RUXOLITINIB

Ruxolitinib treatment should only be initiated by a physician experienced in the administration of anti-cancer medicinal products. A complete blood cell count, including a white blood cell count differential, must be performed before initiating therapy with Ruxolitinib.

4). Posology Starting dose Myelofibrosis (MF) The recommended starting dose of Ruxolitinib in myelofibrosis (MF) is based on platelet counts (see Table 1): Table 1 Starting doses in myelofibrosis Platelet count Starting dose Greater than 200,000/mm3 20 mg orally twice daily 100,000 to 200,000/mm3 15 mg orally twice daily 75,000 to less than 100,000/mm3 10 mg orally twice daily 50,000 to less than 75,000/mm3 5 mg orally twice daily Polycythaemia vera (PV) The recommended starting dose of Ruxolitinib in PV is 10 mg given orally twice daily.

Graft versus host disease (GvHD) The recommended starting dose of Ruxolitinib in acute and chronic graft versus host disease (GvHD) is based on age (see Table 2): Table 2 Starting doses in acute and chronic graft versus host disease Age group Starting dose 12 years old and above 10 mg orally twice daily 6 years to less than 12 years old 5 mg orally twice daily 2 years to less than 6 years old 4 mg/m2 orally twice daily These starting doses in GvHD can be administered using either the tablet for patients at or above 6 years old who can swallow tablets or the oral solution for patients under 12 years old.

Dose modifications Doses may be titrated based on efficacy and safety. Myelofibrosis and polycythaemia vera If efficacy is considered insufficient and blood counts are adequate, doses may be increased by a maximum of 5 mg twice daily, up to the maximum dose of 25 mg twice daily.

The starting dose should not be increased within the first four weeks of treatment and thereafter no more frequently than at 2-week intervals. Treatment should be discontinued for platelet counts less than 50 000/mm3 or absolute neutrophil counts less than 500/mm3.

In PV, treatment should also be interrupted when haemoglobin is below 8 g/dl. After recovery of blood counts above these levels, dosing may be re-started at 5 mg twice daily and gradually increased based on careful monitoring of complete blood cell count, including a white blood cell count differential.

Dose reductions should be considered if the platelet count decreases during treatment as outlined in Table 3, with the goal of avoiding dose interruptions for thrombocytopenia. Table 3 Dosing recommendation for thrombocytopenia Dose at time of platelet decline 25 mg twice daily 20 mg twice daily 15 mg twice daily 10 mg twice daily 5 mg twice daily Platelet count New dose 100,000 to <125,000/mm3 20 mg twice daily 15 mg twice daily No change No change No change 75,000 to <100,000/mm3 10 mg twice daily 10 mg twice daily 10 mg twice daily No change No change 50,000 to <75,000/mm3 5 mg twice daily 5 mg twice daily 5 mg twice daily 5 mg twice daily No change Less than 50,000/mm3 Hold Hold Hold Hold Hold In PV, dose reductions should also be considered if haemoglobin decreases below 12 g/dl and is recommended if it decreases below 10 g/dl.

Summary of the safety profile Myelofibrosis The most frequently reported adverse drug reactions were thrombocytopenia and anaemia. 8%). Anaemia, thrombocytopenia and neutropenia are dose-related effects. 9%). 2%). In phase 3 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 observed.

0% of patients. Polycythaemia vera The most frequently reported adverse drug reactions were anaemia and increased alanine aminotransferase. 3%). 6% of the patients, respectively. 9%). 7%). No CTCAE grade 4 increased alanine aminotransferase or hypercholesterolaemia, and one CTCAE grade 4 increased aspartate aminotransferase were observed.

4% of patients. Acute GvHD REACH 1 The most frequently reported adverse drug reactions were anaemia, thrombocytopenia, and neutropenia. 2%). 03). 2% of patients, respectively. 5%). 7%). The majority were of grade 1 and 2. 4% of patients REACH 2 The most frequently reported adverse drug reactions (>50%) in REACH2 (adult and adolescent patients) were thrombocytopenia, anaemia neutropenia, increased alanine aminotransferase and increased aspartate aminotransferase.

The most frequently reported adverse drug reactions (>50%) in the pool of paediatric patients (adolescents from REACH2 and paediatric patients from REACH4) were anaemia, neutropenia, increased alanine aminotransferase, hypercholesterolaemia and thrombocytopenia.

0%), respectively. 8% of paediatric patients. 4% of patients in the paediatric pool, respectively. 0% of patients in the paediatric pool, respectively. 9%), respectively. 2%), respectively. 3% of patients in the paediatric pool. 6% of patients in the paediatric pool.

Chronic GvHD The most frequently reported adverse drug reactions (>50%) in REACH3 (adult and adolescent patients) were anaemia, hypercholesterolemia and increased aspartate aminotransferase. The most frequently reported adverse drug reactions (>50%) in the pool of paediatric patients (adolescents from REACH3 and paediatric patients from REACH5) were neutropenia, hypercholesterolaemia and increased alanine aminotransferase.

Myelosuppression Treatment with Ruxolitinib 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 Ruxolitinib.

2). 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. 8). 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. 1%). 0 g/dl. 8). 8). Infections Serious bacterial, mycobacterial, fungal, viral and other opportunistic infections have occurred in patients treated with Ruxolitinib.

Patients should be assessed for the risk of developing serious infections. Physicians should carefully observe patients receiving Ruxolitinib for signs and symptoms of infections and initiate appropriate treatment promptly. Treatment with Ruxolitinib should not be started until active serious infections have resolved.

Tuberculosis has been reported in patients receiving Ruxolitinib. 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 Ruxolitinib.

1. Pregnancy and lactation.