upadacitinib (Rx)

>10%

Upper respiratory tract infection (13.5%)

1-10%

Nausea (3.5%)

Neutropenia (1.1-2.4%)

Lymphopenia (0.3-2.4%)

Cough (2.2%)

Elevated ALT (0.8-2.1%)

Increased creatine phosphokinase (0.3-1.6%)

Elevated AST (1-1.5%)

Pyrexia (1.2%)

<1%

Pneumonia

Herpes zoster

Herpes simplex (includes oral herpes)

Oral candidiasis

Anemia (<0.1%)

Frequency Not Defined

Tuberculosis

Malignancies, excluding nonmelanoma skin cancer

Venous thrombosis

Elevated LDL

Elevated HDL

Contraindications

None

Cautions

Malignancies reported; consider risks and benefits of treatment before initiating in patients with known malignancy, other than previously treated nonmelanoma skin cancer; screen for malignancies during treatment according to guidelines

Thrombosis reported, including DVT, PE, and arterial thrombosis

Gastrointestinal perforation reported; unknown if JAK inhibition is implicated in these events; many patients were also receiving NSAIDs

May cause neutropenia, lymphopenia, anemia, elevated lipids, or elevated liver enzymes; monitor for abnormal laboratory values and assess the need to interrupt dosing

Based on findings in animal studies, may cause fetal harm when administered to pregnant women

Serious and fatal infections

• Serious and fatal infections reported
• Most frequent infections reported included pneumonia and cellulitis
• Opportunistic infections reported included TB, multidermatomal herpes zoster, oral/esophageal candidiasis, and cryptococcosis
• Avoid in patients with an active, serious infection, including localized infections
• Monitor for viral reactivation (eg, hepatitis B, herpes zoster) during treatment
• Patients should be screen for opportunistic infections and treated according to guidelines

Drug interaction overview

• Upadacitinib is a substrate of CYP3A4 (major) and CYP2D6 (minor)

• Strong CYP3A4 inhibitors

  • Use caution
  • Upadacitinib systemic exposure is increased when coadministered with strong CYP3A4 inhibitors

• Strong CYP3A4 inducers

  • Coadministration not recommended
  • Upadacitinib systemic exposure is decreased when coadministered with strong CYP3A4 inducers

• Vaccines

  • Use of live, attenuated vaccines during or immediately before initiating upadacitinib is not recommended
  • Before initiating, assess vaccination history, including prophylactic zoster vaccinations
  • Ensure vaccinations are current before initiating upadacitinib

Pregnancy

Limited human data on use in pregnant women are not sufficient to evaluate a drug-associated risk for major birth defects or miscarriage

Verify pregnancy status of females of reproductive potential before starting treatment

Animal data

• Based on animal studies, upadacitinib has the potential to adversely affect a developing fetus
• In animal embryofetal development studies, oral upadacitinib administration to pregnant rats and rabbits at exposures greater or equal than ~1.6 and 15 times the maximum recommended human dose (MRHD), respectively, resulted in dose-related increases in skeletal malformations (rats only), an increased incidence of cardiovascular malformations (rabbits only), increased postimplantation loss (rabbits only), and decreased fetal body weights in both rats and rabbits

Contraception

• Females of reproductive potential: Use effective contraception during treatment and for 4 weeks after final dose

Clinical considerations

• Published data suggest that increased disease activity is associated with risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis
• Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth

Lactation

No data available on the presence of upadacitinib in human milk, the effects on the breastfed infant, or the effects on milk production

Available data in animals have shown upadacitinib excreted in milk

If a drug is present in animal milk, it is likely the drug will be present in human milk

Because of the potential for serious adverse reactions in the breastfed infant, advise patients that breastfeeding is not recommended during treatment with upadacitinib, and for 6 days (~10 half-lives) after the last dose

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 kinase-1 (JAK1)-selective inhibitor; JAK1 is essential for signaling for certain cytokines to elicit signals from various interleukins, cardiotrophin, neurotrophin, and interferons

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

Absorption

Peak plasma time: 2-4 hr

Steady-state reached within 4 days

Distribution

Protein bound: 52%

Metabolism

Metabolized by mainly CYP3A4 and potentially minor contribution from CYP2D6

Elimination

Half-life: 8-14 hr

Excretion

• Urine (24%); feces (38%)
• ~34% of upadacitinib dose was metabolites

Oral Administration

Take orally with or without food

Swallow tablet whole; do not split, crush, or chew

Storage

Store at 2-25ºC (36-77ºF)

Store in original bottle to protect from moisture