JAKAFI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for JAKAFI (JAKAFI).
Janus kinase (JAK) inhibitor. Inhibits JAK1 and JAK2, mediating signaling of cytokines and growth factors involved in hematopoiesis and immune function.
| Metabolism | Primarily metabolized by CYP3A4, with minor contributions from CYP2C9. |
| Excretion | Ruxolitinib is primarily metabolized in the liver, with 74% of the dose excreted in urine (as metabolites) and 22% in feces (as metabolites). Unchanged drug accounts for <1% of urinary excretion. |
| Half-life | The terminal elimination half-life of ruxolitinib is approximately 2.3 to 3 hours. This short half-life supports twice-daily dosing to maintain therapeutic levels. |
| Protein binding | Approximately 97% bound to plasma proteins, primarily to albumin. |
| Volume of Distribution | Volume of distribution is approximately 82 L (about 1.1 L/kg in an average 70 kg adult), indicating extensive distribution into tissues. |
| Bioavailability | Oral bioavailability is approximately 95% relative to an oral solution. Food does not significantly affect absorption. |
| Onset of Action | Oral administration: reduction in splenomegaly and improvement in symptoms (e.g., pruritus) can be observed within 1–2 weeks, with maximal effect by 12–24 weeks. No intravenous formulation is approved. |
| Duration of Action | Duration of action is approximately 8–12 hours, consistent with twice-daily dosing. Dosing frequency is every 12 hours to maintain JAK-STAT pathway inhibition. |
5 mg orally twice daily for myelofibrosis; 10 mg orally twice daily for polycythemia vera.
| Dosage form | TABLET |
| Renal impairment | For GFR 15-49 mL/min: reduce dose by 50%; for GFR <15 mL/min or on dialysis: not recommended. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment required; monitor for dose-related toxicities in elderly. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for JAKAFI (JAKAFI).
| Breastfeeding | No data on presence in human milk, effects on breastfed infant, or effects on milk production. Ruxolitinib and its metabolites are excreted in rat milk at concentrations 13 times higher than maternal plasma. Because of the potential for serious adverse reactions in breastfed infants, women should not breastfeed during treatment and for at least 2 weeks after the last dose. M/P ratio in rats: ~13. |
| Teratogenic Risk | FDA Pregnancy Category D. In pregnant rats and rabbits, ruxolitinib caused increased post-implantation loss, reduced fetal weights, and fetal skeletal anomalies at exposures 0.15 and 0.11 times the human AUC at the recommended dose, respectively. There are no adequate and well-controlled studies in pregnant women. Ruxolitinib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Based on its mechanism of action, ruxolitinib may cause fetal harm when administered to a pregnant woman. Embryofetal developmental studies in rats and rabbits showed increased post-implantation loss and reduced fetal weights at clinically relevant exposures. |
■ FDA Black Box Warning
WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS. Increased risk of bacterial, mycobacterial, fungal, viral, and other opportunistic infections; increased mortality in patients >70 years with myelofibrosis; increased risk of malignancy (e.g., lymphoma); increased risk of major adverse cardiovascular events (MACE); increased risk of thrombosis (e.g., DVT, PE).
| Serious Effects |
None known (based on FDA labeling; no absolute contraindications listed, but avoid use in patients with severe hepatic impairment and active serious infections).
| Precautions | ["Serious infections","Progressive multifocal leukoencephalopathy (PML)","Malignancy","Thrombosis","Major adverse cardiovascular events (MACE)","Hepatotoxicity","Neutropenia, thrombocytopenia, anemia","Lipid elevations","Immunizations: avoid live vaccines","Second primary malignancies (including EBV-related lymphoma)","Graft failure and/or organ rejection (in transplant patients)"] |
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| Fetal Monitoring | Monitor complete blood count (CBC) with differential at baseline and every 2-4 weeks until doses are stabilized, then every 1-3 months during pregnancy if clinically indicated. Assess for bleeding, infection, and signs of anemia or thrombocytopenia. Monitor liver function tests and lipid panel periodically. In pregnant patients, monitor fetal growth and development via serial ultrasound to assess for possible intrauterine growth restriction due to potential hematologic effects. |
| Fertility Effects | In animal studies, ruxolitinib did not affect male or female fertility in rats at exposures up to 0.9 times the human exposure at the maximum recommended dose. However, based on its mechanism of action (JAK kinase inhibition), ruxolitinib may impair fertility in humans. Effects on spermatogenesis and ovarian function have not been adequately studied. In clinical trials, decreased sperm count was not reported; however, potential for reduced fertility should be considered. |