Jakafi (Ruxolitinib)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Intermediate- or high-risk myelofibrosis (MF) | Adults with primary MF, post-PV MF, or post-ET MF | Monotherapy; dose based on platelet count | FDA Approved |
| Polycythemia vera (PV) | Adults with inadequate response to or intolerance of hydroxyurea | Monotherapy | FDA Approved |
| Steroid-refractory acute GVHD (aGVHD) | Adults and pediatric patients ≥12 years | Monotherapy | FDA Approved |
| Chronic GVHD (cGVHD) | Adults and pediatric patients ≥12 years after failure of 1–2 lines of systemic therapy | Monotherapy | FDA Approved |
Ruxolitinib was the first JAK inhibitor approved by the FDA (2011) and remains the reference standard for JAK inhibition in myeloproliferative neoplasms. Its indications span two distinct therapeutic areas: myeloproliferative neoplasms (MF, PV) where it targets dysregulated JAK2 signalling, and graft-versus-host disease (aGVHD, cGVHD) where it modulates immune cell activation through JAK1/JAK2 pathway inhibition. There are no formal contraindications listed in the prescribing information.
Dosing
Starting Doses by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| MF — platelets >200 × 109/L | 20 mg BID | Titrate by 5 mg BID increments | 25 mg BID | No dose increase in first 4 weeks or more frequently than q2 weeks. Discontinue if no response after 6 months. COMFORT-I/II trial setting |
| MF — platelets 100–200 × 109/L | 15 mg BID | Titrate by 5 mg BID increments | 25 mg BID | Same titration rules. Hold for platelets <50 × 109/L or ANC <0.5 × 109/L. |
| MF — platelets 50–<100 × 109/L | 5 mg BID | Titrate by 5 mg daily increments | 10 mg BID | Hold for platelets <25 × 109/L or ANC <0.5 × 109/L. More conservative dose modifications apply. |
| Polycythemia vera | 10 mg BID | Titrate based on efficacy & safety | 25 mg BID | Reduce or hold for Hb <8 g/dL, platelets <50 × 109/L, or ANC <1.0 × 109/L. RESPONSE trial setting |
| Steroid-refractory acute GVHD | 5 mg BID | 5 mg BID | 10 mg BID | Consider tapering after 6 months if responding and off therapeutic corticosteroids. Taper q8 weeks (10 → 5 mg BID → 5 mg daily). REACH2 trial setting |
| Chronic GVHD after 1–2 prior therapies | 10 mg BID | 10 mg BID | 10 mg BID | Consider tapering after 6 months if responding and off therapeutic corticosteroids. Same taper schedule as aGVHD. REACH3 trial setting |
Dose Modifications for Drug Interactions
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| MF/PV + strong CYP3A4 inhibitor or fluconazole ≤200 mg (platelets ≥100) | 10 mg BID | Per safety/efficacy | 10 mg BID | Reduce dose by 50% (rounded up). If stabilised on 5 mg BID, reduce to 5 mg daily. If on 5 mg daily, avoid inhibitor or hold ruxolitinib (FDA PI). |
| MF/PV + strong CYP3A4 inhibitor or fluconazole ≤200 mg (platelets 50–<100) | 5 mg daily | Per safety/efficacy | 5 mg daily | Avoid combination if possible (FDA PI). |
| aGVHD + ketoconazole | 5 mg daily | 5 mg daily | 5 mg daily | No dose adjustment for other CYP3A4 inhibitors in aGVHD except ketoconazole (FDA PI). |
| Any indication + fluconazole >200 mg/day | Avoid combination | Fluconazole doses >200 mg cause excessive dual CYP3A4/CYP2C9 inhibition (FDA PI). | ||
| Any indication + strong CYP3A4 inducer (e.g., rifampicin) | No dose adjustment; monitor closely | AUC decreases ~61%; titrate based on safety and efficacy (FDA PI). | ||
Unlike most oral oncology agents, ruxolitinib starting dose for myelofibrosis is determined entirely by the patient’s baseline platelet count, not by body weight or body surface area. This reflects the drug’s primary dose-limiting toxicity: thrombocytopenia. The dose titration system is intricate, with different interruption, restart, and reduction rules depending on whether the patient started with platelets above or below 100 × 109/L. Familiarity with the full FDA PI dosing tables is essential for safe prescribing. Ruxolitinib should not be abruptly discontinued in MF patients as this can trigger acute symptom flare and rare septic shock-like events; gradual tapering is recommended.
Pharmacology
Mechanism of Action
Ruxolitinib is a potent and selective inhibitor of Janus Associated Kinases JAK1 and JAK2, which mediate signalling for a range of cytokines and growth factors that are central to haematopoiesis and immune function. In myeloproliferative neoplasms, constitutive activation of JAK-STAT signalling (often driven by the JAK2 V617F mutation) leads to uncontrolled myeloid proliferation, splenomegaly, and systemic inflammatory symptoms. Ruxolitinib interrupts this aberrant signalling, reducing spleen size and alleviating constitutional symptoms such as fatigue, night sweats, pruritus, and bone pain. In GVHD, JAK-STAT pathways regulate the development, proliferation, and activation of alloreactive T cells and other immune cells driving tissue damage. By inhibiting JAK1/JAK2, ruxolitinib reduces inflammatory cytokine levels and immune cell infiltration into target organs.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapid; Tmax ~1–2 h; bioavailability >95%; food decreases Cmax ~24% but does not significantly affect AUC; dose-proportional PK over 5–200 mg; steady state by Day 2 | Can be taken with or without food; rapid onset supports twice-daily dosing; very fast steady state achieved |
| Distribution | Vd 53–65 L at steady state (MF patients); protein binding ~97% (albumin); not a P-gp substrate | Moderate distribution; high protein binding; no P-gp-mediated interactions expected |
| Metabolism | Primarily CYP3A4 (~43–75%); secondarily CYP2C9 (~19–56%); forms pharmacologically active metabolites contributing 20–50% of total activity | Dual CYP pathway creates vulnerability to both CYP3A4 inhibitors and dual CYP3A4/CYP2C9 inhibitors (fluconazole); active metabolites extend effective half-life to ~5.8 h |
| Elimination | t½ ~3 h (parent), ~5.8 h (parent + metabolites); 74% urine, 22% feces (<1% as unchanged drug); almost completely eliminated by oxidative metabolism | Short parent half-life supports rapid PD offset; renal impairment increases metabolite exposure, requiring dose reduction; eliminated almost entirely as metabolites |
Side Effects
Adverse reaction data are from the FDA prescribing information (June 2025 revision). Side effect profiles differ substantially between indications: haematological toxicities predominate in MF/PV, while infections are more prominent in GVHD. Incidence rates shown are from pivotal trials in the most relevant indication.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Thrombocytopenia | 70–84% (MF) | Primary dose-limiting toxicity in MF; Grade 3–4 in ~11% at week 24, increasing to ~23% with long-term treatment (5-year COMFORT-I); manage with dose reduction/interruption per platelet thresholds; transfusion may be needed (FDA PI) |
| Anaemia | ~99% (MF, lab abnormality) | Nearly universal hemoglobin decline due to JAK2 inhibition of erythropoietin signalling; Grade 3–4 in ~45% (COMFORT-I); nadir at weeks 8–12 with partial recovery by week 24; transfusion frequently required early in treatment; women at higher risk (FDA PI) |
| Neutropenia | 19% (MF); >50% (aGVHD) | Grade 3–4 in ~7% (MF); higher in GVHD setting; hold for ANC <0.5 (MF) or <0.75 (GVHD) × 109/L (FDA PI) |
| Infections | >50% (GVHD) | Bacterial, viral, fungal, and mycobacterial infections reported; herpes zoster, hepatitis B reactivation, TB, and PML are specific risks; screen for TB and hepatitis B before starting (FDA PI) |
| Bruising | 23% (MF) | Related to thrombocytopenia; monitor for more significant bleeding |
| Dizziness | 18% (MF) | Caution with driving and hazardous activities |
| Headache | 15% (MF) | Usually mild; self-limiting |
| Diarrhoea | 15% (PV) | Generally Grade 1–2; manage supportively |
| Oedema | >50% (aGVHD) | Common in GVHD setting; assess for fluid overload |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Weight gain | 7% (MF) | May be partially related to improved appetite and symptom relief |
| Herpes zoster | 2–6% | Prompt antiviral treatment required; consider prophylaxis in high-risk patients (FDA PI) |
| Hypercholesterolaemia / hypertriglyceridaemia | Lipid elevations reported | Check lipids 8–12 weeks after starting; treat per guidelines (FDA PI Section 5.5) |
| Urinary tract infection | ~9% (MF) | Routine urinalysis if symptomatic; higher risk with immunosuppression |
| Non-melanoma skin cancer (NMSC) | ~6% (long-term MF) | Periodic skin examinations recommended; most patients had prior HU use or risk factors (FDA PI Section 5.4) |
| Flatulence | 5% (PV) | Generally mild and self-limiting |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Serious infections (TB, hepatitis B reactivation, PML, invasive fungal) | Variable; includes fatal cases | Any time | Screen for TB, HBV, HCV before starting. Resolve active serious infections before initiating. Treat promptly. Consider holding ruxolitinib for serious infections (FDA PI Section 5.2) |
| Symptom exacerbation / withdrawal syndrome (MF) | Occurs with abrupt discontinuation | Within 1 week of discontinuation | Gradual taper recommended rather than abrupt cessation. Manage with supportive care; consider resuming ruxolitinib if severe. Rare septic shock-like syndrome reported (FDA PI Section 5.3) |
| Major adverse cardiovascular events (MACE) | JAK inhibitor class warning | Any time | Monitor for cardiovascular events. Consider risk factors before initiating, particularly in patients ≥50 years with cardiovascular risk factors (FDA PI Section 5.6) |
| Thrombosis (arterial and venous) | JAK inhibitor class warning | Any time | Evaluate and treat thrombotic symptoms promptly. Consider underlying thrombotic risk in MPN patients (FDA PI Section 5.7) |
| Secondary malignancies (including lymphoma) | JAK inhibitor class warning | Any time, particularly long-term use | Monitor; particular risk in current/past smokers. Screen according to age-appropriate guidelines (FDA PI Section 5.8) |
| Severe thrombocytopenia / bleeding | Grade 3–4: ~11% (MF) | Weeks to months | Interrupt for platelet count thresholds per indication; manage with dose reduction and platelet transfusions. Interrupt for any bleeding requiring intervention (FDA PI) |
Thrombocytopenia, anaemia, and neutropenia are the defining dose-limiting toxicities of ruxolitinib. In COMFORT-I, the nadir for haemoglobin and platelets typically occurred at weeks 8–12, with partial recovery thereafter. Monthly CBC is mandatory during the dose-stabilisation phase (first 2–4 months), then as clinically indicated. Importantly, dose reduction and interruption are the primary management tools — not growth factor support or erythropoiesis-stimulating agents, which have not been formally studied in combination with ruxolitinib.
Drug Interactions
Ruxolitinib is metabolised by both CYP3A4 (primary) and CYP2C9 (secondary). This dual metabolic pathway means that drugs inhibiting both enzymes simultaneously (notably fluconazole) can produce disproportionately large exposure increases. Ruxolitinib itself is not a clinically significant CYP inhibitor or inducer and is not a P-gp substrate.
Monitoring
- CBC with differentialBaseline, then q2–4 weeks until stable, then as indicated
RoutineCritical for managing thrombocytopenia (dose-limiting), anaemia, and neutropenia. Dose modifications are tied to specific platelet, Hb, and ANC thresholds (FDA PI). - Lipid panel8–12 weeks after initiation
RoutineTotal cholesterol, LDL, and triglyceride elevations have been reported. Treat hyperlipidaemia according to standard guidelines (FDA PI Section 5.5). - Infection screeningBefore initiating treatment
RoutineScreen for tuberculosis, hepatitis B (HBsAg, anti-HBc), hepatitis C, and herpes simplex/zoster history. Resolve active serious infections before starting. Consider herpes zoster prophylaxis (FDA PI Section 5.2). - Spleen size (MF)Baseline and periodically
RoutineMeasure by palpation or imaging (MRI/CT). Primary efficacy marker: ≥35% spleen volume reduction. Discontinue if no spleen response or symptom improvement after 6 months (FDA PI). - Skin examinationPeriodically
RoutineNon-melanoma skin cancer reported (~6%); perform periodic skin examinations, particularly in patients with prior hydroxyurea use (FDA PI Section 5.4). - Cardiovascular risk assessmentBefore initiating and periodically
Trigger-basedJAK inhibitor class warning for MACE and thrombosis. Assess cardiovascular risk factors; particular caution in patients ≥50 years with existing risk factors (FDA PI Sections 5.6, 5.7). - GVHD response assessmentAt 6 months and ongoing
Trigger-basedConsider tapering ruxolitinib after 6 months in responding patients who have discontinued therapeutic corticosteroids. Taper q8 weeks (FDA PI).
Contraindications & Cautions
Absolute Contraindications
The FDA prescribing information lists no formal contraindications for ruxolitinib.
Relative Contraindications (Specialist Input Recommended)
- Active serious infection (including TB, hepatitis B, invasive fungal): Serious infections should have resolved before starting ruxolitinib. Screen for TB and hepatitis B before initiation (FDA PI Section 5.2).
- Severe thrombocytopenia (platelets <50 × 109/L for MF, or <50 for PV): Starting doses cannot be safely administered. Consider alternative therapy or wait for platelet recovery.
- Pregnancy: Adverse developmental outcomes observed in animal studies at maternally toxic doses. Use only if potential benefit justifies potential risk to the fetus (FDA PI Section 8.1).
Use with Caution
- Hepatic impairment with low platelets: AUC increases 28–87% across impairment severity. Dose reduction required for any hepatic impairment when platelets are between 100–150 × 109/L. Avoid use if platelets <100 × 109/L and hepatic impairment present (FDA PI Section 2.7).
- Renal impairment (moderate-to-severe, ESRD on dialysis): Metabolite exposure increases. Dose reduction required for MF patients with platelets 100–150 × 109/L and moderate/severe renal impairment. ESRD patients not on dialysis: avoid use. ESRD on dialysis: give dose after dialysis session only on dialysis days (FDA PI Section 2.7).
- Concurrent fluconazole >200 mg: Causes excessive ruxolitinib exposure via dual CYP3A4/CYP2C9 inhibition; avoid combination (FDA PI Section 2.6).
- JAK inhibitor class warnings (MACE, thrombosis, secondary malignancies): These class-wide concerns apply to all JAK inhibitors including ruxolitinib. Consider cardiovascular risk, thrombotic risk, and malignancy risk before initiation (FDA PI Sections 5.6–5.8).
The FDA requires all JAK inhibitors, including ruxolitinib, to carry warnings for major adverse cardiovascular events (MACE), thrombosis (arterial and venous), secondary malignancies (including lymphoma), and serious infections including tuberculosis, hepatitis B reactivation, herpes zoster, and progressive multifocal leukoencephalopathy (PML). Additional ruxolitinib-specific warnings include symptom exacerbation following abrupt discontinuation in MF patients (including rare septic shock-like syndrome), non-melanoma skin cancer, and lipid elevations. Monthly CBC monitoring during dose stabilisation is mandatory for all indications.
Patient Counselling
Purpose of Therapy
Ruxolitinib works by blocking specific proteins (JAK1 and JAK2) that are overactive in the condition being treated. For myelofibrosis and polycythemia vera, it helps reduce spleen enlargement and relieve symptoms like fatigue, night sweats, itching, and bone pain, but it does not cure the underlying disease. For graft-versus-host disease, it calms the overactive immune system that is attacking the body’s own tissues after a transplant.
How to Take
Take ruxolitinib at the prescribed dose twice daily, approximately 12 hours apart, with or without food. The dose may be different from other patients because it is based on blood test results. Do not change the dose or stop taking ruxolitinib without talking to the prescriber first, as stopping suddenly can cause symptoms to return quickly and sometimes severely. Ruxolitinib can be given through a nasogastric tube if the patient cannot swallow tablets.
Sources
- Jakafi (ruxolitinib) prescribing information. Incyte Corporation. Revised June 2025. DailyMedPrimary regulatory source for all dosing, safety, pharmacokinetic, and drug interaction data cited in this monograph.
- Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807. doi:10.1056/NEJMoa1110557COMFORT-I trial — first phase 3 evidence establishing ruxolitinib for intermediate/high-risk myelofibrosis with significant spleen volume reduction.
- Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–798. doi:10.1056/NEJMoa1110556COMFORT-II trial — randomised comparison of ruxolitinib vs best available therapy in MF, demonstrating superiority in spleen volume reduction.
- Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426–435. doi:10.1056/NEJMoa1409002RESPONSE trial — established ruxolitinib in PV patients with inadequate response to or intolerance of hydroxyurea.
- Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382(19):1800–1810. doi:10.1056/NEJMoa1917635REACH2 trial — phase 3 evidence for ruxolitinib in steroid-refractory acute GVHD with superior overall response rate.
- Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. 2021;385(3):228–238. doi:10.1056/NEJMoa2033122REACH3 trial — established ruxolitinib for chronic GVHD after failure of 1–2 systemic therapies.
- Marchetti M, Palandri F, Cattaneo D, et al. Recommendations for the management of myelofibrosis: the SIE, SIES, GITMO position. Blood Adv. 2022;6(2):575–588. doi:10.1182/bloodadvances.2021004856Contemporary consensus guideline on MF management including JAK inhibitor positioning and response assessment criteria.
- Quintás-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115(15):3109–3117. doi:10.1182/blood-2009-04-214957Preclinical characterisation of ruxolitinib demonstrating selective JAK1/JAK2 inhibition and efficacy in MPN models.
- Appeldoorn TYJ, Munnink THO, Morsink LM, et al. Pharmacokinetics and pharmacodynamics of ruxolitinib: a review. Clin Pharmacokinet. 2023;62(4):559–571. doi:10.1007/s40262-023-01225-7Comprehensive PK/PD review covering absorption, distribution, metabolism, drug interactions, and special populations.
- Chen X, Shi JG, Emm T, et al. Pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in renal and hepatic impairment patients. Clin Pharmacol Drug Dev. 2014;3(1):34–42. doi:10.1002/cpdd.72Key PK study establishing dose adjustments for patients with renal and hepatic impairment.
- Shi JG, Chen X, Emm T, et al. The effect of CYP3A4 inhibition or induction on the pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in healthy volunteers. J Clin Pharmacol. 2012;52(6):809–818. doi:10.1177/0091270011405663Clinical DDI study establishing the effects of ketoconazole (CYP3A4 inhibitor) and rifampicin (CYP3A4 inducer) on ruxolitinib exposure.