JAKAVI

Jakavi 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 Jakavi.

4). 2 Posology The recommended starting dose of Jakavi in acute and chronic graft versus host disease (GvHD) is based on age (see Table 1): Table 1 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 The patient should drink water after taking the oral solution to ensure the medicinal product has been completely swallowed.

If the patient is unable to swallow and has a nasogastric or gastric tube in situ, the Jakavi oral solution can be administered via a nasogastric or gastric feeding tube of size French 4 (or greater) and not exceeding 125 cm in length.

The tube should be flushed with water after delivering the oral solution. Volume of ruxolitinib to be administered when using a dose of 4 mg/m2 is presented in Table 2. 5 Dose modifications Doses may be titrated based on efficacy and safety.

Dose reductions and temporary interruptions of treatment may be needed in GvHD-patients with thrombocytopenia, neutropenia, or elevated total bilirubin after standard supportive therapy including growth-factors, anti-infective therapies and transfusions.

The recommended starting dose for GvHD patients should be reduced by approximately 50% to be administered twice daily. In patients who are 3 unable to tolerate Jakavi at the reduced dose level, treatment should be interrupted. Detailed dosing recommendations are provided in Table 3.

Table 3 Dosing recommendations for GvHD patients with thrombocytopenia, neutropenia, or elevated total bilirubin Laboratory parameter Dosing recommendation Platelet count <20,000/mm3 Reduce Jakavi by one dose level. If platelet count ≥20,000/mm3 within seven days, dose may be increased to initial dose level, otherwise maintain reduced dose.

Platelet count <15,000/mm3 Hold Jakavi until platelet count ≥20,000/mm3, then resume at one lower dose level. Absolute neutrophil count (ANC) ≥500/mm3 to <750/mm3 Reduce Jakavi by one dose level. Resume at initial dose level if ANC >1,000/mm3.

Absolute neutrophil count <500/mm3 Hold Jakavi until ANC >500/mm3, then resume at one lower dose level. If ANC >1,000/mm3, dosing may resume at initial dose level. 0 x ULN. 0 x ULN. 0 x ULN dosing may resume at current dose. 0 x ULN after 14 days, resume at one lower dose level.

0 x ULN, then resume at one lower dose level. 0 x ULN. g. 5). The concomitant use of ruxolitinib with fluconazole doses greater than 200 mg daily should be avoided. g. twice a week) of haematology parameters and of clinical signs and symptoms of ruxolitinib-related adverse drug reactions is recommended while on strong CYP3A4 inhibitors or dual inhibitors of CYP2C9 and CYP3A4 enzymes.

Special populations Renal impairment No specific dose adjustment is needed in patients with mild or moderate renal impairment. The recommended starting dose for GvHD patients with severe renal impairment (creatinine clearance less than 30 ml/min) should be reduced by approximately 50% to be administered twice daily.

Patients should be carefully monitored with regard to safety and efficacy during ruxolitinib treatment. There are no data for GvHD patients with end-stage renal disease (ESRD). 4 Hepatic impairment Patients diagnosed with hepatic impairment while receiving ruxolitinib should have complete blood counts, including a white blood cell count differential, monitored at least every one to two weeks for the first 6 weeks after initiation of therapy with ruxolitinib and as clinically indicated thereafter once their liver function and blood counts have been stabilised.

Ruxolitinib dose can be titrated to reduce the risk of cytopenia. 2). In patients with GvHD liver involvement and an increase of total bilirubin to >3 x ULN, blood counts should be monitored more frequently for toxicity and a dose reduction by one dose level may be considered.

Paediatric population The safety and efficacy of Jakavi in paediatric patients have been established in GvHD based on clinical studies (see section […]

Summary of the safety profile 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.

2%) respectively. 0% of patients in the paediatric pool. 1% of patients in the paediatric pool, respectively. 1% of patients in the paediatric pool, respectively. 2%), respectively. 9%). 5%). 5% of patients in the paediatric pool. Tabulated list of adverse drug reactions from clinical studies The safety of Jakavi in acute GvHD patients was evaluated in the phase 2 study REACH1 and in the phase 2 study REACH4.

, including data from 71 patients treated with Jakavi, and the phase 3 study 12 REACH2, including data from 201 patients ≥12 years of age initially randomised to Jakavi (n=152) and patients who received Jakavi after crossing over from the best available therapy BAT arm (n=49).

9 weeks). 1 weeks). […]

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.

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 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. 6 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. , 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. 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. Major adverse cardiac events (MACE) In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years of age and older with at least one additional cardiovascular risk factor, a higher rate of MACE, defined as cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke, was observed with tofacitinib compared to tumour necrosis factor (TNF) inhibitors.

MACE have been reported in patients receiving Jakavi. Prior to initiating or continuing therapy with Jakavi, the benefits and risks for the individual patient should be considered particularly in patients 65 years of age and older, patients who are current or past long-time smokers, and patients with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors.

Thrombosis In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years of age and older with at least one additional cardiovascular risk factor, a dose dependent higher rate of venous thromboembolic events (VTE) including deep venous thrombosis (DVT) and pulmonary embolism (PE) was observed with tofacitinib compared to TNF inhibitors.

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving Jakavi. In patients with MF and PV treated with Jakavi in clinical studies, the rates of thromboembolic events were similar in Jakavi and control-treated patients.

4 “Major adverse cardiovascular events (MACE)”). Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately. Second primary malignancies In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years of age and older with at least one additional cardiovascular risk factor, a higher rate of malignancies, particularly lung […]

1. Pregnancy and lactation. 5