
Regulatory Affairs
JAKAVI (ruxolitinib)
5 mg, 15 mg and 20 mg Tablets
National Succinct Statement (NSS)
Version 3.2
Effective date: 12-Jan-2021
Safety Label Change (SLC) 2024-PSB/GLC-1420-l
Tracking number:
Document status: Final
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
JAKAVI
Important note: Before prescribing, consult full prescribing information:
This link will contain the most updated product information approved by the reference country.
Presentation: Tablets containing 5 mg, 15 mg, and 20 mg ruxolitinib.
Indications:
Myelofibrosis (MF)
Jakavi is indicated for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis.
Polycythaemia vera (PV)
Jakavi is indicated for the treatment of adult patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea.
Graft versus host disease (GvHD)
Jakavi is indicated for the treatment of patients aged 12 years and older with acute graft versus host disease or chronic graft versus host disease who have inadequate response to corticosteroids or other systemic therapies.
Dosage and 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.
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 polycythaemia 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).
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 MF patients with 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.
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.
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) ≥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.
|
Total bilirubin elevation not caused by GvHD (no liver GvHD)
|
>3.0 to 5.0 x upper limit of normal (ULN): Continue Jakavi 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 GvHD (liver GvHD)
|
>3.0 x ULN: Continue Jakavi at one lower dose level until
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. 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.
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.
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%.
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.
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.
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.
Contraindications: Hypersensitivity to ruxolitinib or to any of the excipients
Warnings and precautions: ♦Decrease in blood cell count: hematologic adverse drug reactions, including thrombocytopenia, anemia and neutropenia, have been reported with Jakavi treatment. Complete blood counts monitoring recommended. Dose reduction or interruption may be required in patients developing thrombocytopenia, anemia and neutropenia.
♦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. Jakavi therapy should not be started until active serious infections have resolved. Tuberculosis cases have been reported. Before starting treatment patients should be evaluated for active and inactive (“latent”) tuberculosis, as per local recommendations. Hepatitis B viral load (HBV-DNA titre) increases have been reported in patients with chronic HBV infections. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines. ♦Herpes zoster: Physician to educate patients about early signs and symptoms of herpes zoster, advising for immediate treatment. ♦Progressive multifocal leukencephalopathy (PML) has been reported. Physicians should be alert for neuropsychiatric symptoms suggestive of PML. If PML suspected suspend treatment until PML is excluded. ♦Non-Melanoma Skin Cancer (NMSC): NMSC, including basal cell, squamous cell, and Merkel cell carcinoma, have been reported in Jakavi treated patients. Periodic skin examination recommended. ♦Lipid Abnormalities/Elevations: Increases in lipid parameters, including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides have been associated with Jakavi. Monitoring and treatment of dyslipidaemia is recommended. ♦Hepatic and severe renal impairment: Due to increased Jakavi exposure, dose reduction is required.
Pregnancy, lactation, females and males of reproductive potential
Pregnancy: Use in pregnancy is contraindicated.
Breast-feeding: Women taking Jakavi should not breast-feed.
Contraception: Sexually active females should use effective contraception during treatment.
Adverse drug reactions:
Myelofibrosis
Very common (>10%): Urinary tract infections, herpes zoster, pneumonia, anaemia, thrombocytopenia, neutropenia, hypercholesterolaemia, hypertriglyceridaemia, dizziness, headache, constipation, ALT increased, AST increased, hypertension, bruising, weight gain.
Common (1 to 10%): Pancytopenia, flatulence.
Uncommon (0.1 to 1%): Tuberculosis.
Polycythemia vera
Very common (>10%): Urinary tract infections, herpes zoster, anaemia, thrombocytopenia, bruising, hypercholesterolaemia, hypertriglyceridaemia, weight gain, dizziness, headache, constipation, ALT increased, AST increased, hypertension.
Common (1 to 10%): Pneumonia, neutropenia, pancytopenia, flatulence.
Not known (frequency cannot be estimated): Tuberculosis.
Acute Graft versus host disease
Very common (>10%): CMV infections, sepsis, UTI, thrombocytopenia, anemia, neutropenia, pancytopenia, hypercholesterolemia, hypertension, nausea, increased ALT and AST.
Common (1 to 10%): headache.
Chronic Graft versus host disease
Very common (>10%): thrombocytopenia, anemia, neutropenia, hypercholesterolemia, headache, hypertension, increased lipase, increased amylase, increased ALT and AST, increased blood CPK, and increased blood creatinine.
Common (1 to 10%): CMV infections, UTI, BK virus infections, weight gain, and constipation.
Interactions: ♦Caution with CYP3A4 inhibitors in MF and PV patients or dual moderate inhibitors of CYP2C9 and CYP3A4 enzymes. Dose reduction recommended when co-administered with strong CYP3A4 inhibitors or dual moderate inhibitors of CYP2C9 and CYP3A4 enzymes in MF, PV and GvHD patients. Avoid fluconazole daily doses >200 mg.
Packs and prices: Country-specific.
Legal classification: Country-specific.
NSS Version: 3.2
Leaflet Revision Date: March 2024
Leaflet Presentation Type: R02