Jakafi
Jakafi
Generic Name
Jakafi
Mechanism
* Inhibition of JAK1/2: Ruxolitinib competitively binds to the ATP‑binding site of JAK1 and JAK2, blocking phosphorylation of signal transducer and activator of transcription (STAT) proteins.
* Downregulation of cytokine signaling: Resultant suppression of the overactive JAK‑STAT pathway limits proliferation of malignant megakaryocytes and erythrocytosis, reduces splenomegaly, and improves constitutional symptoms.
* Selective potency: Higher affinity for JAK1 than JAK2 (≈10 : 1) → broad anti‑inflammatory effects with relatively lower myelosuppression compared to first‑generation JAK inhibitors.
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Pharmacokinetics
| Parameter | Details |
| Absorption | Oral tablet, peak plasma concentration within 1–2 h. Food increases Cmax by ≈20 %. |
| Distribution | Extensive tissue distribution; protein binding ~50 % (both albumin and alpha‑1‑acid glycoprotein). |
| Metabolism | Hepatic CYP3A4/5 major pathways; also metabolized by UGT1A9. Minor contribution from CYP2C8. |
| Elimination | ~15 % renal excretion of unchanged drug; rest as metabolites via biliary/fecal routes. |
| Half‑life | ~3 h (steady state: 15 h dosing). Steady state reached after 4–5 days. |
| Drug interactions | Strong CYP3A4 inhibitors (ketoconazole, clarithromycin) increase exposure; strong inducers (rifampin, carbamazepine) decrease it. Grapefruit juice *does not* have a major impact due to extensive intestinal metabolism. |
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Indications
* Myeloproliferative Neoplasms (MPNs)
* Primary Myelofibrosis (PMF) – symptomatic splenomegaly and constitutional symptoms.
* Secondary (post‑polycythemia vera or essential thrombocythemia) Myelofibrosis – symptomatic disease.
* Polycythemia Vera (PV) – phlebotomy‑refractory or splenomegaly‑associated disease.
*Approved dosing requires confirmation of JAK2V617F or CALR mutation status, generally not a strict requirement but helps guide therapy.*
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Contraindications
* Absolute contraindications
* Active bacterial, viral, or fungal infection.
* Known hypersensitivity to ruxolitinib or its excipients.
* Relative contraindications
* Severe hepatic impairment (Child‑Pugh C).
* Severe renal disease (creatinine clearance <30 mL/min).
* Pregnancy – Category D; avoid and use effective contraception.
* Breastfeeding – excretion in milk; contraindicated.
* Warnings/Precautions
* Myelosuppression – anemia, thrombocytopenia, neutropenia.
* Immunosuppression – opportunistic infections (TB reactivation).
* Infections – increased risk of pneumonia and urinary tract infections.
* Lung and liver toxicities – monitor for pulmonary infiltrates and hepatotoxicity.
* Lymphoproliferative disorders – limited long‑term data; monitor CBC/chemistry.
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Dosing
| Disease State | Initiative Dose | Maintenance Dose | Administration | Notes |
| PMF | 15 mg PO BID (12–15 mg BID in pts with platelet count 50–100 ×10⁶/L) | ≥12 mg BID | Oral tablets | Initiate 4–6 weeks, monitor CBC. Adjust +5 mg BID increments every 2–4 weeks. |
| Post‑PV/ET MF | Same as PMF | Same | Same | Similar titration. |
| PV (phlebotomy‑refractory) | 5–10 mg PO BID | Same | Same | Begin 2–4 weeks after phlebotomy; titrate to symptomatic relief. |
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• Dose adjustments for renal or hepatic impairment are recommended only in clinical trials; no official dose change guidelines exist.
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• Switch to a single daily dose only if the patient can tolerate; otherwise maintain BID dosing for optimal plasma concentration.
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• If grade ≥ 3 cytopenia develops, hold therapy until recovery; consider dose reduction on restart.
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Adverse Effects
| Category | Adverse Effects |
| Hematologic | Thrombocytopenia (up to 30 % ≥ grade 3), anemia, neutropenia |
| Infection | Bacterial (UTIs, cellulitis), viral (herpes zoster), opportunistic (TB, fungal) |
| GI | Nausea, diarrhea, vomiting (usually mild) |
| Pulmonary | Pneumonitis, pulmonary embolism (rare) |
| Dermatologic | Rash (rare), hyperpigmentation |
| Metabolic | Elevated triglycerides, mild hyperglycemia |
| Other | Headache, fatigue, dizziness, hypertension (secondary), GI bleeding (rare) |
*Serious adverse events (*SAEs*) include serious infections, severe cytopenias, and liver enzyme elevation >5× ULN. Monitor labs and treat promptly.*
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Monitoring
| Parameter | Frequency | Rationale |
| CBC (Hgb, WBC, Platelets) | Every 2 weeks until stable, then monthly | Detect cytopenias early |
| CMP (LFTs, electrolytes) | Every 4 weeks | Detect hepatotoxicity, renal changes |
| Renal function | Every 4 weeks | Dose adjustment, safety in CKD |
| Echocardiogram/Imaging | Baseline, then annually | Identify cardiac dysfunction |
| TB screening (IGRA/TST) | Baseline, annually | Prevent reactivation |
| Vaccinations | Prior to therapy (influenza, pneumococcal) | Reduce infection risk |
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Clinical Pearls
- Start Low, Go Slow: Use the lowest effective dose (15 mg BID) and titrate by 5 mg increments every 2–4 weeks to mitigate cytopenias.
- Food and Bioavailability: Ruxolitinib has modest food effects—take with or without food at consistent intervals to maintain steady plasma levels.
- CYP3A4 Interaction Matrix: Avoid concurrent strong CYP3A4 inducers (e.g., rifampin) and consider dose reduction if strong inhibitors are unavoidable.
- Pregnancy Guidance: Women of childbearing potential must use two effective contraception methods for one month before and throughout treatment; abruptly discontinue only if risk outweighs benefit.
- Long‑Term Outcome Signals: In the RESPONSE trial, Jakafi improved red cell transfusion independence but overall survival benefit remains unclear; real‑world data suggest durable splenomegaly reduction.
- Rebound Hematologic Risks: Discontinuation can precipitate a rapid rise in WBC/platelets—plan dose tapering in patients who require cessation.
- Patient Education: Emphasize infection monitoring and promptly report fevers, sore throats, or respiratory symptoms; consider prophylactic antivirals during high‑risk periods (e.g., winter flu season).
- Pulmonary Side‑Effect Surveillance: Sudden dyspnea or hypoxia should prompt chest imaging; early detection of ruxolitinib‑associated pneumonitis improves outcomes.
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• *The information above reflects current FDA‑approved indications and clinical practice guidelines as of 2026. Always refer to updated product labels and institutional protocols when prescribing Jakafi.*