Usage
Ruxolitinib is prescribed for the treatment of:
- Myelofibrosis: A bone marrow disorder that disrupts the body’s normal production of blood cells. Ruxolitinib helps reduce enlarged spleen size and alleviate myelofibrosis-related symptoms. It is indicated for intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis.
- Polycythemia Vera: A type of blood cancer that causes the bone marrow to make too many red blood cells. It may also result in an overproduction of white blood cells and platelets. Ruxolitinib is used to treat polycythemia vera when patients have not responded adequately to or cannot tolerate hydroxyurea.
- Steroid-Refractory Acute and Chronic Graft-versus-Host Disease (GVHD): A complication that can occur after a stem cell or bone marrow transplant where the donated cells attack the recipient’s body. Ruxolitinib is used in adults and children 12 years and older when GVHD does not respond to steroid treatment.
Pharmacological Classification: Janus kinase (JAK) 1 and JAK2 inhibitor.
Mechanism of Action: Ruxolitinib inhibits JAK1 and JAK2, which are enzymes that play a crucial role in signaling pathways involved in inflammation, immune response, and blood cell production. By inhibiting these enzymes, Ruxolitinib helps reduce the abnormal cell growth and activity seen in myelofibrosis, polycythemia vera, and GVHD.
Alternate Names
- International Nonproprietary Name (INN): Ruxolitinib
- Brand Names: Jakafi®, Jakavi®
How It Works
Pharmacodynamics: Ruxolitinib primarily works by inhibiting JAK1 and JAK2, thereby reducing the activity of signaling pathways that drive the abnormal blood cell production and inflammatory processes in myelofibrosis, polycythemia vera, and GVHD. It effectively reduces splenomegaly (enlarged spleen) and disease-related symptoms.
Pharmacokinetics:
- Absorption: Orally administered Ruxolitinib is rapidly absorbed, reaching peak plasma concentrations within approximately one hour. Food does not significantly affect its absorption.
- Metabolism: Primarily metabolized by the liver enzyme CYP3A4, with minor contributions from CYP2C9.
- Elimination: Excreted mainly through urine (70%) and feces (25%). Its half-life is approximately 3 hours.
Mode of Action: Ruxolitinib binds to the ATP-binding sites of JAK1 and JAK2, inhibiting their kinase activity. This blocks the downstream signaling pathways that rely on these enzymes, ultimately suppressing the production of cytokines and growth factors that contribute to myelofibrosis, polycythemia vera, and GVHD.
Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Ruxolitinib inhibits JAK1 and JAK2 enzyme activity.
Elimination Pathways: Primarily hepatic metabolism via CYP3A4 and CYP2C9, with subsequent renal and fecal excretion.
Dosage
Standard Dosage
Adults:
-
Myelofibrosis: Starting dose is based on platelet count:
- Platelets > 200 x 109/L: 20 mg orally twice daily.
- Platelets 100-200 x 109/L: 15 mg orally twice daily.
- Platelets 50-<100 x 109/L: 5 mg orally twice daily.
-
Polycythemia Vera: Starting dose is 10 mg orally twice daily.
-
GVHD: Starting dose is 5 mg orally twice daily for patients aged 12 years and older. The dose may be titrated based on response and tolerability up to a maximum of 25 mg twice daily (for myelofibrosis and polycythemia vera).
Children:
- GVHD (12 years and older): 5 mg twice daily. Dosing for younger than 12 with GVHD should be based on body surface area.
- Myelofibrosis and Polycythemia Vera: Use and dose must be determined by the doctor for children younger than 12.
Special Cases:
- Elderly Patients: No specific dose adjustments are recommended, but careful monitoring is advised.
- Patients with Renal Impairment: Dose reduction (by about 50%) is recommended for patients with moderate to severe renal impairment.
- Patients with Hepatic Dysfunction: Dose reduction (by about 50%) is recommended for patients with hepatic impairment.
- Patients with Comorbid Conditions: Careful monitoring and dose adjustments may be necessary for patients with diabetes, cardiovascular disease, or other relevant conditions.
Clinical Use Cases Ruxolitinib’s primary clinical uses are for myelofibrosis, polycythemia vera, and GVHD. It is not typically used in settings like intubation, surgical procedures, mechanical ventilation, ICU, or general emergency situations (e.g., status epilepticus, cardiac arrest).
Dosage Adjustments
Dose modifications may be necessary based on patient response, tolerability, blood counts (platelets, neutrophils), and other factors like renal or hepatic impairment, drug interactions, and specific comorbid conditions. Monitoring of complete blood counts and other relevant laboratory parameters is crucial for adjusting the dosage effectively.
Side Effects
Common Side Effects
- Thrombocytopenia (low platelet count)
- Anemia (low red blood cell count)
- Bruising
- Dizziness
- Headache
- Diarrhea
- Constipation
- Nausea
- Increased cholesterol level
- Weight Gain
Rare but Serious Side Effects
- Serious infections
- Progressive multifocal leukoencephalopathy (PML)
- Tuberculosis (TB) reactivation
- Shingles (herpes zoster) reactivation
Long-Term Effects
- Increased risk of non-melanoma skin cancer
- Lipid elevations
- Potential for hepatic or renal dysfunction with prolonged use
Adverse Drug Reactions (ADR)
Clinically significant ADRs requiring immediate intervention include severe thrombocytopenia, anemia, neutropenia (low neutrophil count), serious infections, and signs of PML or TB.
Contraindications
- Hypersensitivity to ruxolitinib or any of its components.
- Pregnancy and breastfeeding.
Drug Interactions
Ruxolitinib is primarily metabolized by CYP3A4 and CYP2C9. Therefore, interactions can occur with:
- Strong CYP3A4 Inhibitors: (e.g., ketoconazole, clarithromycin, grapefruit juice) can increase Ruxolitinib levels and require dose reduction.
- Strong CYP3A4 Inducers: (e.g., rifampin, phenytoin, St. John’s wort) can decrease Ruxolitinib levels and may necessitate dose adjustments.
- Dual CYP3A4 and CYP2C9 Inhibitors: (e.g., fluconazole) can also significantly increase Ruxolitinib levels and necessitate dose adjustments.
- Other Medications: Ruxolitinib may interact with other drugs, such as those affecting heart rate or prolonging PR interval (e.g. antiarrhythmics, beta-blockers).
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Ruxolitinib is contraindicated during pregnancy due to potential fetal risks. Effective contraception is necessary during treatment.
- Breastfeeding: Ruxolitinib is contraindicated during breastfeeding as it may be excreted in breast milk and potentially harm the infant.
Drug Profile Summary
- Mechanism of Action: JAK1 and JAK2 inhibitor.
- Side Effects: Common: Thrombocytopenia, anemia, bruising, dizziness, headache. Serious: Infections, PML.
- Contraindications: Hypersensitivity, pregnancy, breastfeeding.
- Drug Interactions: Strong CYP3A4 inhibitors/inducers, dual CYP3A4/2C9 inhibitors.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Based on indication and platelet count; adjusted for renal/hepatic impairment.
- Monitoring Parameters: Complete blood count (CBC), liver function tests (LFTs), renal function tests, lipid profile.
Precautions
- General Precautions: Assess for infections, bleeding risks, renal/hepatic function before and during treatment. Monitor for skin cancer, lipid abnormalities.
- Specific Populations:
- Pregnant Women: Contraindicated.
- Breastfeeding Mothers: Contraindicated.
- Children & Elderly: Careful monitoring recommended.
- Menstruating Individuals: No specific precautions identified.
- Lifestyle Considerations: Smoking cessation is highly encouraged. Advise on limiting alcohol consumption and interactions with food and other medications. Driving restrictions may be necessary if dizziness occurs.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ruxolitinib?
A: The Ruxolitinib dosage depends on the indication and platelet count. Refer to the detailed dosage guidelines provided above for specific recommendations for myelofibrosis, polycythemia vera, and GVHD, including adjustments for renal/hepatic impairment and special patient populations.
Q2: What are the most common side effects of Ruxolitinib?
A: The most frequent side effects include thrombocytopenia, anemia, bruising, dizziness, headache, diarrhea, constipation, nausea, elevated cholesterol, and weight gain.
Q3: How does Ruxolitinib work?
A: Ruxolitinib inhibits JAK1 and JAK2, blocking intracellular signaling pathways that contribute to myeloproliferative neoplasms and inflammatory responses.
Q4: What are the serious risks associated with Ruxolitinib?
A: Serious risks include severe infections, PML, TB reactivation, and an increased risk of non-melanoma skin cancer.
Q5: Is Ruxolitinib safe during pregnancy and breastfeeding?
A: No. Ruxolitinib is contraindicated during pregnancy and breastfeeding due to potential harm to the fetus or infant.
Q6: Which drugs should be avoided while taking Ruxolitinib?
A: Avoid strong CYP3A4 inhibitors and inducers, and dual CYP3A4/2C9 inhibitors, as they can significantly alter Ruxolitinib levels. Consult a comprehensive drug interaction checker for a full list of potential drug interactions.
Q7: What are the key monitoring parameters for patients on Ruxolitinib?
A: Monitor complete blood count (CBC), including platelet and neutrophil counts, liver function tests (LFTs), renal function tests, lipid profile, and watch for signs and symptoms of infection. Regular skin examinations are also recommended.
Q8: What should be done if a patient misses a dose of Ruxolitinib?
A: If a dose is missed, the patient should take the next scheduled dose as prescribed and should not double the dose.
Q9: When should Ruxolitinib be discontinued?
A: Ruxolitinib should be discontinued if the patient experiences severe side effects, or if there is no improvement in spleen size or symptom control after six months of therapy for myelofibrosis. The decision to discontinue should be based on a thorough risk-benefit assessment.
