Introduction
Ojjaara (momelotinib) is an oral Janus kinase (JAK) inhibitor approved for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post-polycythemia vera and post-essential thrombocythemia), in adults with anemia. It represents a significant advancement in myelofibrosis management by addressing both the constitutional symptoms and the anemia commonly associated with this condition.
Mechanism of Action
Momelotinib is a small molecule inhibitor that targets Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2). It demonstrates inhibitory activity against ACVR1 (activin A receptor type I), which is involved in hepcidin production. By inhibiting JAK1 and JAK2, momelotinib reduces the inflammatory cytokines and abnormal signaling responsible for myelofibrosis symptoms. Through ACVR1 inhibition, it decreases hepcidin production, improving iron availability and potentially ameliorating anemia associated with myelofibrosis.
Indications
- Treatment of intermediate or high-risk myelofibrosis in adults, including:
- Primary myelofibrosis - Secondary myelofibrosis (post-polycythemia vera) - Secondary myelofibrosis (post-essential thrombocythemia)
- Specifically indicated for patients with anemia
Dosage and Administration
Recommended dosage: 200 mg orally once daily with or without food Dose modifications:- Renal impairment:
- Mild to moderate (eGFR 30-89 mL/min): No dose adjustment required - Severe (eGFR 15-29 mL/min): Reduce to 100 mg once daily - End-stage renal disease (eGFR <15 mL/min): Not recommended
- Hepatic impairment:
- Mild (Child-Pugh A): No dose adjustment required - Moderate to severe (Child-Pugh B or C): Not recommended
Administration:- Swallow tablets whole with water
- Do not crush, chew, or split tablets
- If a dose is missed, take as soon as remembered unless it is within 12 hours of the next dose
Pharmacokinetics
Absorption: Median Tmax is approximately 1-4 hours post-dose. Food does not significantly affect absorption. Distribution: Mean apparent volume of distribution is approximately 119 L. Protein binding is approximately 97%. Metabolism: Primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8. The major circulating metabolite is M21 (formed by CYP3A4), which is pharmacologically active. Elimination: Mean terminal half-life is approximately 4-5 hours. Approximately 60% of the dose is excreted in feces (44% as unchanged drug) and 30% in urine (<1% as unchanged drug).Contraindications
- Hypersensitivity to momelotinib or any component of the formulation
- Concomitant use with strong CYP3A4 inhibitors in patients with severe renal impairment
Warnings and Precautions
Thrombocytopenia: Ojjaara can cause thrombocytopenia. Monitor platelet counts before initiation and regularly during treatment. Manage with dose modifications or interruptions. Anemia: May cause or worsen anemia. Monitor hemoglobin before initiation and regularly during treatment. Hepatotoxicity: May cause liver enzyme elevations. Monitor liver function tests before initiation and periodically during treatment. Infections: Serious bacterial, mycobacterial, fungal, and viral infections may occur. Monitor for signs and symptoms of infection during treatment. Malignancy: JAK inhibitors may increase the risk of malignancies. Major Adverse Cardiovascular Events: Increased risk of major adverse cardiovascular events has been observed with JAK inhibitors. Thrombosis: Increased risk of thrombosis, including arterial and venous thrombosis. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception.Drug Interactions
Strong CYP3A4 Inhibitors: Concomitant use may increase momelotinib exposure. Avoid concomitant use with strong CYP3A4 inhibitors. If unavoidable, reduce Ojjaara dose to 100 mg once daily. Strong CYP3A4 Inducers: Concomitant use may decrease momelotinib exposure. Avoid concomitant use with strong CYP3A4 inducers. Gastric Acid Reducing Agents: Proton pump inhibitors may decrease momelotinib exposure. Separate administration by at least 2 hours.Adverse Effects
Most common adverse reactions (≥10%):- Thrombocytopenia
- Hemorrhage
- Bacterial infection
- Fatigue
- Dizziness
- Diarrhea
- Nausea
- Thrombocytopenia
- Hemorrhage
- Bacterial infection
- Herpes zoster
- Sepsis
- Acute kidney injury
- Hepatic failure
Monitoring Parameters
- Complete blood count with differential (baseline, every 2 weeks for first 3 months, then monthly)
- Liver function tests (baseline and periodically)
- Signs and symptoms of infection
- Signs and symptoms of thrombosis
- Cardiovascular status
- Renal function
Patient Education
- Take Ojjaara exactly as prescribed
- Report signs of infection (fever, chills, body aches)
- Report unusual bleeding or bruising
- Report symptoms of thrombosis (swelling, pain, redness in limbs, shortness of breath)
- Use effective contraception during treatment and for 1 week after final dose
- Inform all healthcare providers about Ojjaara use
- Do not stop treatment without consulting your healthcare provider
- Store at room temperature in original container
References
1. FDA prescribing information: Ojjaara (momelotinib) tablets 2. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naïve Patients With Myelofibrosis. J Clin Oncol. 2017;35(34):3844-3850. 3. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018;5(2):e73-e81. 4. Verstovsek S, Mesa RA, Salama ME, et al. A phase 1 study of the Janus kinase 2 inhibitor momelotinib in patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis. Leuk Lymphoma. 2017;58(10):2382-2389. 5. Asshoff M, Petzer V, Warr MR, et al. Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents. Blood. 2017;129(13):1823-1830.