tofacitinib (Rx)

Brand and Other Names:Xeljanz, Xeljanz XR
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet (Xeljanz)

  • 5mg
  • 10mg

tablet, extended-release (Xeljanz XR)

  • 11mg
  • 22mg

Rheumatoid Arthritis

Xeljanz or Xeljanz XR

Indicated for moderate-to-severe active rheumatoid arthritis (RA) in adults with an inadequate response or intolerance to methotrexate; may be used as monotherapy or in combination with methotrexate or other nonbiologic DMARDs

Xeljanz: 5 mg PO BID

Xeljanz XR: 11 mg PO qDay

Psoriatic Arthritis

Xeljanz or Xeljanz XR

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

Recommended dose in combination with nonbiologic DMARDs

  • Xeljanz: 5 mg PO BID
  • Xeljanz XR: 11 mg PO qDay

Ulcerative Colitis

Xeljanz or Xeljanz XR

Indicated for adults with moderately to severely active ulcerative colitis (UC)

Xeljanz

  • Induction
    • 10 mg PO BID for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response
    • If needed, continue 10 mg BID for maximum of 16 weeks; discontinue after 16 weeks if adequate therapeutic benefit not achieved
  • Maintenance
    • 5 mg PO BID; may consider 10 mg BID (limited to shorter duration) in patients with loss of response during maintenance treatment
    • Use the lowest effective dose needed to maintain response

Xeljanz XR

  • Induction
    • 22 mg PO qDay for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response
    • If needed, continue 22 mg qDay for maximum of 16 weeks; discontinue after 16 weeks if adequate therapeutic benefit not achieved
  • Maintenance
    • 11 mg PO qDay; may consider 22 mg qDay (limited to shorter duration) in patients with loss of response during maintenance treatment
    • Use the lowest effective dose needed to maintain response

Dosage Modifications

Strong CYP3A4 inhibitors OR moderate CYP3A4 inhibitors with strong CYP2C19 inhibitors

  • RA or PsA
    • Xeljanz: Not to exceed 5 mg qDay
    • Xeljanz XR: Switch to Xeljanz 5 mg qDay
  • UC
    • Xeljanz: If taking 10 mg BID, reduce to 5 mg BID; if taking 5 mg BID, reduce to 5 mg qDay
    • Xeljanz XR: If taking 22 mg qDay, reduce to 11 mg qDay; if taking 11 mg qDay, switch to Xeljanz 5 mg qDay

Renal impairment

  • RA or PsA
    • Mild: No dosage adjustment required
    • Moderate-to-severe (Xeljanz): Not to exceed 5 mg qDay
    • Moderate-to-severe (Xeljanz XR): Switch to Xeljanz 5 mg qDay
  • UC
    • Mild (Xeljanz and Xeljanz XR): No dosage adjustment required
    • Moderate-to-severe (Xeljanz): If taking 10 mg BID, reduce to 5 mg BID; if taking 5 mg BID, reduce to 5 mg qDay
    • Moderate-to-severe (Xeljanz XR): If taking 22 mg qDay, reduce to 11 mg qDay; if taking 11 mg qDay, switch to Xeljanz 5 mg qDay
    • For patients undergoing hemodialysis, administer dose after session on dialysis days

Hepatic impairment

  • Safety and efficacy have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology (Add to adult)
  • RA or PsA
    • Mild (Xeljanz and Xeljanz XR): No dosage adjustment required
    • Moderate (Xeljanz): Not to exceed 5 mg qDay
    • Moderate (Xeljanz XR): Switch to Xeljanz 5 mg qDay
    • Severe (Xeljanz and Xeljanz XR): Not recommended
  • UC
    • Mild (Xeljanz and Xeljanz XR): No dosage adjustment required
    • Moderate (Xeljanz): If taking 10 mg BID, reduce to 5 mg BID; if taking 5 mg BID, reduce to 5 mg qDay
    • Moderate (Xeljanz XR): If taking 22 mg qDay, reduce to 11 mg qDay; if taking 11 mg qDay, switch to Xeljanz 5 mg qDay
    • Severe (Xeljanz and Xeljanz XR): Not recommended

Lymphopenia

  • RA, PsA, or UC
    • Lymphocytes ≥500 cells/mm3: Maintain dose
    • Lymphocytes <500 cells/mm3: Confirmed by repeat testing; discontinue until infection controlled

ANC 500-1000cells/mm³

  • RA or PsA
    • Interrupt dosing for persistent decreases; when ANC >1000/mm3, resume dose at Xeljanz 5 mg BID or Xeljanz XR 11 mg qDay
    • ANC <500 cells/mm3: Confirmed by repeat testing; discontinue
  • UC
    • Xeljanz: If taking 10 mg BID, reduce to 5 mg BID; when ANC >1000, increase to 10 mg BID based on clinical response; if taking 5 mg BID, interrupt dosing; when ANC >1000, resume 5 mg BID
    • Xeljanz XR: If taking 22 mg qDay, reduce to 11 mg qDay when ANC >1000, increase to 22 mg qDay based on clinical response; if taking 11 mg qDay, interrupt dosing; when ANC >1000, resume 11 mg qDay

Anemia

  • RA, PsA, or UC
    • Hgb ≤2 g/dL decrease and level ≥9.0 g/dL: Maintain dose
    • Hgb >2 g/dL decrease or level <8.0 g/dL: Confirmed by repeat testing; interrupt treatment until Hgb levels have normalized

Dosing Considerations

Should not be used in combination with biologic DMARDs or potent immunosuppressive agents (eg, azathioprine, cyclosporine)

Interrupt dose for management of lymphopenia, neutropenia, and anemia

Interrupt use if patient develops a serious infection until the infection is controlled

There is a higher incidence of infections in geriatric patients; use with caution

Do not initiate if

  • Absolute lymphocyte count <500 cells/mm³ OR
  • ANC <1000 cells/mm³ OR
  • Hgb <9 g/dL

Dosage Forms & Strengths

oral solution (Xeljanz)

  • 1mg/mL

tablet (Xeljanz)

  • 5mg
  • 10mg

Polyarticular Course Juvenile Idiopathic Arthritis

Indicated for active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients aged ≥2 years

≥2 years

  • Oral solution
    • 10 to <20 kg: 3.2 mg PO BID
    • 20 to <40 kg: 4 mg PO BID
  • Oral solution or tablet
    • ≥40 kg: 5 mg PO BID

Dosage Modifications

Coadministration with strong CYP3A4 inhibitors, OR a moderate CYP3A4 inhibitor(s) with a strong CYP2C19 inhibitor(s)

  • pcJIA
    • If taking 3.2 mg BID, reduce to 3.2 mg qDay
    • If taking 4 mg BID, reduce to 4 mg qDay
    • If taking 5 mg BID, reduce to 5 mg qDay

Hematologic abnormalities

  • Do not initiate in patients with an absolute lymphocyte count <500 cells/mm3, ANC <1000 cells/mm3 or Hgb <9 g/dL
  • Lymphocyte count <500 cells/mm3: Confirmed by repeat testing; discontinue dosing
  • ANC 500-1000 cells/mm3: Interrupt dosing until ANC >1000 cells/mm3
  • ANC <500 cells/mm3: Discontinue dosing
  • Hgb <8 g/dL or a decrease of >2 g/dL: Interrupt dosing until Hgb normalized

Renal impairment

  • pcJIA
    • Mild: No dosage adjustment required
    • Moderate-to-severe: Reduce dosing frequency to qDay (eg, 3.2 mg BID to 3.2 mg qDay)
    • Hemodialysis: Administer after dialysis session on dialysis days; if dose taken before dialysis, supplemental doses are not recommended after dialysis

Hepatic impairment

  • pcJIA
    • Mild: No dosage adjustment required
    • Moderate: Reduce dosing frequency to qDay (eg, 3.2 mg BID to 3.2 mg qDay)
    • Severe: Not studied; not recommended
    • Safety and efficacy have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology (Add to adult)

Dosing Considerations

Limitation of use: Use in combination with biologic DMARDs or potent immunosuppressants (eg, azathioprine, cyclosporine) is not recommended

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Interactions

Interaction Checker

and tofacitinib

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    No Interactions Found
    Interactions Found

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      Serious - Use Alternative

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            Adverse Effects

            >10%

            UC

            • Nasopharyngitis (10-14%)

            1-10%

            RA

            • Upper respiratory tract infection (4%)
            • Nasopharyngitis (3-4%)
            • Diarrhea (3-4%)
            • Headache (3-4%)
            • Hypertension (2%)

            UC

            • Elevated cholesterol levels (5-9%)
            • Headache (3-9%)
            • Upper respiratory tract infection (6-7%)
            • Increased blood creatine phosphokinase (3-7%)
            • Rash (3-6%)
            • Diarrhea (2-5%)
            • Herpes zoster (1-5%)
            • Gastroenteritis (3-4%)
            • Anemia (2-4%)
            • Nausea (1-4%)

            Frequency Not Defined

            RA

            • Blood and lymphatic system disorders: Anemia
            • Infections and infestations: Diverticulitis
            • Metabolism and nutrition disorders: Dehydration
            • Psychiatric disorders: Insomnia
            • Nervous system disorders: Paresthesia
            • Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with rheumatoid arthritis and some were fatal)
            • Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea
            • Hepatobiliary disorders: Hepatic steatosis
            • Skin and subcutaneous tissue disorders: Rash, erythema, pruritus
            • Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling
            • Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers
            • General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema

            Postmarketing Reports

            Immune system disorders: Drug hypersensitivity

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            Warnings

            Serious infections

            • Increased risk for developing serious infections that may lead to hospitalization or death; most patients who developed these infections were taking concomitant immunosuppressants (eg, methotrexate, corticosteroid)
            • If serious infection develops, interrupt until infection controlled
            • Reported infections include active TB, invasive fungal infections, and bacterial, viral, or other opportunistic pathogens
            • Test for latent TB before and during tofacitinib treatment; treatment for latent TB infection should be initiated prior to tofacitinib treatment

            Malignancies

            • Lymphoma and other malignancies reported
            • Epstein Barr virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with tofacitinib and concomitant immunosuppressive medications

            Mortality

            • A higher rate of all-cause mortality, including sudden cardiovascular death, reported in rheumatoid arthritis patients ≥50 years with at least 1 cardiovascular risk factor treated with 10 mg BID compared to those treated with 5 mg BID or TNF blockers

            Increased risk of blood clots

            • Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis have occurred in patients treated with Janus kinase inhibitors used to treat inflammatory conditions
            • Patients with rheumatoid arthritis aged ≥50 years with at least 1 CV risk factor treated with 10 mg BID showed an increased incidence of thrombosis compared with 5 mg BID or TNF blockers in a large, ongoing postmarketing safety study
            • Avoid in patients at risk
            • Discontinue therapy and promptly evaluate patients with thrombosis symptoms
            • For patients with ulcerative colitis, use lowest effective dose and for shortest duration needed to achieve/maintain therapeutic response

            Contraindications

            None

            Cautions

            Malignancy and lymphoproliferative disorders reported (see Black Box Warnings); malignancies were observed in clinical studies and the postmarketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer

            GI perforation reported, although role of JAK inhibition in these events is unknown; caution in patients at increased risk for gastrointestinal perforation (eg, diverticulitis)

            Associated with gradual decrease in lymphocyte and neutrophils counts, and hemoglobin levels that may require treatment interruption

            Associated with increased LFTs

            Associated with increase lipid parameters including total cholesterol, LDL, and HDL

            Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), reported; hepatitis B reactivation reported; impact on chronic viral hepatitis reactivation unknown; perform screening for viral hepatitis in accordance with clinical guidelines before starting therapy

            Non-melanoma skin cancers (NMSCs) reported; periodic skin examination recommended for patients at increased risk for skin cancer

            Use caution when treating patients with diabetes; higher incidence of infection in diabetic population in general reported

            Diverticulitis reported

            Twice daily dosing of tofacitinib 10 mg or 11 mg tofacitinib XR not recommended in patients with rheumatoid arthritis or psoriatic arthritis

            Rheumatoid arthritis patients ≥50 years of age with at least 1 cardiovascular (CV) risk factor treated with tofacitinib 10 mg BID had a higher rate of all-cause mortality

            Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, have occurred

            Structural joint damage progression

            • Radiographic response data from the ORAL Scan and ORAL Start studies evaluated the efficacy of tofacitinib on structural joint damage progression as measured by mean change from baseline in van der Heijde modified Total Sharp Score (mTSS) and its components, erosion score, and joint space narrowing (JSN) score

            Serious infections

            • Serious and sometimes fatal infections reported due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens; the most common serious infections reported have included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis
            • In the UC population, treatment with 10 mg BID was associated with greater risk of serious infections compared with 5 mg BID; additionally, opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with 10 mg twice daily
            • Use caution in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections
            • Risk of infection may be higher with increasing degrees of lymphopenia; consideration should be given to lymphocyte counts when assessing individual patient risk of infection
            • Avoid use in patients with an active, serious infection, including localized infections
            • Consider the risks and benefits of tofacitinib prior to initiating treatment
              • Patients with chronic or recurrent infection
              • Patients who have been exposed to tuberculosis
              • Patients with a history of a serious or an opportunistic infection
              • Patients who have resided or traveled in areas of endemic tuberculosis or endemic mycoses
              • Patients with underlying conditions that may predispose them to infection

            Extended-release tablet

            • Patients may notice an inert tablet shell passing in the stool or via colostomy
            • Caution when administering the extended-release tablet to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic); rare reports of obstructive symptoms with strictures in association with the ingestion of other drugs utilizing a non-deformable extended release formulation

            Drug interactions overview

            • Tofacitinib is a CYP3A4 substrate and a minor CYP2C19 substrate
            • Strong CYP3A4 inducers may decrease clinical response
            • Decreased dose required if coadministered with strong CYP3A4 inhibitors, or moderate CYP3A4 inhibitors plus CYP2C19 inhibitors (see Dosage Modifications)
            • Avoid coadministration with live virus vaccines
            • Risk of added immunosuppression when tofacitinib is concomitantly used with potent immunosuppressive drugs (eg, azathioprine, tacrolimus, cyclosporine); combined use of multiple dose tofacitinib with potent immunosuppressants has not been studied in rheumatoid arthritis and psoriatic arthritis
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            Pregnancy & Lactation

            Pregnancy

            There is a pregnancy exposure registry that monitors pregnancy outcomes in women during pregnancy; patients can call the toll free number 1-877-311-8972

            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
            • Feticidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 146 times and 13 times the human dose of 5 mg BID, respectively
            • In a peri and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73 times the human dose of 5 mg BID
            • 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

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Janus kinases (JAKs) pathways inhibitor; JAK consists of a group of intracellular tyrosine kinases that transmit signals from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoieses 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

            These signals are essential in maintaining the inflammatory condition in rheumatoid arthritis (RA); inhibition of JAKs reduces production of and modulates proinflammatory cytokines central to RA

            Absorption

            Bioavailability

            • Xeljanz: 74%

            Minimum plasma concentration

            • Xeljanz: 1.41-3.1 ng/mL
            • Xeljanz XR: 1.07-3.11 ng/mL

            Peak plasma concentration

            • Xeljanz: 42.7-84.7 ng/mL
            • Xeljanz XR: 38.2-83.8 ng/mL

            Peak plasma time

            • Xeljanz or oral solution: 0.5-1 hr
            • Xeljanz XR: 4 hr

            AUC

            • Xeljanz: 263.4-539.6 ng⋅hr/mL
            • Xeljanz XR: 269-596.6 ng⋅hr/mL

            Steady-state reached

            • Xeljanz or oral solution: 24-48 hr
            • Xeljanz XR: 48 hr

            Distribution

            Protein Bound: ~40% (predominately to albumin)

            Vd: 87 L (following IV administration)

            Distributes equally between RBCs and plasma

            Metabolism

            Clearance mechanisms: ~70% hepatic metabolism and 30% renal excretion

            Primarily metabolized by CYP3A4 (accounting for ~53% of total clearance) and by CYP2C19 (accounting for ~17% of total clearance)

            Metabolites: Potency <10% of parent compound

            Elimination

            Renal clearance: 30%

            Excretion: 30% urine

            Half-life

            • Xeljanz or oral solution: 0.8-1 hr
            • Xeljanz XR: 4 hr
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            Administration

            Oral Administration

            May take with or without food

            Extended-release tablets: Swallow whole; do not crush, split, or chew

            Switching from regular tablets to extended-release tablets

            • Patients treated with tofacitinib 5 mg BID may switch to tofacitinib ER 11 mg qDay the day following the last dose of tofacitinib 5 mg

            • Patients treated with tofacitinib 10 mg BID may switch to tofacitinib 22 mg qDay the day following the last dose of tofacitinib 10 mg

            Storage

            Xeljanz or Xeljanz ER: Store at 20-25ºC (68-77ºF)

            Oral solution

            • Store at room temperature 20-25ºC (68-77ºF) in the original bottle and carton to protect from light
            • Safely throw away solution that is out of date or no longer needed
            • Use within 60 days of opening bottle; discard remaining oral solution after 60 days
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            Images

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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