Frequency category of adverse drug reaction reported in MF patients in COMFORT-I and COMFORT-II¹

Adapted from JAKAVI® Summary of Product Characteristics.¹

*ADR derived from post-marketing experience.^1
†Frequency is based on new or worsened laboratory abnormalities compared to baseline.^1
‡Common Terminology Criteria for Adverse Events (CTCAE) version 3.0; grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening.^1
§Pancytopenia is defined as haemoglobin level <100 g/L, platelet count <100x10⁹/L, and neutrophil count <1.5x10⁹/L (or low white blood cell count of grade 2 if neutrophil count is missing), imultaneously in the same lab assessment.¹
 

ADR, adverse drug reaction; AE, adverse event; BAT, best available therapy; BCSH, British Committee for Standards in Haematology; COMFORT, Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment; CTCAE, common terminology criteria for adverse events; DNA, deoxyribonucleic acid; EPO, erythropoietin; ESA, erythropoietin-stimulating agents; ET, essential thrombocythaemia; GvHD, graft versus host disease; HBV, hepatitis B; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MF, myelofibrosis; NMSC, non-melanoma skin cancer; PML, progressive multifocal leukoencephalopathy; PV, polycythaemia vera; SmPC, summary of product characteristics; ULN, upper limit of normal.

Summary of the safety profile

• The most frequently reported adverse drug reactions were thrombocytopenia and anaemia¹

• Haematological adverse drug reactions (any CTCAE grade) included anaemia (83.8%), thrombocytopenia (80.5%) and neutropenia (20.8%)¹

• Anaemia, thrombocytopenia and neutropenia are dose-related effects¹

• The three most frequent non-haematological adverse drug reactions were bruising (33.3%), other bleeding (including epistaxis, post-procedural haemorrhage and haematuria) (24.3%) and dizziness (21.9%)¹

• Discontinuation due to adverse events, regardless of causality, was observed in 30.0% of patients¹

• The three most frequent non-haematological laboratory abnormalities identified as adverse reactions were increased alanine aminotransferase (40.7%), increased aspartate aminotransferase (31.5%) and hypertriglyceridaemia (25.2%). In Phase III clinical studies in MF, neither CTCAE grade 3 or 4 hypertriglyceridaemia or increased aspartate aminotransferase, nor CTCAE grade 4 increased alanine aminotransferase or hypercholesterolaemia were observed¹

Please refer to the JAKAVI (ruxolitinib) Summary of Product Characteristics for full safety information.¹

Contraindications¹

• Hypersensitivity to the active substance or to any of the excipients

• Pregnancy and lactation

Special warnings and precautions¹

Myelosuppression:
Treatment with JAKAVI® can cause haematological adverse drug reactions, including thrombocytopenia, anaemia and neutropenia. A complete blood count, including a white blood cell count differential, must be performed before initiating therapy with JAKAVI®. Treatment should be discontinued in patients with platelet count less than 50,000/mm³ or absolute neutrophil count less than 500/mm³.

It has been observed that MF patients with low platelet counts (<200,000/mm³) at the start of therapy are more likely to develop thrombocytopenia during treatment.


Thrombocytopenia is generally reversible and is usually managed by reducing the dose or temporarily withholding JAKAVI®. However, platelet transfusions may be required as clinically indicated.


Patients developing anaemia may require blood transfusions. Dose modifications or interruption for patients developing anaemia may also need to be considered.


Patients with a haemoglobin level below 10.0 g/dL at the beginning of the treatment have a higher risk of developing a haemoglobin level below 8.0 g/dL during treatment compared to patients with a higher baseline haemoglobin level (79.3% versus 30.1%). More frequent monitoring of haematology parameters and of clinical signs and symptoms of JAKAVI®-related adverse drug reactions is recommended for patients with baseline haemoglobin below 10.0 g/dL.


Neutropenia (absolute neutrophil count <500) was generally reversible and was managed by temporarily withholding JAKAVI®.


Complete blood counts should be monitored as clinically indicated and dose adjusted as required.

Infections:
Serious bacterial, mycobacterial, fungal, viral and other opportunistic infections have occurred in patients treated with JAKAVI®. Patients should be assessed for the risk of developing serious infections. Physicians should carefully observe patients receiving JAKAVI® for signs and symptoms of infections and initiate appropriate treatment promptly. Treatment with JAKAVI® should not be started until active serious infections have resolved.


Tuberculosis has been reported in patients receiving JAKAVI®. Before starting treatment, patients should be evaluated for active and inactive (‘latent’) tuberculosis, as per local recommendations. This can include medical history, possible previous contact with tuberculosis, and/or appropriate screening such as lung x-ray, tuberculin test and/or interferon-gamma release assay, as applicable. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.


Hepatitis B viral load (HBV-DNA titre) increases, with and without associated elevations in alanine aminotransferase and aspartate aminotransferase, have been reported in patients with chronic HBV infections taking JAKAVI®. It is recommended to screen for HBV prior to commencing treatment with JAKAVI®. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines.
 

Herpes zoster:
Physicians should educate patients about early signs and symptoms of herpes zoster, advising that treatment should be sought as early as possible.
 

Progressive multifocal leukoencephalopathy:
Progressive multifocal leukoencephalopathy (PML) has been reported with JAKAVI® treatment. Physicians should be particularly alert to symptoms suggestive of PML that patients may not notice (e.g., cognitive, neurological or psychiatric symptoms or signs). Patients should be monitored for any of these new or worsening symptoms or signs, and if such symptoms/signs occur, referral to a neurologist and appropriate diagnostic measures for PML should be considered. If PML is suspected, further dosing must be suspended until PML has been excluded.
 

Non-melanoma skin cancer:
Non-melanoma skin cancers (NMSCs), including basal cell, squamous cell, and Merkel cell carcinoma, have been reported in patients treated with ruxolitinib. Most of the MF and PV patients had histories of extended treatment with hydroxyurea and prior NMSC or pre-malignant skin lesions. A causal relationship to ruxolitinib has not been established. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
 

Lipid abnormalities/elevations:
Treatment with JAKAVI® has been associated with increases in lipid parameters including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. Lipid monitoring and treatment of dyslipidaemia according to clinical guidelines is recommended.
 

Special populations:
Renal impairment
The starting dose of JAKAVI® should be reduced in patients with severe renal impairment. For patients with end-stage renal disease on haemodialysis the starting dose should be based on platelet counts for MF patients, while the recommended starting dose is a single dose of 10 mg for PV patients. Subsequent doses (single dose of 20 mg or two doses of 10 mg given 12 hours apart in MF patients; single dose of 10 mg or two doses of 5 mg given 12 hours apart in PV patients) should be administered only on haemodialysis days following each dialysis session. Additional dose modifications should be made with careful monitoring of safety and efficacy.
 

Hepatic impairment
The starting dose of JAKAVI® should be reduced by approximately 50% in MF and PV patients with hepatic impairment. Further dose modifications should be based on the safety and efficacy of the medicinal product. In GvHD patients with hepatic impairment not related to GvHD, the starting dose of JAKAVI® should be reduced by approximately 50%.
 

Interactions:
If JAKAVI® is to be co-administered with strong CYP3A4 inhibitors in MF and PV patients or dual inhibitors of CYP3A4 and CYP2C9 enzymes (e.g. fluconazole) in MF, PV and GvHD patients, the unit dose of JAKAVI® should be reduced by approximately 50%, to be administered twice daily.


The concomitant use of cytoreductive therapies with JAKAVI® was associated with manageable cytopenias.
 

Withdrawal effects:
Following interruption or discontinuation of JAKAVI®, symptoms of MF may return over a period of approximately one week. There have been cases of patients discontinuing JAKAVI® who experienced severe adverse events, particularly in the presence of acute intercurrent illness. It has not been established whether abrupt discontinuation of JAKAVI® contributed to these events. Unless abrupt discontinuation is required, gradual tapering of the dose of JAKAVI® may be considered, although the utility of the tapering is unproven.
 

Excipients:
JAKAVI® contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.


This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
 

Please refer to the JAKAVI (ruxolitinib) Summary of Product Characteristics for further information.¹