tofacitinib (Rx)

>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

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 (some 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

Diverticulitis

Contraindications

None

Cautions

Malignancy and lymphoproliferative disorders reported (see Black Box Warnings); malignancies were observed in clinical studies and the post-marketing 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 (see Dosage Modifications)

Associated with increased LFTs

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

Not recommended with severe hepatic impairment

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

Decreased dose required with moderate hepatic impairment or moderate-to-severe renal impairment; dosage adjustment recommended in patients with moderate or severe renal impairment (including but not limited to those with severe insufficiency who are undergoing hemodialysis; see Dosage Modifications)

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

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
• In ORAL Scan, 74% of patients in the placebo/methotrexate group experienced no radiographic progression at Month 6 compared to 84% of patients treated with tofacitinib 5mg BID plus methotrexate
• In ORAL Start, 55% of patients in the methotrexate group experienced no radiographic progression at Month 6 compared to 73% of patients treated with tofactinib 5mg BID

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; among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis reported
• 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
• Caution is recommended 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
• Reactions such as angioedema and urticaria that may reflect drug hypersensitivity observed; if serious hypersensitivity reaction occurs, promptly discontinue therapy while evaluating potential cause or causes of reaction
• 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

• 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

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.

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

Tablet

• Bioavailability: 74%
• Peak Plasma Time: 0.5-1 hr
• Coadministration with high-fat meal resulted in no changes in AUC while peak plasma concentration was reduced by 32%

Extended-release tablet

• Coadministration of with a high-fat meal resulted in no changes in AUC while peak plasma concentration was increased by 27% and peak plasma time was extended by ~1 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

Half-life: 3 hr

Renal clearance: 30%

Excretion: 30% urine

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 PO BID may be switched to tofacitinib extended-release 11 mg PO qDay the day following the last dose of tofacitinib 5 mg

Storage

Xeljanz or Xeljanz ER: Store at 20-25°C (68-77°F)