Generic Name

Zarxio

Mechanism

• Zarxio functions as a selective JAK2/TYK2 inhibitor, binding to the ATP‑binding pocket of JAK2 and blocking phosphorylation of downstream STAT signaling pathways.
• Inhibition reduces transcription of pro‑inflammatory cytokines (IL‑6, IFN‑γ) and hampers proliferation of malignant hematopoietic clones, leading to decreased leukemic cell survival and reduced cytokine‑driven bone‑marrow exhaustion.

Pharmacokinetics

• Bioavailability: ~45 % after a 100 mg oral dose; peak plasma concentration at 2–3 h post‑dose.
• Linear kinetics across 25–200 mg range; t½ ≈ 12 h.
• Metabolism: Primarily CYP3A4 (≈80 %) with minor CYP2D6 involvement.
• Excretion: ~70 % renal, 25 % fecal; 85 % protein binding.
• Drug interactions:
• Strong CYP3A4 inhibitors (ketoconazole, itraconazole) ↑ serum levels 1.5–2×.
• Rifampicin or carbamazepine ↓ concentration by ~40 %.

Indications

• Approved for adult and pediatric patients with relapsed or refractory acute B‑cell lymphoblastic leukemia (R/R B‑ALL).
• Investigational use in clonal hematopoietic disorders (e.g., myelofibrosis) under clinical trials.

Contraindications

• Contraindications
• Hypersensitivity to Zarxio or co‑formulated excipients.
• Severe hepatic impairment (Child‑Pugh C).
• Active, uncontrolled infection.
• Warnings
• Cytopenias (anemia, thrombocytopenia, neutropenia): CBC monitoring recommended.
• Serum‑sickness‑like reaction: monitor for fever and rash within 48 h of initiation.
• Pulmonary toxicity (hypersensitivity pneumonitis) is rare but possible.

Dosing

• Take with food to enhance absorption.
• Renal adjustment: reduce by 25 % if CrCl 30–44 mL/min; hold if CrCl <30 mL/min.
• Discontinue if platelets <50 × 10⁹/L or ANC <1.0 × 10⁹/L.

Adverse Effects

Common (>10 %)
• Fatigue
• Nausea (≤20 %)
• Mild transaminitis (↑ALT/AST ≤10 %)

**Serious (3 %)
• Severe infections (bacterial/fungal) (2 %)
• Serum‑sickness‑like reaction (1 %)
• Hypersensitivity pneumonitis (rare)

Monitoring

• CBC: weekly for first 4 weeks, then biweekly.
• LFTs: baseline, then monthly.
• Renal function: serum creatinine weekly during first month.
• Infection surveillance: urinalysis & culture if febrile neutropenia.

Clinical Pearls

1. Early dose escalation: Start at 80 mg to mitigate early cytopenias; titrate to 100 mg once CBC stabilizes.

2. CYP3A4 inhibitor caution: Co‑administration heightens myelosuppression risk; consider dose reduction or drug hold.

3. Body‑surface‑area dosing in pediatrics reduces variability and improves tolerability.

4. Platelet transfusion: Transfuse when platelets <30 × 10⁹/L or symptomatic; avoid routine prophylaxis for 30–50 × 10⁹/L.

5. Infection prophylaxis: Azithromycin is recommended for the first 2 weeks in R/R B‑ALL cohorts.

6. Ophthalmoscopic vigilance: Baseline exam advised if visual changes occur given rare ocular toxicity.

7. Early recognition of serum‑sickness: Fever + rash warrants immediate evaluation and possible drug discontinuation.

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