Tofara^® (Tablets) Instructions for Use

Marketing Authorization Holder

Mediff Pharma, Pvt. Ltd. (India)

Manufactured By

PSK Pharma, LLC (Russia)

ATC Code

L04AA29 (Tofacitinib)

Active Substance

Tofacitinib (Rec.INN registered by WHO)

Dosage Forms

	Tofara®	Film-coated tablets, 5 mg: 56 pcs.
		Film-coated tablets, 10 mg: 56 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex; the core is white or almost white.

Excipients : lactose monohydrate – 61.307 mg, microcrystalline cellulose type 102 – 98.063 mg, croscarmellose sodium – 20 mg, poloxamer 407 – 7.5 mg, sodium lauryl sulfate – 4 mg, magnesium stearate – 2 mg.

Film coating composition Novomix Gen II-10528 (firm specification): hypromellose – 2.4 mg, macrogol – 0.48 mg, triacetin – 0.36 mg, lactose monohydrate – 1.26 mg, titanium dioxide – 1.5 mg.

14 pcs. – blisters (4) – cardboard packs.
56 pcs. – jars (1) – cardboard packs.

Film-coated tablets white or almost white, round, biconvex; the core is white or almost white.

Excipients : lactose monohydrate – 122.614 mg, microcrystalline cellulose type 102 – 196.126 mg, croscarmellose sodium – 40 mg, poloxamer 407 – 15 mg, sodium lauryl sulfate – 8 mg, magnesium stearate – 4 mg.

Film coating composition Novomix Gen II-10528 (firm specification): hypromellose – 4.8 mg, macrogol – 0.96 mg, triacetin – 0.72 mg, lactose monohydrate – 2.52 mg, titanium dioxide – 3 mg.

14 pcs. – blisters (4) – cardboard packs.
56 pcs. – jars (1) – cardboard packs.

Clinical-Pharmacological Group

Immunosuppressive drug

Pharmacotherapeutic Group

Immunosuppressants, selective immunosuppressants

Pharmacological Action

Selective immunosuppressant. Tofacitinib is a potent, selective inhibitor of the Janus kinase family, with high selectivity for other kinases in the human genome. According to kinase study results, Tofacitinib inhibits Janus kinases 1, 2, 3 and to a lesser extent – tyrosine kinase 2. In cells where Janus kinases signal in pairs, Tofacitinib preferentially inhibits signaling by heterodimeric receptors associated with Janus kinase 3 and/or Janus kinase 1, exhibiting functional selectivity for receptors that signal through Janus kinase 2 pairs. Inhibition of Janus kinase 1 and Janus kinase 3 by tofacitinib blocks signaling via common gamma-chain-containing receptors for several cytokines, including IL-2, -4, -7, -9, -15 and -21.

These cytokines play an integrative role in lymphocyte activation, proliferation, function and inhibition of signal transduction, leading to modulation of various aspects of the immune response. Furthermore, inhibition of Janus kinase 1 leads to attenuation of signaling by additional proinflammatory cytokines such as IL-6 and IFN-γ. At higher drug exposures, inhibition of Janus kinase 2 signaling leads to inhibition of erythropoietin signaling.

Treatment with tofacitinib is accompanied by a dose-dependent decrease in circulating natural killer cells CD16/56+. The estimated maximum reduction is achieved after about 8-10 weeks of therapy initiation. The described changes usually resolve within 2-6 weeks after therapy completion. Treatment with tofacitinib was accompanied by a dose-dependent increase in B-cell count. Changes in the number of circulating T-lymphocytes and their subpopulations were minor and inconsistent. The clinical significance of these changes is unknown. The change in total serum levels of IgG, M and A over a 6-month treatment period in patients with rheumatoid arthritis was small, dose-independent and similar to that with placebo.

After treatment with tofacitinib in patients with rheumatoid arthritis, a rapid decrease in serum C-reactive protein (CRP) was noted, which persisted throughout the treatment period. Changes in CRP levels noted during treatment with tofacitinib did not resolve within 2 weeks after therapy discontinuation, indicating a longer duration of pharmacodynamic activity compared to T_1/2.

Pharmacokinetics

The pharmacokinetic profile of tofacitinib is characterized by rapid absorption (C_max is reached within 0.5-1 h), rapid elimination (T_1/2 about 3 h) and dose-proportional increase in systemic exposure. C_ss is reached within 24-48 h with minimal accumulation after administration twice daily.

Tofacitinib is well absorbed, its bioavailability is 74%. Administration of tofacitinib with a high-fat meal was not accompanied by changes in AUC, whereas C_max in plasma decreases by 32%. In clinical studies, Tofacitinib was administered regardless of meals.

The binding of tofacitinib to plasma proteins is approximately 40%. Tofacitinib predominantly binds to albumin and does not bind to α₁-acid glycoprotein.

It is equally distributed between erythrocytes and plasma.

Elimination of tofacitinib is approximately 70% via hepatic metabolism and 30% by renal excretion as unchanged tofacitinib. Metabolism of tofacitinib is primarily mediated by the CYP3A4 isoenzyme and to a lesser extent by the CYP2C19 isoenzyme. In a study of radiolabeled tofacitinib, more than 65% of the total circulating radioactivity was accounted for by unchanged Tofacitinib, and the remaining 35% by 8 metabolites (each less than 8% of total radioactivity). Pharmacological activity is associated with unmetabolized tofacitinib.

Indications

Moderate or severe active rheumatoid arthritis in adults with an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

ICD codes

Dosage Regimen

Orally, regardless of meals.

Tofacitinib can be used as monotherapy or in combination with methotrexate or other non-biological DMARDs.

The recommended dose is 5 mg twice daily. In some patients, the dose may need to be increased to 10 mg twice daily, depending on the clinical response to therapy.

Dose adjustment or therapy discontinuation may be required in case of development of dose-dependent laboratory abnormalities, including neutropenia and anemia.

It is not recommended to initiate therapy in patients with an absolute neutrophil count (ANC) less than 1000/µL and/or a hemoglobin level less than 90 g/L.

In patients with severe renal and/or hepatic impairment, in patients receiving potent CYP3A4 isoenzyme inhibitors, in patients receiving one or more concomitant drugs that can moderately inhibit the CYP3A4 isoenzyme and potently inhibit the CYP2C19 isoenzyme (e.g., fluconazole), the dose of tofacitinib should not exceed 5 mg twice daily.

Adverse Reactions

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

Cardiovascular system common – increased blood pressure.

Digestive system common – abdominal pain, vomiting, gastritis, diarrhea, nausea, dyspepsia; uncommon – hepatic steatosis.

Metabolism common – hyperlipidemia, dyslipidemia; uncommon – dehydration.

Nervous system common – headache, insomnia; uncommon – paresthesia.

Musculoskeletal system common – muscle and bone pain, arthralgias; uncommon – tendonitis, joint swelling, muscle tension.

Hemostatic system common – leukopenia, anemia; uncommon – neutropenia.

Respiratory system common – dyspnea, cough; uncommon – nasal congestion.

Skin common – rash; uncommon – erythema, skin itching.

Benign, malignant and unspecified neoplasms (including cysts and polyps) uncommon – non-melanoma skin cancer.

Laboratory and instrumental parameters common – increased liver enzyme activity, CPK, increased LDL concentration, blood cholesterol (in clinical studies first noted after the first month of therapy and subsequently remained stable), increased body weight; uncommon – increased transaminase activity, increased plasma creatinine concentration, increased GGT concentration, abnormal liver function tests.

Other common – fever, fatigue, peripheral edema.

Contraindications

Severe hepatic impairment; infection with hepatitis B and/or C viruses (presence of serological markers of HBV and HCV infection); CrCl less than 40 ml/min; concurrent use of live vaccines; concurrent use with biological drugs, such as TNF inhibitors, interleukin antagonists (IL-1R, IL-6R), monoclonal anti-CD20 antibodies, selective co-stimulatory modulators, as well as potent immunosuppressants such as azathioprine, cyclosporine and tacrolimus (to avoid enhanced immunosuppression and risk of infections); severe infections, active infections, including local; pregnancy; lactation (breastfeeding); children and adolescents under 18 years of age; hypersensitivity to tofacitinib.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Special Precautions

Use with caution in patients with an increased risk of gastrointestinal perforation (e.g., in patients with a history of diverticulitis); in elderly patients due to the high risk of infectious diseases.

In patients with rheumatoid arthritis receiving immunomodulators, including biological drugs and Tofacitinib, serious and sometimes fatal infections caused by bacterial, mycobacterial, fungal, viral or other opportunistic pathogens have been observed. The most common serious infections noted with tofacitinib use include pneumonia, cellulitis, herpes zoster and urinary tract infection.

Among opportunistic infections with tofacitinib use, cases of tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, herpes zoster involving various dermatoses, cytomegalovirus infection, and BK virus infection have been reported. Some patients had disseminated diseases, most often with concurrent use of immunomodulators – methotrexate or corticosteroids, which themselves and in addition to the underlying rheumatoid arthritis disease may predispose to the development of infections. The development of other serious infections not registered in clinical studies (e.g., histoplasmosis, coccidioidomycosis and listeriosis) is also possible.

Tofacitinib should not be used in patients with an active infection, including local infections. The risk/benefit ratio of therapy should be assessed before using tofacitinib in patients with chronic or recurrent infection, after contact with a tuberculosis patient, with a history of severe or opportunistic infection, in patients who have lived in or recently visited tuberculosis or mycosis endemic areas, and in patients predisposed to developing infections. Patients should be carefully monitored for the development of signs and symptoms of infection during and after Tofacitinib therapy.

Tofacitinib should be temporarily discontinued if a patient develops a serious infection, opportunistic infection, or sepsis. If a new infection develops during tofacitinib use, the patient should undergo prompt and complete diagnostic evaluation similar to a patient with immunodeficiency. Appropriate antibacterial therapy and careful follow-up are indicated.

Since elderly patients usually have a higher frequency of infections, caution should also be exercised in such cases.

Before using tofacitinib, examination for signs of latent or active tuberculosis infection should be performed.

Before initiating tofacitinib therapy in patients with a history of latent or active tuberculosis, without confirmation of an adequate course of anti-tuberculosis therapy, and in patients with a negative test for latent tuberculosis but with risk factors for tuberculosis infection, appropriate anti-tuberculosis therapy should be administered. When deciding on the need for anti-tuberculosis therapy in a particular patient, consultation with a phthisiatrician is recommended.

Patients should be carefully monitored for the development of signs of tuberculosis, including patients with a negative test for latent tuberculosis prior to therapy initiation.

The incidence of tuberculosis with tofacitinib use in the global clinical development program was 0.1-0.2%. Patients with latent tuberculosis should receive standard antimycobacterial therapy before initiating tofacitinib therapy.

Reactivation of viral infections has been described with DMARD therapy. Cases of herpes virus reactivation (e.g., herpes zoster) have also been described in clinical studies of tofacitinib. The effect of tofacitinib on the reactivation of chronic viral hepatitis is unknown. Screening for viral hepatitis should be performed before initiating tofacitinib therapy.

There is a possibility that Tofacitinib affects the body’s defense against malignancies. The effect of tofacitinib therapy on the development and course of malignancies is unknown, but cases of malignancy development were registered in clinical studies of this drug.

Periodic skin examination is recommended during treatment in patients at increased risk of skin cancer.

Tofacitinib should be used with caution in patients with an increased risk of gastrointestinal perforation (e.g., in patients with a history of diverticulitis). Patients with new gastrointestinal symptoms should be examined immediately for early detection of gastrointestinal perforation.

Drug Interactions

Since Tofacitinib is metabolized by the CYP3A4 isoenzyme, interaction with drugs that inhibit or induce this isoenzyme is highly probable. When used concomitantly with potent CYP3A4 isoenzyme inhibitors (e.g., ketoconazole), as well as when used concomitantly with one or more moderate CYP3A4 isoenzyme inhibitors and potent CYP2C19 isoenzyme inhibitors (e.g., fluconazole), the exposure to tofacitinib increases. Concomitant use of ketoconazole (a potent CYP3A4 isoenzyme inhibitor) and a single dose of tofacitinib increases the AUC and C_max of tofacitinib by 103% and 16%, respectively. Concomitant use of fluconazole (a moderate CYP3A4 isoenzyme inhibitor, as well as a potent CYP2C19 isoenzyme inhibitor) increases the AUC and C_max of tofacitinib by 79% and 27%, respectively.

When used concomitantly with potent CYP3A4 isoenzyme inducers (e.g., rifampicin), the exposure to tofacitinib decreases. Concomitant use of rifampicin (a potent CYP3A4 isoenzyme inducer) reduces the AUC and C_max of tofacitinib by 84% and 74%, respectively.

The likelihood of influence of CYP2C19 isoenzyme or P-glycoprotein inhibitors on the pharmacokinetics of tofacitinib is low.

Concomitant use of tacrolimus (a weak CYP3A4 isoenzyme inhibitor) increases the AUC of tofacitinib by 21% and decreases the C_max of tofacitinib by 9%. Concomitant use of cyclosporine (a moderate CYP3A4 isoenzyme inhibitor) increases the AUC of tofacitinib by 73% and decreases the C_max of tofacitinib by 17%. Concomitant multiple use of tofacitinib and potent immunosuppressants in patients with rheumatoid arthritis has not been studied.

In vitro studies have shown that Tofacitinib at concentrations even more than 150 times exceeding C_ss^max, which is achieved at recommended therapeutic doses, does not significantly inhibit or induce the activity of major drugs metabolized by CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 isoenzymes. These results were confirmed by in vitro drug interaction studies, which showed no changes in the pharmacokinetics of midazolam, a highly selective CYP3A4 isoenzyme substrate, when used concomitantly with tofacitinib. In vitro data have shown that the ability of tofacitinib at therapeutic concentrations to inhibit transporters such as P-glycoprotein, organic anion or cation transporters is very low.

Concomitant use of tofacitinib with methotrexate at a dose of 15-25 mg once weekly reduced the AUC and C_max of methotrexate by 10% and 13%, respectively. These changes in methotrexate pharmacokinetics did not require dose adjustment or individual methotrexate dosing. At the same time, the pharmacokinetics of tofacitinib did not change.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.