Presentation and Status in Health Basket
56 X 5 mg
56 X 10 mg
56 X 15 mg
56 X 20 mg
Starting dose: The recommended starting dose of Jakavi in MF is 15 mg twice daily for patients with a platelet count between 100,000/mm³ and 200,000/mm³ and 20 mg twice daily for patients with a platelet count of >200,000/mm³. The recommended starting dose of Jakavi in PV is 10 mg given orally twice daily. There is limited information to recommend a starting dose for patients with platelet counts between 50,000/mm³ and <100,000/mm³. The maximum recommended starting dose in these patients is 5 mg twice daily and the patients should be titrated cautiously.
Dose modifications: Doses may be titrated based on safety and efficacy. 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 below 100,000/mm³ , with the goal of avoiding dose interruptions for thrombocytopenia. 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. 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. The maximum dose of Jakavi is 25 mg twice daily.
Dose adjustment with concomitant strong CYP3A4 inhibitors or fluconazole: When Jakavi is administered with strong CYP3A4 inhibitors or dual inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole) the unit dose of Jakavi should be reduced by approximately 50%, to be administered twice daily. Avoid the concomitant use of Jakavi with fluconazole doses greater than 200 mg daily. More frequent monitoring (e.g. twice a week) of haematology parameters and of clinical signs and symptoms of Jakavi-related adverse drug reactions is recommended while on strong CYP3A4 inhibitors or dual inhibitors of CYP2C9 and CYP3A4 enzymes.
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 patients with severe renal impairment is 5 mg twice daily. Patients should be carefully monitored with regard to safety and efficacy during Jakavi 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.
Hepatic impairment: In 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. Patients diagnosed with hepatic impairment while receiving Jakavi 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 Jakavi and as clinically indicated thereafter once their liver function and blood counts have been stabilised. Jakavi dose can be titrated to reduce the risk of cytopenia.
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 have not been established. No data are available.
Treatment discontinuation: Treatment 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, Jakavi 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.
Myelofibrosis (MF): 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): indicated for the treatment of adult patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea.
Hypersensitivity to the active substance or to any of the excipients. Pregnancy and lactation.
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 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 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. The effect of Jakavi on viral replication in patients with chronic HBV infection is unknown. 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: 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: NMSCs, including basal cell, squamous cell, and Merkel cell carcinoma, have been reported in patients treated with ruxolitinib. Most of these patients had histories of extended treatment with hydroxyurea and prior NMSC or pre-malignant skin lesions. A causal relationship to Jakavi 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.
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 for MF patients should be based on platelet counts. 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 patients with hepatic impairment. Further dose modifications should be based on the safety and efficacy of the medicinal product.
Interactions: If Jakavi is to be co-administered with strong CYP3A4 inhibitors or dual inhibitors of CYP3A4 and CYP2C9 enzymes (e.g. fluconazole), the unit dose of Jakavi should be reduced by approximately 50%, to be administered twice daily (for monitoring frequency see sections 4.2 and 4.5).
The concomitant use of cytoreductive therapies or haematopoietic growth factors with Jakavi has not been studied. The safety and efficacy of these co-administrations are not known.
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 sustained more severe 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, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
See prescribing information for full details.
Summary of the safety profile: The safety assessment was based on a total of 982 patients (with MF or PV) receiving Jakavi in phase 2 and 3 studies.
Myelofibrosis: In the randomised period of the two pivotal studies, COMFORT-I and COMFORT-II, the median duration of exposure to Jakavi was 10.8 months (range 0.3 to 23.5 months). The majority of patients (68.4%) were treated for at least 9 months. Of 301 patients, 111 (36.9%) had a baseline platelet count of between 100,000/mm3 and 200,000/mm3 and 190 (63.1%) had a baseline platelet count of >200,000/mm3.
In these clinical studies, discontinuation due to adverse events, regardless of causality, was observed in 11.3% of patients. The most frequently reported adverse drug reactions were thrombocytopenia and anaemia.
Haematological adverse drug reactions (any Common Terminology Criteria for Adverse Events [CTCAE] grade) included anaemia (82.4%), thrombocytopenia (69.8%) and neutropenia (16.6%). Anaemia, thrombocytopenia and neutropenia are dose-related effects.
The three most frequent non-haematological adverse drug reactions were bruising (21.3%), dizziness (15.3%) and headache (14.0%).
The three most frequent non-haematological laboratory abnormalities were raised alanine aminotransferase (27.2%), raised aspartate aminotransferase (19.9%) and hypercholesterolaemia (16.9%). In phase 3 clinical studies in MF, neither CTCAE grade 3 or 4 hypercholesterolaemia, raised aspartate aminotransferase nor CTCAE grade 4 raised alanine aminotransferase were observed.
Long-term safety: Long term safety data from two pivotal phase 3 studies assessed 457 patients with MF who were treated with ruxolitinib, including patients initially randomised to ruxolitinib (n=301; exposure 0.3–68.1 months, median exposure 33.4 months) and patients who received ruxolitinib after crossing over from control treatments (n=156; exposure: 0.5–59.8 months, median exposure 25.0 months). The cumulative frequency of adverse events in these studies increased proportionally to the increase in the follow-up time. With these updated data, therapy discontinuation due to adverse events was observed in 27.4% of patients treated with ruxolitinib.
Polycythaemia vera: The safety of Jakavi was assessed in 184 patients with PV in two open-label, randomised, controlled studies, the phase 3 RESPONSE study and the phase 3b RESPONSE 2 study. The adverse drug reactions listed below reflect the randomised study period (up to week 32 for RESPONSE and up to week 28 for RESPONSE 2) with equivalent exposure to ruxolitinib and Best Available Therapy (BAT). The median duration of exposure to Jakavi during the randomised study periods was 7.85 months (range 0.03 to 7.85 months). Discontinuation due to adverse events, regardless of causality, was observed in 2.2% of patients. Haematological adverse reactions (any CTCAE grade) included anaemia (40.8%) and thrombocytopenia (16.8%). Anaemia or thrombocytopenia CTCAE grade 3 and 4 were reported in respectively 1.1% or 3.3%.
The three most frequent non-haematological adverse reactions were dizziness (9.2%), constipation (8.7%) and hypertension (6. 5%).
The three most frequent non-haematological laboratory abnormalities (any CTCAE grade) identified as adverse reactions were raised aspartate aminotransferase (26.1%), raised alanine aminotransferase (22.3%) and hypercholesterolaemia (20.7%). These were all CTCAE grade 1 and 2 with the exception of one CTCAE grade 3 raised alanine aminotransferase event.
Long-term safety was evaluated using data from two phase 3 studies including data from patients initially randomised to ruxolitinib (n=184; exposure 0.03 to 43.5 months, median exposure 18.9 months) and patients who received ruxolitinib after crossing over from control treatments (n=149; exposure: 0.2 to 33.5 months, median exposure 12.0 months): With longer exposure, the cumulative frequency of adverse events increased but no new safety findings emerged. When adjusted for exposure, the adverse events rates were generally comparable with those observed during the comparative periods of the randomised studies.
See prescribing information for full details.
Interaction studies have only been performed in adults.
Jakavi is eliminated through metabolism catalysed by CYP3A4 and CYP2C9. Thus, medicinal products inhibiting these enzymes can give rise to increased Jakavi exposure.
Interactions resulting in dose reduction of Jakavi:
In healthy subjects co-administration of Jakavi (10 mg single dose) with a strong CYP3A4 inhibitor, ketoconazole, resulted in Jakavi Cmax and AUC that were higher by 33% and 91%, respectively, than with Jakavi alone. The half-life was prolonged from 3.7 to 6.0 hours with concurrent ketoconazole administration. When administering Jakavi with strong CYP3A4 inhibitors the unit dose of Jakavi should be reduced by approximately 50%, to be administered twice daily. Patients should be closely monitored (e.g. twice weekly) for cytopenias and dose titrated based on safety and efficacy.
Dual CYP2C9 and CYP3A4 inhibitors: 50% dose reduction should be considered when using medicinal products which are dual inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole). Avoid the concomitant use of Jakavi with fluconazole doses greater than 200 mg daily.
CYP3A4 inducers: Patients should be closely monitored and the dose titrated based on safety and efficacy.
Other interactions to be considered affecting Jakavi:
Mild or moderate CYP3A4 inhibitors: In healthy subjects co-administration of Jakavi (10 mg single dose) with erythromycin 500 mg twice daily for four days resulted in Jakavi Cmax and AUC that were higher by 8% and 27%, respectively, than with Jakavi alone.
No dose adjustment is recommended when Jakavi is co-administered with mild or moderate CYP3A4 inhibitors (e.g. erythromycin). However, patients should be closely monitored for cytopenias when initiating therapy with a moderate CYP3A4 inhibitor.
Effects of Jakavi on other medicinal products:
Substances transported by P-glycoprotein or other transporters: Jakavi may inhibit P-glycoprotein and breast cancer resistance protein (BCRP) in the intestine. This may result in increased systemic exposure of substrates of these transporters, such as dabigatran etexilate, ciclosporin, rosuvastatin and potentially digoxin. Therapeutic drug monitoring (TDM) or clinical monitoring of the affected substance is advised. It is possible that the potential inhibition of P-gp and BCRP in the intestine can be minimised if the time between administrations is kept apart as long as possible.
Haematopoietic growth factors: The concurrent use of haematopoietic growth factors and Jakavi has not been studied.
Cytoreductive therapies: The concomitant use of cytoreductive therapies and Jakavi has not been studied.
See prescribing information for full details.
Pregnancy and Lactation
Pregnancy: There are no data from the use of Jakavi in pregnant women. Animal studies have shown that Jakavi is embryotoxic and foetotoxic. Teratogenicity was not observed in rats or rabbits. However, the exposure margins compared to the highest clinical dose were low and the results are therefore of limited relevance for humans. The potential risk for humans is unknown. As a precautionary measure, the use of Jakavi during pregnancy is contraindicated.
Breast-feeding: Jakavi must not be used during breast-feeding and breast-feeding should therefore be discontinued when treatment is started. It is unknown whether Jakavi and/or its metabolites are excreted in human milk. A risk to the breast-fed child cannot be excluded. Available
pharmacodynamic/toxicological data in animals have shown excretion of Jakavi and its metabolites in milk.
There is no known antidote for overdoses with Jakavi. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anaemia and thrombocytopenia. Appropriate supportive treatment should be given. Haemodialysis is not expected to enhance the elimination of ruxolitinib.
Storage: Do not store above 30°C.