for 5 mg and 10 mg twice daily regimens, respectively. For patients (total 3,117) receiving concomitant DMARD therapy, the incidence rates of infections were 41.0 and 50.3 patients with corresponding reactions per 100 patient-years for 5 mg and 10 mg twice daily regimens, respectively.

Ankylosing Spondylitis

According to combined data from phase 2 and phase 3 clinical trials, during the placebo-controlled period of up to 16 weeks, the incidence of infections in the group receiving tofacitinib 5 mg twice daily (185 patients) was 27.6%, compared to 23.0% in the placebo group (187 patients). According to combined data from phase 2 and phase 3 clinical trials, among 316 patients receiving tofacitinib 5 mg twice daily for 48 weeks, the incidence of infections was 35.1%.

Serious Infections

Rheumatoid Arthritis

In 6-month and 24-month controlled clinical trials, the incidence of serious infections in the monotherapy group receiving tofacitinib 5 mg twice daily was 1.7 patients with corresponding events per 100 patient-years. In the monotherapy group receiving tofacitinib 10 mg twice daily, the incidence of corresponding events was 1.6 patients per 100 patient-years; in the placebo group, the incidence was 0 events per 100 patient-years, and in the methotrexate group, it was 1.9 patients with corresponding events per 100 patient-years.

In studies lasting 6, 12, or 24 months, the incidence of serious infections in groups receiving tofacitinib 5 mg twice daily or 10 mg twice daily plus DMARDs was 3.6 and 3.4 patients with corresponding events per 100 patient-years, respectively, compared to 1.7 patients with corresponding events per 100 patient-years in the placebo plus DMARDs group.

In the long-term safety evaluation population, which included patients receiving tofacitinib for all approved indications, the overall incidence of serious infections was 2.4 and 3.0 patients with corresponding events per 100 patient-years for the tofacitinib 5 mg and 10 mg twice daily groups, respectively. The most common serious infections included pneumonia, herpes zoster, urinary tract infections, cellulitis, gastroenteritis, and diverticulitis. Cases of opportunistic infections were reported (see section "Special Warnings and Precautions for Use").

In a large (N = 4,362) randomized post-marketing safety study involving RA patients aged 50 years or older with at least one additional cardiovascular risk factor, a dose-dependent increase in serious infections was observed with tofacitinib compared to TNF inhibitors (see section "Special Warnings and Precautions for Use"). The incidence rate (95% CI) of serious infections in the tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitor groups was 2.86 (2.41; 3.37), 3.64 (3.11; 4.23), and 2.44 (2.02; 2.92) events per 100 patient-years, respectively. The risk ratios for serious infections with tofacitinib 10 mg twice daily and tofacitinib 5 mg twice daily compared to TNF inhibitors were 1.17 (0.92; 1.50) and 1.48 (1.17; 1.87), respectively.

Ankylosing Spondylitis

According to combined data from phase 2 and phase 3 clinical trials, among 316 patients receiving tofacitinib 5 mg twice daily for up to 48 weeks, one case of serious infection (aseptic meningitis) was recorded, corresponding to an incidence rate of 0.43 patients with corresponding events per 100 patient-years.

Serious Infections in Elderly Patients

Among 4,271 patients who participated in RA studies I–VI, a total of 608 RA patients were aged 65 years or older, including 85 patients aged 75 years or older. The incidence of serious infections in patients aged 65 years or older receiving tofacitinib was higher than in patients under 65 years of age (4.8 vs. 2.4 per 100 patient-years, respectively).

In a large (N = 4,362) randomized post-marketing safety study involving RA patients aged 50 years or older with at least one additional cardiovascular risk factor, an increase in serious infections was observed in patients aged 65 years or older receiving tofacitinib 10 mg twice daily compared to TNF inhibitors or tofacitinib 5 mg twice daily (see section "Special Warnings and Precautions for Use"). The incidence rate (95% CI) of serious infections in patients aged 65 years or older in the tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitor groups was 4.03 (3.02; 5.27), 5.85 (4.64; 7.30), and 3.73 (2.81; 4.85) events per 100 patient-years, respectively.

The risk ratios for serious infections in patients aged 65 years or older receiving tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily compared to TNF inhibitors were 1.08 (0.74; 1.58) and 1.55 (1.10; 2.19), respectively.

Serious Infections Observed in Post-Marketing Non-Interventional Safety Studies

Data from a post-marketing non-interventional safety study evaluating tofacitinib in RA patients from a registry (US Corrona) indicate a numerically higher incidence of serious infections with the 11 mg extended-release tablet once daily regimen compared to the 5 mg immediate-release tablet twice daily regimen. The approximate incidence rate (95% CI) (i.e., unadjusted for age or sex) at 12 months after treatment initiation was 3.45 (1.93; 5.69) and 2.78 (1.74; 4.21), and at 36 months was 4.71 (3.08; 6.91) and 2.79 (2.01; 3.77) events per 100 patient-years in the groups receiving 11 mg tofacitinib extended-release tablets once daily or 5 mg tofacitinib immediate-release tablets twice daily, respectively. The unadjusted risk ratio was 1.30 (95% CI: 0.67; 2.50) at 12 months and 1.93 (95% CI: 1.15; 3.24) at 36 months for 11 mg tofacitinib extended-release tablets once daily compared to 5 mg tofacitinib immediate-release tablets twice daily. These statements are based on data from a small number of patients with events observed with relatively wide confidence intervals and over a limited observation period.

Reactivation of Viral Infection

Patients of Japanese or Korean descent receiving tofacitinib, patients with long-standing rheumatoid arthritis who previously received two or more biological DMARDs, patients with absolute lymphocyte count (ALC) < 1,000 cells/mm³, or patients receiving tofacitinib 10 mg twice daily may have an increased risk of developing herpes zoster (see section "Special Warnings and Precautions for Use").

In a large (N = 4,362) randomized post-marketing safety study involving RA patients aged 50 years or older with at least one additional cardiovascular risk factor, an increased number of herpes zoster cases was observed in the tofacitinib group compared to the TNF inhibitor group. The incidence rate (95% CI) of herpes zoster in the tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitor groups was 3.75 (3.22; 4.34), 3.94 (3.38; 4.57), and 1.18 (0.90; 1.52) events per 100 patient-years, respectively.

Laboratory Tests

Lymphocytes

In controlled clinical trials of RA, confirmed ALC reduction below 500 cells/mm³ was observed in 0.3% of patients, and ALC between 500 and 750 cells/mm³ in 1.9% of patients in the combined population receiving 5 mg twice daily and 10 mg twice daily doses.

In the long-term safety evaluation population of RA patients, confirmed ALC reduction below 500 cells/mm³ was observed in 1.3% of patients, and ALC between 500 and 750 cells/mm³ in 8.4% of patients in the combined population receiving 5 mg twice daily and 10 mg twice daily doses.

Confirmed ALC below 750 cells/mm³ was associated with an increased incidence of serious infections (see section "Special Warnings and Precautions for Use").

Neutrophils

In controlled clinical trials of RA, confirmed absolute neutrophil count (ANC) reduction below 1,000 cells/mm³ was observed in 0.08% of patients in the combined population receiving 5 mg twice daily and 10 mg twice daily doses. Confirmed ANC reduction below 500 cells/mm³ was not observed in any treatment group. No clear association between neutropenia and occurrence of serious infections was observed.

In the long-term safety evaluation population of RA patients, the nature and frequency of confirmed ANC reduction remained at the same level observed in controlled clinical trials (see section "Special Warnings and Precautions for Use").

Platelets

Only patients with platelet counts ≥ 100,000 cells/mm³ were allowed to participate in phase 3 controlled clinical trials (RA, PsA, AS indications); therefore, there is currently no information on the use of tofacitinib in patients with platelet counts < 100,000 cells/mm³ prior to tofacitinib initiation.

Liver Enzymes

Confirmed cases of liver enzyme elevation to three times above the upper limit of normal (3 × ULN) in RA patients were uncommon. In patients with elevated liver enzymes, changes in treatment regimen (e.g., dose reduction of concomitant DMARD, temporary discontinuation or dose reduction of tofacitinib) helped reduce or normalize liver enzyme levels.

In the controlled part of the phase 3 monotherapy RA study (0–3 months) (Study I), alanine aminotransferase (ALT) elevation above 3 × ULN occurred in 1.65%, 0.41%, and 0% of patients receiving placebo, tofacitinib 5 mg, and tofacitinib 10 mg twice daily, respectively. In this study, aspartate aminotransferase (AST) elevation above 3 × ULN occurred in 1.65%, 0.41%, and 0% of patients receiving placebo, tofacitinib 5 mg, and tofacitinib 10 mg twice daily, respectively.

In the phase 3 monotherapy RA study (0–24 months) (Study VI), ALT elevation above 3 × ULN was observed in 7.1%, 3.0%, and 3.0% of patients receiving methotrexate, tofacitinib 5 mg, and tofacitinib 10 mg twice daily, respectively. In this study, AST elevation above 3 × ULN was observed in 3.3%, 1.6%, and 1.5% of patients receiving methotrexate, tofacitinib 5 mg, and 10 mg twice daily, respectively.

In the controlled parts of phase 3 trials in RA patients receiving concomitant DMARDs (0–3 months) (Studies II–V), ALT elevation above 3 × ULN was observed in 0.9%, 1.24%, and 1.14% of patients receiving placebo, tofacitinib 5 mg, and 10 mg twice daily, respectively. In these studies, AST elevation above 3 × ULN was observed in 0.72%, 0.5%, and 0.31% of patients receiving placebo, tofacitinib 5 mg, and tofacitinib 10 mg twice daily, respectively.

In long-term extension studies in RA patients receiving monotherapy, ALT elevation above 3 × ULN was observed in 1.1% and 1.4% of patients receiving tofacitinib 5 mg or 10 mg twice daily, respectively. AST elevation above 3 × ULN was observed in < 1.0% of patients in the tofacitinib 5 mg and 10 mg twice daily groups.

In long-term extension studies in RA patients receiving concomitant DMARDs, ALT elevation above 3 × ULN was observed in 1.8% and 1.6% of patients receiving tofacitinib 5 mg or 10 mg twice daily, respectively. AST elevation above 3 × ULN was observed in < 1.0% of patients in the tofacitinib 5 mg and 10 mg twice daily groups.

In a large (N = 4,362) randomized post-marketing safety study involving RA patients aged 50 years or older with at least one additional cardiovascular risk factor, ALT activity elevation to 3 × ULN or higher was observed in 6.01%, 6.54%, and 3.77% of patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or TNF inhibitors, respectively. AST activity elevation to 3 × ULN or higher was observed in 3.21%, 4.57%, and 2.38% of patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, or TNF inhibitors, respectively.

Lipids

In controlled double-blind clinical trials of RA, the first monitoring of lipid levels (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) was performed one month after initiation of tofacitinib therapy. Elevations were observed at this time point and remained stable thereafter.

Changes in lipid profile from baseline to study end (6–24 months) in controlled clinical trials in RA patients are summarized below.

• Mean LDL cholesterol levels increased by 15% in the tofacitinib 5 mg twice daily group and by 20% in the tofacitinib 10 mg twice daily group over 12 months of therapy, and by 16% in the tofacitinib 5 mg twice daily group and by 19% in the tofacitinib 10 mg twice daily group over 24 months of therapy.
• Mean HDL cholesterol levels increased by 17% in the tofacitinib 5 mg twice daily group and by 18% in the tofacitinib 10 mg twice daily group over 12 months of therapy, and by 19% in the tofacitinib 5 mg twice daily group and by 20% in the tofacitinib 10 mg twice daily group over 24 months of therapy.

After discontinuation of tofacitinib therapy, lipid levels returned to baseline levels.

The mean LDL cholesterol/HDL cholesterol ratio and apolipoprotein B (ApoB)/apolipoprotein A1 (ApoA1) ratio remained virtually unchanged in patients receiving tofacitinib.

In a controlled clinical trial of RA, elevated LDL cholesterol and ApoB levels decreased to pre-treatment levels in response to statin therapy.

In long-term safety evaluation populations of RA patients, lipid elevations remained at the same level observed in controlled clinical trials.

Below are summarized changes in lipid profile from baseline to 24 months observed in a large (N = 4,362) randomized post-marketing safety study involving RA patients aged 50 years or older with at least one additional cardiovascular risk factor.

• Mean LDL cholesterol level increased by 13.80%, 17.04%, and 5.50% at month 12 in patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors, respectively. At month 24, increases were 12.71%, 18.14%, and 3.64%, respectively.
• Mean HDL cholesterol level increased by 11.71%, 13.63%, and 2.82% at month 12 in patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors, respectively. At month 24, increases were 11.58%, 13.54%, and 1.42%, respectively.

Myocardial Infarction

Rheumatoid Arthritis

In a large (N = 4,362) randomized post-marketing safety study involving RA patients aged 50 years or older with at least one additional cardiovascular risk factor, the incidence rate (95% CI) of non-fatal myocardial infarction in patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors was 0.37 (0.22; 0.57), 0.33 (0.19; 0.53), and 0.16 (0.07; 0.31) events per 100 patient-years, respectively. Several cases of fatal myocardial infarction were reported, with similar incidence rates in patients receiving tofacitinib and those receiving TNF inhibitors (see section "Special Warnings and Precautions for Use"). The study required observation of at least 1,500 patients for 3 years.

Malignant Neoplasms, excluding non-melanoma skin cancer (NMSC)

Rheumatoid Arthritis

In a large (N = 4,362) post-marketing randomized safety study involving RA patients aged 50 years or older with at least one additional cardiovascular risk factor, the incidence rate (95% CI) of lung cancer in patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors was 0.23 (0.12; 0.40), 0.32 (0.18; 0.51), and 0.13 (0.05; 0.26) events per 100 patient-years, respectively (see section "Special Warnings and Precautions for Use"). The study required observation of at least 1,500 patients for 3 years.

The incidence rate (95% CI) of lymphoma during treatment with tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors was 0.07 (0.02; 0.18), 0.11 (0.04; 0.24), and 0.02 (0.00; 0.10) events per 100 patient-years, respectively (see section "Special Warnings and Precautions for Use").

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all cases of suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf Life. 3 years.

Storage Conditions.

No special storage conditions required. Store in original packaging to protect from moisture. Keep out of reach of children.

Packaging.

7 extended-release tablets per blister, 4 blisters per cardboard box.

Prescription Category. Prescription only.

Manufacturer.

Pfizer Manufacturing Deutschland GmbH.

Manufacturer's Address and Place of Business.

Mooswaldallee 1, 79108 Freiburg Im Breisgau, Germany.