Tofacitinib

Indications

Tofacitinib is used for: Rheumatoid Arthritis, Psoriatic Arthritis, Ulcerative Colitis, • Rheumatoid Arthritis: Tofacitinib / Tofacitinib XR is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). • Psoriatic Arthritis: Tofacitinib / Tofacitinib XR is indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs). • Ulcerative Colitis: Tofacitinib is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC). Limitations of Use: Use of Tofacitinib / Tofacitinib XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Adult Dose

Recommended Dosage: • Rheumatoid Arthritis: Tofacitinib 5 mg twice daily or Tofacitinib XR 11 mg once daily. • Psoriatic Arthritis (in combination with nonbiologic DMARDs): Tofacitinib 5 mg twice daily or Tofacitinib XR 11 mg once daily. • Ulcerative Colitis: • Induction: Tofacitinib 10 mg twice daily or Tofacitinib XR 22 mg once daily for 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed, continue Tofacitinib 10 mg twice daily or Tofacitinib XR 22 mg once daily for a maximum of 16 weeks. Discontinue Tofacitinib 10 mg twice daily or Tofacitinib XR 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved. • Maintenance: Tofacitinib 5 mg twice daily or Tofacitinib XR 11 mg once daily. For patients with loss of response during maintenance treatment, Tofacitinib 10 mg twice daily or Tofacitinib XR 22 mg once daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient. Hepatic impairment Mild: No dosage adjustment required Moderate: Not to exceed 5 mg qDay Severe: Not recommended

Child Dose

Safety and efficacy not established

Renal Dose

Renal impairment Mild: No dosage adjustment required Moderate-to-severe: Not to exceed 5 mg qDay

Administration

May be taken with or without food. Administration Instructions Do not initiate Tofacitinib / Tofacitinib XR if absolute lymphocyte count <500 cells/mm3, an absolute neutrophil count (ANC) <1000 cells/mm3 or hemoglobin <9 g/dL.

Contra Indications

Hypersensitivity to the active substance or to any of the excipients.

Precautions

Serious Infections – Do not administer Tofacitinib during an active infection, including localized infections. If a serious infection develops, interrupt Tofacitinib until the infection is controlled. Lymphomas and other malignancies have been reported in patients treated with Tofacitinib Gastrointestinal Perforations – Use with caution in patients that may be at increased risk. Laboratory monitoring –Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. Immunizations –Live vaccines should not be given concurrently with Tofacitinib Do not initiate therapy in patients w/ an active infection including localized infections, chronic or recurrent infections, or those who have been exposed to TB, history of a serious or an opportunistic infection, resided or travelled in areas of endemic TB or endemic mycoses; underlying conditions that may predispose to infection. Evaluate & test patients for latent or active infection prior to administration. Monitor for signs & symptoms of TB. Perform screening for viral hepatitis before starting therapy. Malignancy & lymphoproliferative disorder excluding nonmelanoma skin cancer. Periodic skin exam for patients who are at increased risk of skin cancer. Patients who may be at increased risk for GI perforation (eg, history of diverticulitis). Monitor lymphocyte at baseline & every 3 mth thereafter; neutrophils & Hb at baseline & after 4-8 wk of treatment & every 3 mth thereafter. Discontinue if Hb levels <8>2 g/dL while on treatment. Assess lipid parameters approx 4-8 wk following initiation of therapy. Not recommended to be given w/ concurrent live vaccines. Moderate or severe renal impairment. Severe hepatic impairment. Avoid use in RA patients in combination w/ biological DMARDs. Pregnancy & lactation. Childn <18 yr. Elderly >65 yr.

Pregnancy-Lactation

Pregnancy There are no adequate and well-controlled studies therapy in pregnant women In the tofacitinib clinical development programs, birth defects and miscarriages were reported Animal data Based on animal studies, tofacitinib has the potential to affect a developing fetus Based on findings in rats, females of reproductive potential taking tofacitinib may result in reduced fertility Contraception Advise females of reproductive potential to use effective contraception during treatment and for >4 weeks after the last dose Advise females to inform their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment Lactation It is not known whether the drug is excreted in human milk There are no data to assess effects of drug on breastfed child; drug is excreted in rat milk at concentrations higher than in maternal serum Women should not breastfeed while treated; a decision should be made whether to discontinue breastfeeding or to discontinue therapy

Interactions

Increased exposure w/ potent CYP3A4 inhibitors (eg, ketoconazole), moderate CYP3A4 inhibitors & potent CYP2C19 inhibitors (eg, fluconazole). Decreased exposure w/ potent CYP inducers (eg, rifampin). Increased AUC & decreased Cmax w/ tacrolimus & cyclosporine. Decreased AUC & Cmax of MTX.

Adverse Effects

Side effects of Tofacitinib : >10% Overall infections (20-22%) 1-10% URTI (4.5%), Headache (4.3%), Diarrhea (4%), Nasopharyngitis (3.8%), UTI (2%), Hypertension (1.6%) <1% ANC <500/mm³ (0.07%), Lymphocytes <500/mm³ (0.04%) Frequency Not Defined Serious infections: 1.7 events per 100 patient-years Malignancies: 0.3 events per 100 patient-years

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 and 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.