TOFACITINIB CITRATE
Clinical safety rating: avoid
Strong CYP3A4 inhibitors may increase levels Can cause serious infections and increased risk of malignancy.
Janus kinase (JAK) inhibitor; inhibits JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2), thereby modulating cytokine signaling and downregulating immune and inflammatory responses.
| Metabolism | Primarily metabolized by CYP3A4 with minor contribution from CYP2C19. |
| Excretion | Approximately 70% of the dose is eliminated by hepatic metabolism, with about 30% excreted unchanged in urine and <10% in feces. Renal excretion accounts for ~30% of total clearance. |
| Half-life | Terminal elimination half-life is approximately 3 hours (range 2–4 hours) in patients with normal renal function, allowing twice-daily dosing. Half-life is prolonged in moderate to severe renal impairment (up to 5–8 hours) and in hepatic impairment. |
| Protein binding | Approximately 40% bound to plasma proteins (mainly albumin), which is relatively low and not clinically significant for displacement interactions. |
| Volume of Distribution | Volume of distribution is about 0.7–1.0 L/kg (total Vd ~50–70 L), indicating extensive distribution into tissues beyond plasma, consistent with good tissue penetration. |
| Bioavailability | Oral bioavailability is approximately 74% (range 65–80%) for the immediate-release tablet, with no significant food effect; administered with or without food. |
| Onset of Action | Oral: Clinical improvement in rheumatoid arthritis symptoms can be observed within 2 weeks of starting therapy, with maximal effect typically seen by 3–6 months. |
| Duration of Action | Duration of action aligns with dosing interval (twice daily). Steady-state concentrations are achieved within 2–3 days. The drug is rapidly cleared, so effects wane within 12–24 hours if doses are missed. |
5 mg orally twice daily for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis; 10 mg orally twice daily for ulcerative colitis induction (8 weeks maximum).
| Dosage form | TABLET |
| Renal impairment | For GFR 30-59 mL/min: 5 mg once daily. For GFR <30 mL/min: not recommended. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: 5 mg once daily. Child-Pugh C: not recommended. |
| Pediatric use | Not approved for pediatric use; safety and efficacy not established for ages <18 years. |
| Geriatric use | No specific dose adjustment based on age alone; monitor for infections and renal function; limited data for >65 years. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP3A4 inhibitors may increase levels Can cause serious infections and increased risk of malignancy.
| FDA category | Contraindicated |
| Breastfeeding | No human data; tofacitinib is excreted in rat milk. M/P ratio unknown. Because of potential serious adverse reactions in nursing infants, advise against breastfeeding during treatment and for at least 18 hours after last dose (based on half-life). |
| Teratogenic Risk | In animal studies, tofacitinib was teratogenic in rats and rabbits at exposures 2.3 and 5.3 times the maximum recommended human dose (MRHD) respectively. In humans, there are no adequate studies; based on mechanism (JAK inhibition), there is a potential risk of fetal harm. Use is contraindicated in pregnancy. First trimester: highest risk; second and third trimester: continued risk, but limited human data. Advise effective contraception during treatment and for at least 4 weeks after last dose. |
■ FDA Black Box Warning
WARNING: SERIOUS INFECTIONS AND MORTALITY, MALIGNANCY, THROMBOSIS. (1) Serious infections leading to hospitalization or death, including tuberculosis, invasive fungal infections, bacterial, viral, and opportunistic infections. Discontinue if serious infection develops. (2) Lymphoma and other malignancies observed; higher risk in rheumatoid arthritis patients with tofacitinib 10 mg twice daily vs 5 mg twice daily. (3) Thrombosis, including pulmonary embolism, deep vein thrombosis, and arterial thrombosis; avoid in patients at risk.
| Common Effects | psoriatic arthritis |
| Serious Effects |
None stated in labeling.
| Precautions | Serious infections; tuberculosis screening and treatment before use; malignancies; thrombosis; gastrointestinal perforation; monitor for lab abnormalities (lymphocytes, neutrophils, hemoglobin, liver enzymes, lipids); avoid use with strong CYP3A4 inhibitors or inducers; vaccination with live vaccines contraindicated; consider risks before use in patients with chronic lung disease, diverticulitis, or those who develop symptoms of thrombosis. |
Loading safety data…
| Fetal Monitoring | Monitor for infections (including tuberculosis), anemia, neutropenia, lymphopenia, and elevated liver enzymes. In pregnancy, consider serial growth ultrasounds due to potential for fetal harm (animal data). Monitor for signs of thrombosis, as JAK inhibitors increase risk. |
| Fertility Effects | Based on animal studies, tofacitinib may impair female fertility. In female rats, decreased fertility and increased post-implantation loss occurred at exposures 2.3 times MRHD. Human data are limited; advise women of reproductive potential of potential risk and to use effective contraception. |