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. |
| Molecular Weight | 312.37 |
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 | Limited human data; animal studies show teratogenicity at high doses. Avoid use unless no safer alternative. |
| 2nd trimester | Limited human data; potential for fetal harm. Avoid use unless benefit outweighs risk. |
| 3rd trimester | Limited human data; risk of neonatal immunosuppression. Avoid use near term. |
Clinical note
Strong CYP3A4 inhibitors may increase levels Can cause serious infections and increased risk of malignancy.
| FDA category | Contraindicated |
| Placental transfer | Crosses placenta in animals; expected in humans given low molecular weight. No human data on transfer extent. |
| Breastfeeding |
■ 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 |
Known hypersensitivity to tofacitinib or any excipientSevere hepatic impairment (Child-Pugh C)
| 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…
| Present in animal milk; no human data. Due to potential for serious adverse reactions in nursing infants, advise against breastfeeding during treatment and for at least 18 hours after last dose. |
| Lactation Rating | L5 (Contraindicated) |
| 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. |
| 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. |
| Food/Dietary | No specific food interactions are documented. However, grapefruit juice may affect CYP3A4 metabolism; avoid large amounts of grapefruit juice during therapy as it may increase drug levels and risk of adverse effects. |
| Clinical Pearls | Monitor for serious infections including tuberculosis and herpes zoster before and during therapy. Check lipid profile and liver function tests at baseline and periodically. Avoid use with strong CYP3A4 inhibitors (e.g., ketoconazole) unless benefit outweighs risk; reduce dose to 5 mg twice daily when used with moderate CYP3A4 inhibitors (e.g., fluconazole) or with strong CYP2C19 inhibitors (e.g., omeprazole). Do not use with biologic DMARDs (e.g., TNF inhibitors, IL-6 inhibitors, IL-1 inhibitors, abatacept) or potent immunosuppressants like azathioprine or cyclosporine. Vaccination with live vaccines is contraindicated during therapy. Consider dose reduction in patients with renal impairment (CrCl <30 mL/min) or hepatic impairment (Child-Pugh class B or C). Monitor for GI perforation, especially in patients with diverticulitis history. Hemoglobin, ANC, and platelet counts should be assessed before initiation and as clinically indicated. |
| Patient Advice | Take exactly as prescribed; do not change dose or stop without consulting your doctor. · Tofacitinib can lower your ability to fight infections; report any signs of infection like fever, cough, or skin redness immediately. · Avoid live vaccines (e.g., MMR, nasal flu vaccine) while taking this medication and for a period after stopping as advised by your doctor. · This drug may increase risk of blood clots in the lungs (pulmonary embolism) or deep veins; seek emergency care for sudden chest pain, trouble breathing, or leg swelling. · Inform your doctor if you have a history of diverticulitis or stomach ulcers; report persistent abdominal pain or blood in stool. · Regular blood tests are needed to monitor for side effects (e.g., lipid changes, liver function, blood cell counts). · Use effective contraception during treatment and for at least 4-6 weeks after stopping if you or your partner can become pregnant. · Do not take other medications, including over-the-counter drugs or herbal supplements, without checking with your doctor due to potential interactions. |