1. Mechanism of Action (MOA):

• Zylexx contains the active ingredient Ruxolitinib, which is a Janus Kinase (JAK) Inhibitor.
• Ruxolitinib selectively inhibits JAK1 and JAK2, enzymes involved in the signaling of various cytokines and growth factors that play critical roles in immune function and hematopoiesis (blood cell production).
• By inhibiting JAK1 and JAK2, Zylexx modulates immune responses and reduces inflammation, making it effective in the treatment of conditions like myelofibrosis and polycythemia vera.
• It helps reduce symptoms like splenomegaly (enlarged spleen), pruritus (itching), and bone marrow abnormalities, as well as preventing the progression of myelofibrosis and regulating blood cell production.

2. Indications:

Zylexx (Ruxolitinib 150 mg) is indicated for the treatment of the following conditions:

• Myelofibrosis (MF): A type of bone marrow cancer that causes abnormal blood cell production, leading to symptoms such as splenomegaly, anemia, and fatigue.
• Polycythemia Vera (PV): A blood disorder where the bone marrow produces excessive red blood cells, causing increased blood volume and viscosity, which can lead to complications such as blood clots.
• Graft-Versus-Host Disease (GVHD): A condition that occurs after a bone marrow transplant, where the transplanted immune cells attack the recipient’s tissues. Zylexx is used in steroid-refractory cases of GVHD.

3. Dosage:

• Myelofibrosis:
  • Initial dose: 20 mg twice daily.
  • Dose adjustments are based on patient tolerance and response. For patients with a suboptimal response, the dose may be increased, but not to exceed 25 mg twice daily.
• Polycythemia Vera:
  • Initial dose: 10 mg twice daily.
  • Dosing may be adjusted based on hematocrit levels and platelet counts.
• Graft-Versus-Host Disease (GVHD):
  • Initial dose: 5 mg twice daily.
  • The dose may be adjusted based on response and side effects.
• Dosage adjustments:
  • In cases of renal impairment, particularly in moderate-to-severe renal dysfunction, the dose may need to be reduced.
  • For patients with hepatic impairment, dose adjustments are required (reduce dose for Child-Pugh B or C).
• Administration:
  • Zylexx should be taken orally with or without food.
  • Swallow tablets whole; do not crush or chew.

4. Side Effects:

Common side effects:

• Anemia: Decreased red blood cell count, leading to fatigue and weakness.
• Thrombocytopenia: Low platelet count, increasing the risk of bleeding or bruising.
• Headache.
• Diarrhea, nausea, or constipation.
• Fatigue and dizziness.

Serious side effects:

• Infections: Risk of severe bacterial, viral, or fungal infections due to immune suppression.
• Bone marrow suppression: Significant neutropenia (low white blood cell count) or thrombocytopenia (low platelet count), requiring frequent monitoring.
• Liver toxicity: Increased liver enzymes or signs of liver dysfunction. Liver function tests should be monitored regularly.
• Gastrointestinal bleeding: May occur in patients with severe thrombocytopenia.
• Tumor lysis syndrome: A potential risk, particularly when used in patients with hematologic malignancies, as rapid cell turnover can lead to this condition.
• Skin cancer: Prolonged use may increase the risk of skin cancers, including non-melanoma skin cancer.

5. Precautions:

• Infections: Zylexx can increase the risk of serious infections due to immune suppression. Patients should be screened for tuberculosis (TB) before starting treatment, and appropriate prophylactic treatment should be considered for TB-positive patients.
• Bone marrow suppression: Monitor for anemia, thrombocytopenia, and neutropenia. Regular blood tests are recommended during treatment, particularly in the first few months.
• Liver function: Periodic monitoring of liver function tests is recommended. Dose reduction may be required in patients with liver enzyme elevations or existing hepatic conditions.
• Renal impairment: Use with caution in patients with moderate-to-severe renal impairment. Dose adjustments may be necessary.
• Vaccination: Live vaccines should be avoided during treatment, as Zylexx can suppress the immune system and interfere with the effectiveness of live vaccines.
• Cancer risk: Prolonged treatment may increase the risk of non-melanoma skin cancers and lymphomas. Patients should undergo regular dermatologic exams.
• Pregnancy and breastfeeding:
  • Pregnancy: Zylexx is Category C in pregnancy. It should only be used during pregnancy if the benefits outweigh the risks.
  • Breastfeeding: It is not recommended to breastfeed while on Zylexx, as it may pass into breast milk.

6. Contraindications (CI):

• Hypersensitivity: Known allergy or hypersensitivity to Ruxolitinib or any of the tablet’s excipients.
• Severe infections: Contraindicated in patients with active systemic infections (e.g., tuberculosis, fungal infections, or bacterial infections).
• Severe hepatic impairment: Contraindicated in patients with Child-Pugh Class C liver dysfunction.

Pharmacist Related Data

Chemical Name and Formula:

• Chemical Name: (2S)-1-[(4-Methyl-2-pyrimidinyl)methyl]-3-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine
• Molecular Formula: C17H18N6
• Molecular Weight: 306.37 g/mol

Half-Life:

• Terminal Half-Life: Approximately 3 hours.
  • This refers to the time it takes for the concentration of the drug in the bloodstream to reduce by half.

Metabolism:

• Ruxolitinib is primarily metabolized in the liver by the cytochrome P450 (CYP) enzyme system, especially CYP3A4.
• It is metabolized into inactive metabolites, primarily by oxidation and N-demethylation.
• The major metabolite, M19, is also pharmacologically inactive.
• Excretion:
  • Ruxolitinib is excreted in both urine and feces.
  • Approximately 74% of the dose is eliminated through feces, and 22% is eliminated via urine.

Drug Interactions:

Drug Interactions with Medicines:

1. CYP3A4 Inhibitors:
   • Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) may increase Ruxolitinib plasma concentrations, necessitating dose adjustments.
2. CYP3A4 Inducers:
   • Strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin) may decrease the efficacy of Ruxolitinib, leading to reduced plasma concentrations.
3. Anticoagulants:
   • Ruxolitinib may increase the risk of bleeding, particularly when used in combination with antiplatelet agents (e.g., aspirin, clopidogrel) or anticoagulants like warfarin. Close monitoring of blood coagulation parameters is recommended.
4. Immunosuppressants:
   • The immunosuppressive effect of Ruxolitinib can be potentiated when used with other immunosuppressive drugs (e.g., cyclosporine, tacrolimus), increasing the risk of infections.
5. Live Vaccines:
   • Live vaccines should be avoided while on Ruxolitinib due to the potential for immune suppression and reduced vaccine efficacy.

Drug Interactions with Food:

• Food: There are no significant food interactions with Ruxolitinib, and it can be taken with or without food. However, it is advisable to take the tablets at the same time each day for consistency.
• Grapefruit: Grapefruit and grapefruit juice should be avoided as they can increase the plasma concentration of Ruxolitinib due to their inhibition of CYP3A4, the enzyme responsible for metabolizing the drug.

Pharmacodynamics:

• Ruxolitinib is a selective inhibitor of Janus Kinases (JAK1 and JAK2), which play a crucial role in the signaling pathways of various cytokines and growth factors involved in hematopoiesis (blood cell production) and immune system regulation.
• By inhibiting JAK1 and JAK2, Ruxolitinib reduces cytokine signaling, leading to a reduction in inflammation and control over excessive blood cell production.
• It is particularly useful in myelofibrosis and polycythemia vera, where it helps reduce symptoms like splenomegaly (enlarged spleen), pruritus (itching), and fatigue. It also helps manage complications related to graft-vs-host disease (GVHD) following bone marrow transplants.
• Clinical Effect: The drug helps in improving quality of life and reducing disease progression by regulating cytokine production and hematopoietic function.

Pharmacokinetics:

• Absorption:
  • Ruxolitinib is well absorbed after oral administration, with peak plasma concentration typically occurring within 2 hours.
  • It has an oral bioavailability of approximately 95%.
• Distribution:
  • It is highly protein-bound (~ 97% bound to plasma proteins), primarily to albumin.
  • The volume of distribution (Vd) is about 100 L, indicating wide tissue distribution.
• Metabolism:
  • As mentioned, Ruxolitinib is metabolized by CYP3A4 and CYP3A5 enzymes in the liver, forming mainly inactive metabolites.
  • The half-life of Ruxolitinib is about 3 hours, but this may vary with dosing adjustments.
• Excretion:
  • Ruxolitinib and its metabolites are excreted primarily through feces (approximately 74% of the dose) and to a lesser extent in urine (approximately 22% of the dose).
  • Renal impairment does not significantly affect the pharmacokinetics, but hepatic impairment (especially severe) may require dose adjustments.
• Steady-State:
  • Steady-state plasma concentrations are generally achieved within 3 to 5 days of daily dosing.