Drug information of Tofacitinib

Tofacitinib


Tofacitinib is an inhibitor of Janus kinases, a group of intracellular enzymes involved in signalling pathways that affect hematopoiesis and immune cell function. It is approved by the FDA for treatment of moderate to severe rheumatoid arthritis that responds inadequately to methotrexate or in those who are intolerant to methotrexate.

Besides rheumatoid arthritis, tofacitinib has also been studied in clinical trials for the prevention of organ transplant rejection, and is currently under investigation for the treatment of psoriasis. Known adverse effects include nausea and headache as well as more serious immunologic and hematological adverse effects.

Mechanism of effect

Tofacitinib inhibits Janus kinase (JAK) enzymes, which are intracellular enzymes involved in stimulating hematopoiesis and immune cell function through a signaling pathway. In response to extracellular cytokine or growth factor signaling, JAKs activate signal transducers and activators of transcription (STATs), which regulate gene expression and intracellular activity.

Inhibition of JAKs prevents cytokine- or growth factor-mediated gene expression and intracellular activity of immune cells, reduces circulating CD16/56+ natural killer cells, serum IgG, IgM, IgA, and C-reactive protein, and increases B cells.

Pharmacodynamic

Tofacitinib targets inflammation present in rheumatoid arthritis by inhibiting the janus kinases involved in the inflammatory response pathway.

Pharmacokinetics

  • Absorption: Oral
  • Immediate release: Rapid (74%).
  • Distribution: Vd: 87 L
  • Protein binding: ~40%
  • Metabolism: Hepatic (70%): CYP3A4 and CYP2C19 to inactive metabolites
  • Half-life elimination: ~3 hours (immediate release); ~6 hours (extended release)
  • Excretion: Primarily urine (30%) as unchanged drug

Drug indications

artirit rhomatoid

Dosage

Tablet

5mg

Tablet, extended-release

11mg

Rheumatoid Arthritis

Indicated as second-line treatment for moderate-to-severe active rheumatoid arthritis in patients with an inadequate response or intolerance to methotrexate; may be used as monotherapy or in combination with methotrexate or other nonbiologic DMARDs

Tablet: 5 mg PO BID

Extended-release tablet: 11 mg PO qDay

Psoriatic Arthritis

Indicated for active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other DMARDs

Recommended dose of in combination with nonbiologic DMARDs

Tablet: 5 mg PO BID

Extended-release tablet: 11 mg PO qDay

Renal impairment

Mild: No dosage adjustment required

Moderate-to-severe: Not to exceed 5 mg qDay (tablet)

Hepatic impairment

Mild: No dosage adjustment required

Moderate-to-severe: Not to exceed 5 mg qDay (tablet)

Severe: Not recommended

Alerts

  • Concerns related to adverse effects:

Bone marrow suppression: Lymphocytopenia, neutropenia (<2,000 cells/mm3), and anemia have been observed with tofacitinib therapy. Lymphocyte counts <500 cells/mm3 were associated with increased incidence of treated and serious infections; avoid tofacitinib initiation in patients with lymphocytes <500 cells/mm3 at baseline. Monitor lymphocyte counts at baseline and every 3 months thereafter; platelet counts, and hemoglobin should be assessed at baseline, after 4 to 8 weeks of therapy, and every 3 months thereafter.

Cardiovascular effects: A decrease in heart rate and prolonged PR interval have been reported with tofacitinib in clinical trials. Use caution in patients with baseline heart rate <60 bpm, conduction abnormalities, syncope or arrhythmia, ischemic heart disease, heart failure, or receiving concomitant therapy known to decrease heart rate or prolong the PR interval.

Gastrointestinal perforations: Use with caution in patients at increased risk for gastrointestinal perforation; perforations have been reported in clinical trials. Promptly evaluate new-onset abdominal symptoms in patients taking tofacitinib.

Hepatotoxicity: Increased incidence of liver enzyme elevation was observed in patients taking tofacitinib compared to placebo. Routine liver function test monitoring is recommended; interrupt therapy if drug-induced liver injury is suspected.

Infections: Patients receiving tofacitinib are at increased risk for serious infections, which may result in hospitalization and/or fatality; infections often developed in patients receiving concomitant immunosuppressive agents (eg, methotrexate or corticosteroids). Active tuberculosis (pulmonary or extrapulmonary), invasive fungal (including cryptococcosis and pneumocystosis) and bacterial, viral (including herpes zoster) or other opportunistic infections (including esophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis) have been reported in patients receiving tofacitinib. Closely monitor patients for the development of signs/symptoms of infection during and after tofacitinib treatment. If a serious infection develops, interrupt tofacitinib until the infection is controlled. Carefully consider the risks and benefits of treatment with tofacitinib prior to initiating therapy in patients with chronic or recurrent infection. 

The most common serious infections reported included pneumonia, cellulitis, urinary tract infections, diverticulitis, appendicitis, and herpes zoster infections, although other serious infections may occur. Reactivation of viral infections (eg, herpes zoster) was observed in clinical trials; the incidence of chronic viral hepatitis reactivation is unknown.

 The risk for herpes zoster is increased with tofacitinib; patients within Asian countries appear to have a higher incidence of herpes zoster cases. Use with caution in patients that have been exposed to tuberculosis, with a history of serious or opportunistic infection, taking concomitant immunosuppressants, with comorbid conditions that predispose them to infections (eg, diabetes), or in patients who live in or travel to/from areas of endemic mycoses (ie, blastomycosis, coccidioidomycosis, histoplasmosis). Do not initiate tofacitinib in patients with active infections, including localized infections.

Interstitial lung disease (ILD): ILD has been reported. U se with caution in patients with risk/history of ILD.

Lipid abnormalities: Increases in lipid parameters (eg, total cholesterol, LDL, and HDL cholesterol) were observed in patients receiving tofacitinib; maximum lipid increases were typically seen within 6 weeks of initiation. Assess lipids 4 to 8 weeks after tofacitinib initiation and manage lipid abnormalities accordingly.

Malignancy: Lymphoma and other malignancies have been reported in patients receiving tofacitinib; The most common types of malignancy observed were lung, breast, gastric, colorectal, renal cell, prostate, lymphoma, pancreatic, and malignant melanoma.

Tuberculosis:  Tuberculosis (pulmonary or extrapulmonary) has been reported in patients receiving tofacitinib. Patients should be evaluated for tuberculosis risk factors and active or latent infection (with a tuberculin skin test) before and during therapy. Treatment of latent tuberculosis should be initiated before use. Patients with initial negative tuberculin skin tests should receive continued monitoring for tuberculosis throughout treatment. Use with caution in patients who have resided in regions where tuberculosis is endemic.

  • Disease-related concerns:

Diabetes: Use with caution in patients with diabetes.

Hepatic impairment: Use is not recommended in patients with severe hepatic impairment; dosage reduction required in patients with moderate hepatic impairment.

Lung disease: Patients with a history of chronic lung disease or those who develop interstitial lung disease may be more prone to infections; use with caution.

Renal impairment: Dosage reduction required in patients with moderate or severe renal impairment.

  • Concurrent drug therapy issues:

Immunosuppressant medications: Tofacitinib should not be administered in combination with strong immunosuppressive medications (eg, azathioprine, tacrolimus, cyclosporine) due to the risk of additive immunosuppression.

Biologic DMARDs: Tofacitinib should not be administered in combination with biologic DMARDs.

  • Special populations:

Asian patients: Use with caution in Asian patients; an increased incidence of adverse reactions (eg, herpes zoster, opportunistic infections, decreased WBC, interstitial lung disease, increased transaminases) has been observed.

Elderly: Use with caution in elderly patients; general incidence of infection is higher in elderly.

Points of recommendation

Some viral infections like herpes zoster have become active again with this medicine. Patients should tell their doctor if they have ever had a viral infection like herpes zoster.

Hepatitis B or C testing may be done. A hepatitis B or C infection may get worse during care.

Patients should check cholesterol and blood sugar before starting this medicine.

Patients should talk to their doctor before getting any vaccines. Use with this medicine may either raise the chance of an infection or make the vaccine not work as well.

Wash hands often. Stay away from people with infections, colds, or flu.

This medicine may cause fertility problems. Patients should use birth control while taking this medicine, and for 1 month after stopping this medicine.

If patient gets pregnant while taking this medicine or within 1 month after your last dose, call their doctor right away.

Related drugs

Ruxolitinib , Apremilast , upadacitinib


Ask a Pharmacist


User's questions
    No comments yet.