Posology : מינונים

4.2     Posology and method of administration

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.

Complete blood count, including a white blood cell count differential, should be monitored every 2-4 weeks until Jakavi doses are stabilised, and then as clinically indicated (see section 4.4).

Posology

Starting dose
The recommended starting dose of Jakavi 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 
The recommended starting dose of Jakavi in Polycythemia Vera (PV) is 10 mg given orally twice daily.


The recommended starting dose of Jakavi in acute and chronic graft versus host disease (GvHD) is 10 mg given orally twice daily. Jakavi can be added to the continued use of corticosteroids and/or calcineurin inhibitors (CNIs).


JAK API May24 V7                                                               EU SmPC April 2024 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 2, with the goal of avoiding dose interruptions for thrombocytopenia.

Table 2      Dosing recommendation for thrombocytopenia

Dose at time of platelet decline
25 mg         20 mg          15 mg         10 mg          5 mg twice daily   twice daily    twice daily   twice daily    twice daily Platelet count                                              New dose
20 mg         15 mg
100,000 to <125,000/mm3                                    No change     No change      No change twice daily   twice daily
10 mg         10 mg          10 mg
75,000 to <100,000/mm3                                                   No change      No change twice daily   twice daily    twice daily
5 mg          5 mg           5 mg          5 mg
50,000 to <75,000/mm3                                                                   No change twice daily   twice daily    twice daily   twice daily
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.

Graft versus host disease
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. One dose level reduction step is recommended (10 mg twice daily to 5 mg twice daily or 5 mg twice daily to 5 mg once daily). In patients who are unable to tolerate Jakavi at a dose of 5 mg once daily, treatment should be interrupted. Detailed dosing recommendations are provided in Table 3.



JAK API May24 V7                                                             EU SmPC April 2024 Table 3      Dosing recommendations during ruxolitinib therapy 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)        Reduce Jakavi by one dose level. Resume at initial dose level ≥500/mm3 to <750/mm3                   if ANC >1,000/mm3.
Absolute neutrophil count              Hold Jakavi until ANC >500/mm3, then resume at one lower <500/mm3                               dose level. If ANC >1,000/mm3, dosing may resume at initial dose level.
Total bilirubin elevation not caused   >3.0 to 5.0 x upper limit of normal (ULN): Continue Jakavi by GvHD (no liver GvHD)                at one lower dose level until ≤3.0 x ULN.
>5.0 to 10.0 x ULN: Hold Jakavi up to 14 days until total bilirubin ≤3.0 x ULN. If total bilirubin ≤3.0 x ULN dosing may resume at current dose. If not ≤3.0 x ULN after 14 days,
resume at one lower dose level.
>10.0 x ULN: Hold Jakavi until total bilirubin ≤3.0 x ULN,
then resume at one lower dose level.
Total bilirubin elevation caused by    >3.0 x ULN: Continue Jakavi at one lower dose level until GvHD (liver GvHD)                      total bilirubin ≤3.0 x ULN.

Dose adjustment with concomitant strong CYP3A4 inhibitors or dual CYP2C9/3A4 inhibitors When ruxolitinib is administered with strong CYP3A4 inhibitors or dual inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole) the unit dose of ruxolitinib should be reduced by approximately 50%, to be administered twice daily (see section 4.5). The concomitant use of ruxolitinib with fluconazole doses greater than 200 mg daily should be avoided.

More frequent monitoring (e.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.
In patients with severe renal impairment (creatinine clearance less than 30 ml/min) the recommended starting dose based on platelet count for MF patients should be reduced by approximately 50% to be administered twice daily. The recommended starting dose for PV and GvHD patients with severe renal impairment is 5 mg twice daily. Patients should be carefully monitored with regard to safety and efficacy during ruxolitinib treatment.

There are limited data to determine the best dosing options for patients with end-stage renal disease (ESRD) on haemodialysis. Pharmacokinetic/pharmacodynamic simulations based on available data in this population suggest that the starting dose for MF patients with ESRD on haemodialysis is a single dose of 15-20 mg or two doses of 10 mg given 12 hours apart, to be administered post-dialysis and only on the day of haemodialysis. A single dose of 15 mg is recommended for MF patients with platelet count between 100,000/mm3 and 200,000/mm3. A single dose of 20 mg or two doses of 10 mg given 12 hours apart is recommended for MF patients with platelet count of >200,000/mm3.
Subsequent doses (single administration or two doses of 10 mg given 12 hours apart) should be administered only on haemodialysis days following each dialysis session.
JAK API May24 V7                                                             EU SmPC April 2024 The recommended starting dose for PV patients with ESRD on haemodialysis is a single dose of 10 mg or two doses of 5 mg given 12 hours apart, to be administered post-dialysis and only on the day of haemodialysis. These dose recommendations are based on simulations and any dose modification in ESRD should be followed by careful monitoring of safety and efficacy in individual patients. No data is available for dosing patients who are undergoing peritoneal dialysis or continuous venovenous haemofiltration (see section 5.2).

There are no data for GvHD patients with ESRD.

Hepatic impairment
In MF patients with any hepatic impairment the recommended starting dose based on platelet count should be reduced by approximately 50% to be administered twice daily. Subsequent doses should be adjusted based on careful monitoring of safety and efficacy. The recommended starting dose is 5 mg twice daily for PV patients. 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.

In patients with mild, moderate or severe hepatic impairment not related to GvHD, the starting dose of ruxolitinib should be reduced by 50% (see section 5.2).

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 is recommended.

Elderly patients (≥65 years)
No additional dose adjustments are recommended for elderly patients.

Paediatric population
The safety and efficacy of Jakavi in children and adolescents aged up to 18 years with MF and PV have not been established. No data are available (see section 5.1).

In paediatric patients (12 years of age and older) with GvHD, the safety and efficacy of Jakavi are supported by evidence from the randomised phase 3 studies REACH2 and REACH3. The Jakavi dose in paediatric patients with GvHD aged 12 years and older is the same as in adults. The safety and efficacy of Jakavi have not been established in patients less than 12 years of age.

Treatment discontinuation
Treatment of MF and PV may be continued as long as the benefit-risk remains positive. However the treatment should be discontinued after 6 months if there has been no reduction in spleen size or improvement in symptoms since initiation of therapy.

It is recommended that, for patients who have demonstrated some degree of clinical improvement, ruxolitinib therapy be discontinued if they sustain an increase in their spleen length of 40% compared with baseline size (roughly equivalent to a 25% increase in spleen volume) and no longer have tangible improvement in disease-related symptoms.

In GvHD, tapering of Jakavi may be considered in patients with a response and after having discontinued corticosteroids. A 50% dose reduction of Jakavi every two months is recommended. If signs or symptoms of GvHD reoccur during or after the taper of Jakavi, re-escalation of treatment should be considered.


JAK API May24 V7                                                                EU SmPC April 2024 Method of administration

Jakavi is to be taken orally, with or without food.

If a dose is missed, the patient should not take an additional dose, but should take the next usual prescribed dose.