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Jakavi 5mg, 15mg and 20mg Tablets

Last Updated on eMC 29-Nov-2013 View changes  | Novartis Pharmaceuticals UK Ltd Contact details

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Jakavi 5 mg tablets

Jakavi 15 mg tablets

Jakavi 20 mg tablets

2. Qualitative and quantitative composition

Jakavi 5 mg tablets: Each tablet contains 5 mg ruxolitinib (as phosphate).

Jakavi 15 mg tablets: Each tablet contains 15 mg ruxolitinib (as phosphate).

Jakavi 20 mg tablets : Each tablet contains 20 mg ruxolitinib (as phosphate).

Excipient with known effect:

Jakavi 5 mg tablets: Each tablet contains 71.45 mg lactose monohydrate.

Jakavi 15 mg tablets: Each tablet contains 214.35 mg lactose monohydrate.

Jakavi 20 mg tablets : Each tablet contains 285.80 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet.

Jakavi 5 mg tablets: Round curved white to almost white tablets of approximately 7.5 mm in diameter with “NVR” debossed on one side and “L5” debossed on the other side.

Jakavi 15 mg tablets : Ovaloid curved white to almost white tablets of approximately 15.0 x 7.0 mm with “NVR” debossed on one side and “L15” debossed on the other side.

Jakavi 20 mg tablets : Elongated curved white to almost white tablets of approximately 16.5 x 7.4 mm with “NVR” debossed one one side and “L20” debossed on the other side.

4. Clinical particulars
4.1 Therapeutic indications

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.

4.2 Posology and method of administration

Jakavi treatment should only be initiated by a physician experienced in the administration of anti-cancer agents.

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 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. 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. After recovery of platelet and neutrophil 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.

If efficacy is considered insufficient and platelet and neutrophil counts are adequate, doses may be increased by a maximum of 5 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 (see section 4.5).

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.

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 should be reduced by approximately 50% to be administered 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 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 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 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. 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).

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.

Older people (≥65 years)

No additional dose adjustments are recommended for older people.

Paediatric population

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

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, 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.

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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Pregnancy and lactation.

4.4 Special warnings and precautions for use

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 absoute neutrophil count less than 500/mm3 (see section 4.2).

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 (see sections 4.2 and 4.8). However, platelet transfusions may be required as clinically indicated.

Patients developing anaemia may require blood transfusions. Dose modifications 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 (see sections 4.2 and 4.8).

Complete blood counts should be monitored as clinically indicated and dose adjusted as required (see sections 4.2 and 4.8).

Infections

Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Tuberculosis has been reported in patients receiving Jakavi for myelofibrosis. 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. Jakavi therapy should not be started until active serious infections have resolved. Physicians should carefully observe patients receiving Jakavi for signs and symptoms of infections and initiate appropriate treatment promptly (see section 4.8).

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 for myelofibrosis. 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.

Special populations

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 should be based on platelet counts (see section 4.2). 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. Additional dose modifications should be made with careful monitoring of safety and efficacy (see sections 4.2 and 5.2).

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 (see sections 4.2 and 5.2).

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 (see section 4.5).

Withdrawal effects

Following interruption or discontinuation of Jakavi, symptoms of myelofibrosis 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.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Ruxolitinib is eliminated through metabolism catalysed by CYP3A4 and CYP2C9. Thus, medicinal products inhibiting these enzymes can give rise to increased ruxolitinib exposure.

Interactions resulting in dose reduction of ruxolitinib

CYP3A4 inhibitors

Strong CYP3A4 inhibitors (such as, but not limited to, boceprevir, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole)

In healthy subjects co-administration of Jakavi (10 mg single dose) with a strong CYP3A4 inhibitor, ketoconazole, resulted in ruxolitinib Cmax and AUC that were higher by 33% and 91%, respectively, than with ruxolitinib 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 (see section 4.2).

Dual CYP2C9 and CYP3A4 inhibitors

On the basis of in silico modelling 50% dose reduction should be considered when using medicinal products which are dual inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole).

Enzyme inducers

CYP3A4 inducers (such as, but not limited to, avasimibe, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St.John's wort (Hypericum perforatum))

Patients should be closely monitored and the dose titrated based on safety and efficacy (see section 4.2).

In healthy subjects given ruxolitinib (50 mg single dose) following the potent CYP3A4 inducer rifampicin (600 mg daily dose for 10 days), ruxolitinib AUC was 70% lower than after administration of Jakavi alone. The exposure of ruxolitinib active metabolites was unchanged. Overall, the ruxolitinib pharmacodynamic activity was similar, suggesting the CYP3A4 induction resulted in minimal effect on the pharmacodynamics. However, this could be related to the high ruxolitinib dose resulting in pharmacodynamic effects near Emax. It is possible that in the individual patient, an increase of the ruxolitinib dose is needed when initiating treatment with a strong enzyme inducer.

Other interactions to be considered affecting ruxolitinib

Mild or moderate CYP3A4 inhibitors (such as, but not limited to, ciprofloxacin, erythromycin, amprenavir, atazanavir, diltiazem, cimetidine)

In healthy subjects co-administration of ruxolitinib (10 mg single dose) with erythromycin 500 mg twice daily for four days resulted in ruxolitinib Cmax and AUC that were higher by 8% and 27%, respectively, than with ruxolitinib alone.

No dose adjustment is recommended when ruxolitinib 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 ruxolitinib on other medicinal products

Oral contraceptives

There is no interaction study with oral contraceptives.

Substances metabolised by CYP3A4

It cannot be excluded that ruxolitinib inhibits CYP3A4 in the intestine. Increased systemic exposure may be obtained for substances which are metabolised by CYP3A4, and particularly those that undergo extensive intestinal metabolism. Safety monitoring of orally administered CYP3A4 metabolised substances is advised when combined with ruxolitinib. The interaction is likely to be minimised if the time between co-administrations is kept as long as possible.

Substances transported by P-glycoprotein or other transporters

Ruxolitinib may inhibit P-glycoprotein and breast cancer resistance protein (BCRP) in the intestine. This may result in increased sytemic 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. It is not known whether the Janus Associated Kinase (JAK) inhibition by Jakavi reduces the efficacy of the haematopoietic growth factors or whether the haematopoietic growth factors affect the efficacy of Jakavi (see section 4.4).

Cytoreductive therapies

The concomitant use of cytoreductive therapies and Jakavi has not been studied. The safety and efficacy of this co-administration is not known (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy and contraception in females

There are no data from the use of Jakavi in pregnant women.

Animal studies have shown that ruxolitinib 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 (see section 5.3). The potential risk for humans is unknown. As a precautionary measure, the use of Jakavi during pregnancy is contraindicated (see section 4.3). Women of child-bearing potential should use effective contraception during the treatment with Jakavi. In case pregnancy should occur during treatment with Jakavi, a risk/benefit evaluation must be carried out on an individual basis with careful counselling regarding potential risks to the foetus (see section 5.3).

Breast-feeding

Jakavi must not be used during breast-feeding (see section 4.3) and breast-feeding should therefore be discontinued when treatment is started. It is unknown whether ruxolitinib 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 ruxolitinib and its metabolites in milk (see section 5.3).

Fertility

There are no human data on the effect of ruxolitinib on fertility. In animal studies, no effect on fertility was observed.

4.7 Effects on ability to drive and use machines

Jakavi has no or negligible sedating effect. However, patients who experience dizziness after the intake of Jakavi should refrain from driving or using machines.

4.8 Undesirable effects

Summary of the safety profile

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 (15.6%).

Anaemia, thrombocytopenia and neutropenia are dose-related effects.

The three most frequent non-haematological adverse drug reactions were bruising (21.3%), dizziness (15.0%) and headache (13.9%).

The three most frequent non-haematological laboratory abnormalities were raised alanine aminotransferase (26.9%), raised aspartate aminotransferase (19.3%) and hypercholesterolaemia (16.6%).

Tabulated summary of adverse drug reactions from clinical studies

In the clinical study programme the severity of adverse drug reactions was assessed based on the CTCAE, defining grade 1 = mild, grade 2 = moderate, grade 3 = severe and grade 4=life-threatening.

Adverse drug reactions from clinical studies (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Table 1 Percentage of patients with adverse drug reactions in clinical studies*

Adverse drug reaction

Ruxolitinib – myelofibrosis patients

N=301*

 

All CTCAE gradesc

(%)

CTCAE grade 3/4c

(%)

Frequency category

Infections and infestations

Urinary tract infectionsa,d

12.3

1.0

Very common

Herpes zostera,d

4.3

0.3

Common

Tuberculosise

0.27

0.27

Uncommon

Blood and lymphatic system disordersb,d

Anaemia

82.4

42.5

Very common

Thrombocytopenia

69.8

11.3

Very common

Neutropenia

15.6

6.6

Very common

Bleeding (any bleeding including intracranial, and gastrointestinal bleeding, bruising and other bleeding)

32.6

4.7

Very common

Intracranial bleeding

1.0

1.0

Common

Gastrointestinal bleeding

5.0

1.3

Common

Bruising

21.3

0.3

Very common

Other bleeding (including epistaxis, post-procedural haemorrhage and haematuria)

13.3

2.3

Very common

Metabolism and nutrition disorders

Weight gaina

10.0

1.3

Very common

Hypercholesterolaemiab

16.6

0

Very common

Nervous system disorders

Dizzinessa

15.0

0.3

Very common

Headachea

13.9

0.5

Very common

Gastrointestinal disorders

Flatulencea

2.9

0

Common

Hepatobiliary disorders

Raised alanine aminotransferaseb

26.9

1.3

Very common

Raised aspartate aminotransferaseb

19.3

0

Very common

* Myelofibrosis patients randomised to and treated with ruxolitinib from the phase 3 pivotal COMFORT-I and COMFORT-II studies

a Frequency is based on adverse event data.

- A subject with multiple occurrence of an adverse drug reaction (ADR) is counted only once in that ADR category.

- ADRs reported are on treatment or up to 28 days post treatment end date.

b Frequency is based on laboratory values.

- A subject with multiple occurrences of an ADR is counted only once in that ADR category.

- ADRs reported are on treatment or up to 28 days post treatment end date.

c Common Terminology Criteria for Adverse Events (CTCAE) version 3.0; grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening

d These ADRs are discussed in the text.

e Frequency is based on all patients exposed to ruxolitinib in clinical trials (N=4755)

Upon discontinuation, patients may experience a return of myelofibrosis symptoms such as fatigue, bone pain, fever, pruritus, night sweats, symptomatic splenomegaly and weight loss. In clinical studies the total symptom score for myelofibrosis symptoms gradually returned to baseline value within 7 days after dose discontinuation (see section 4.4).

Description of selected adverse drug reactions

Anaemia

In phase 3 clinical studies, median time to onset of first CTCAE grade 2 or higher anaemia was 1.5 months. One patient (0.3%) discontinued treatment because of anaemia.

In patients receiving Jakavi mean decreases in haemoglobin reached a nadir of approximately 10 g/litre below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 5 g/litre below baseline. This pattern was observed in patients regardless of whether they had received transfusion during therapy.

In the randomised, placebo-controlled study COMFORT-I 60.6% of Jakavi-treated patients and 37.7% of placebo-treated patients received red blood cell transfusions during randomised treatment. In the COMFORT-II study the rate of packed red blood cell transfusions was 53.4% in the Jakavi arm and 41.1% in the best available therapy arm.

Thrombocytopenia

In the phase 3 clinical studies, in patients who developed grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50,000/mm3 was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakavi and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of patients receiving Jakavi and 0.9% of patients receiving control regimens. Patients with a platelet count of 100,000/mm3 to 200,000/mm3 before starting Jakavi had a higher frequency of grade 3 or 4 thrombocytopenia compared to patients with platelet count >200,000/mm3 (64.2% versus 38.5%).

Neutropenia

In the phase 3 clinical studies, in patients who developed grade 3 or 4 neutropenia, the median time to onset was 12 weeks. Dose holding or reductions due to neutropenia were reported in 1.0% of patients, and 0.3% of patients discontinued treatment because of neutropenia.

Bleeding

In the phase 3 pivotal studies bleeding events (including intracranial and gastrointestinal, bruising and other bleeding events) were reported in 32.6% of patients exposed to Jakavi and 23.2% of patients exposed to the reference treatments (placebo or best available therapy). The frequency of grade 3-4 events was similar for patients treated with Jakavi or reference treatments (4.7% versus 3.1%). Most of the patients with bleeding events during the treatment reported bruising (65.3%). Bruising events were more frequently reported in patients taking Jakavi compared with the reference treatments (21.3% versus 11.6%). Intracranial bleeding was reported in 1% of patients exposed to Jakavi and 0.9% exposed to reference treatments. Gastrointestinal bleeding was reported in 5.0% of patients exposed to Jakavi compared to 3.1% exposed to reference treatments. Other bleeding events (including events such as epistaxis, post-procedural haemorrhage and haematuria) were reported in 13.3% of patients treated with Jakavi and 10.3% treated with reference treatments.

Infections

In the phase 3 pivotal studies grade 3 or 4 urinary tract infection was reported in 1.0% of patients, herpes zoster in 4.3% and tuberculosis in 1.0%.

Increased systolic blood pressure

In the phase 3 pivotal clinical studies an increase in systolic blood pressure of 20 mmHg or more from baseline was recorded in 31.5% of patients on at least one visit compared with 19.5% of the control-treated patients. In COMFORT-I the mean increase from baseline in systolic BP was 0-2 mmHg on Jakavi versus a decrease of 2-5 mmHg in the placebo arm. In COMFORT-II mean values showed little difference between the ruxolitinib-treated and the control-treated patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE18

Mechanism of action

Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 (IC50 values of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively). These mediate the signalling of a number of cytokines and growth factors that are important for haematopoiesis and immune function.

Myelofibrosis is a myeloproliferative neoplasm known to be associated with dysregulated JAK1 and JAK2 signalling. The basis for the dysregulation is believed to include high levels of circulating cytokines that activate the JAK-STAT pathway, gain-of-function mutations such as JAK2V617F, and silencing of negative regulatory mechanisms. Myelofibrosis patients exhibit dysregulated JAK signalling regardless of JAK2V617F mutation status.

Ruxolitinib inhibits JAK-STAT signalling and cell proliferation of cytokine-dependent cellular models of haematological malignancies, as well as of Ba/F3 cells rendered cytokine-independent by expressing the JAK2V617F mutated protein, with IC50 ranging from 80-320 nM.

Pharmacodynamic effects

Ruxolitinib inhibits cytokine-induced STAT3 phosphorylation in whole blood from healthy subjects and myelofibrosis patients. Ruxolitinib resulted in maximal inhibition of STAT3 phosphorylation 2 hours after dosing which returned to near baseline by 8 hours in both healthy subjects and myelofibrosis patients, indicating no accumulation of either parent or active metabolites.

Baseline elevations in inflammatory markers associated with constitutional symptoms such as TNFα, IL-6 and CRP in subjects with myelofibrosis were decreased following treatment with ruxolitinib. Myelofibrosis patients did not become refractory to the pharmacodynamic effects of ruxolitinib treatment over time.

In a thorough QT study in healthy subjects, there was no indication of a QT/QTc prolonging effect of ruxolitinib in single doses up to a supratherapeutic dose of 200 mg, indicating that ruxolitinib has no effect on cardiac repolarisation.

Clinical efficacy and safety

Two randomised phase 3 studies (COMFORT-I and COMFORT-II) were conducted in patients with myelofibrosis (primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis). In both studies, patients had palpable splenomegaly at least 5 cm below the costal margin and risk category of intermediate-2 (2 prognostic factors) or high risk (3 or more prognostic factors) based on the International Working Group (IWG) Consensus Criteria. The starting dose of Jakavi was based on platelet count.

COMFORT-I was a double-blind, randomised, placebo-controlled study in 309 patients who were refractory to or were not candidates for available therapy. Patients were given Jakavi or matching placebo. The primary efficacy endpoint was proportion of subjects achieving ≥35% reduction from baseline in spleen volume at week 24 as measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT).

Secondary endpoints included duration of maintenance of a ≥35% reduction from baseline in spleen volume, proportion of patients who had ≥50% reduction in total symptom score from baseline to week 24 as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary, change in total symptom score from baseline to week 24 as measured by the modified MFSAF v2.0 diary, and overall survival.

COMFORT-II was an open-label, randomised study in 219 patients. Patients were randomised 2:1 to Jakavi versus best available therapy. Best available therapy was selected by the investigator on a patient-by-patient basis. In the best available therapy arm, 47% of patients received hydroxyurea and 16% of patients received glucocorticoids. The primary efficacy endpoint was proportion of patients achieving ≥35% reduction from baseline in spleen volume at week 48 as measured by MRI or CT.

A secondary endpoint in COMFORT-II was the proportion of patients achieving a ≥35% reduction of spleen volume measured by MRI or CT from baseline to week 24. Duration of maintenance of a ≥35% reduction from baseline in responding patients was also a secondary endpoint.

In COMFORT-I and COMFORT-II, patient baseline demographics and disease characteristics were comparable between the treatment arms.

Table 2 Percentage of patients with ≥35% reduction from baseline in spleen volume at week 24 in COMFORT-I and at week 48 in COMFORT-II (ITT)

 

COMFORT-I

COMFORT-II

 

Jakavi

(N=155)

Placebo

(N=153)

Jakavi

(N=144)

Best available therapy

(N=72)

Time points

Week 24

Week 48

Number (%) of subjects with spleen volume reduced by ≥35%

65 (41.9)

1 (0.7)

41 (28.5)

0

95% confidence intervals

34.1, 50.1

0, 3.6

21.3, 36.6

0.0, 5.0

p-value

<0.0001

<0.0001

A significantly higher proportion of patients in the Jakavi group achieved ≥35% reduction from baseline in spleen volume (Table 2) regardless of the presence or absence of the JAK2V617F mutation or the disease subtype (primary myelofibrosis, post-polycythaemia vera myelofibrosis, post-essential thrombocythaemia myelofibrosis).

Table 3 Percentage of patients with ≥35% reduction from baseline in spleen volume by JAK mutation status (safety set)

 

COMFORT-I

COMFORT-II

 

Jakavi

Placebo

Jakavi

Best available therapy

JAK mutation status

Positive

(N=113)

n (%)

Negative

(N=40)

n (%)

Positive

(N=121)

n (%)

Negative

(N=27)

n (%)

Positive

(N=110)

n (%)

Negative

(N=35)

n (%)

Positive

(N=49)

n (%)

Negative

(N=20)

n (%)

Number (%) of subjects with spleen volume reduced by ≥35%

54

(47.8)

11

(27.5)

1

(0.8)

0

36

(32.7)

5

(14.3)

0

0

Time point

After 24 weeks

After 48 weeks

Among the 80 patients in COMFORT-I and the 69 patients in COMFORT-II who showed a ≥35% reduction at any time point, the probability that a patient would maintain a response on Jakavi for at least 24 weeks was 89% and 87%, respectively, while the probability of maintaining a response for at least 48 weeks was 52% in COMFORT-II.

Jakavi improves myelofibrosis-associated symptoms and quality of life in patients with myelofibrosis. In COMFORT-I symptoms of myelofibrosis were captured using the modified MFSAF diary v2.0 as an electronic diary which subjects completed daily. A significantly larger proportion of subjects in the Jakavi group achieved a ≥50% improvement from baseline in the week 24 total symptom score compared with the placebo group (45.9% and 5.3%, respectively, p<0.0001 using the chi-square test).

An improvement in overall quality of life was measured by a validated instrument, the EORTC QLQ-C30 in both COMFORT-I and COMFORT-II. At week 24 in COMFORT-I the mean change for the global health status/quality of life score was +12.3 and -3.4 (p<0.0001) for Jakavi and placebo, respectively.

In COMFORT-I, 13 out of 155 patients (8.4%) died in the Jakavi group and 24 out of 154 patients (15.6%) died in the placebo group. In COMFORT-II, 13 out of 146 patients (8.9%) died in the Jakavi group and 5 out of 73 patients (6.8%) died in the best available therapy group.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Jakavi in all subsets of the paediatric population for the treatment of myelofibrosis (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Ruxolitinib is a Biopharmaceutical Classification System (BCS) class 1 compound, with high permeability, high solubility and rapid dissolution characteristics. In clinical studies, ruxolitinib is rapidly absorbed after oral administration with maximal plasma concentration (Cmax) achieved approximately 1 hour post-dose. Based on a human mass balance study, oral absorption of ruxolitinib, as ruxolitinib or metabolites formed under first-pass, is 95% or greater. Mean ruxolitinib Cmax and total exposure (AUC) increased proportionally over a single dose range of 5-200 mg. There was no clinically relevant change in the pharmacokinetics of ruxolitinib upon administration with a high-fat meal. The mean Cmax was moderately decreased (24%) while the mean AUC was nearly unchanged (4% increase) on dosing with a high-fat meal.

Distribution

The apparent volume of distribution at steady state is 53-65 litres in myelofibrosis patients. At clinically relevant concentrations of ruxolitinib, binding to plasma proteins in vitro is approximately 97%, mostly to albumin. A whole body autoradiography study in rats has shown that ruxolitinib does not penetrate the blood-brain barrier.

Biotransformation

Ruxolitinib is mainly metabolised by CYP3A4 (>50%), with additional contribution from CYP2C9. Parent compound is the predominant entity in human plasma, representing approximately 60% of the drug-related material in circulation. Two major and active metabolites are present in plasma representing 25% and 11% of parent AUC. These metabolites have one half to one fifth of the parent JAK-related pharmacological activity. The sum total of all active metabolites contributes to 18% of the overall pharmacodynamics of ruxolitinib. At clinically relevant concentrations, ruxolitinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or hepatic CYP3A4 and is not a potent inducer of CYP1A2, CYP2B6 or CYP3A4 based on in vitro studies. In vitro data indicate that ruxolitinib may inhibit intestinal CYP3A4, P-gp and BCRP.

Elimination

Ruxolitinib is mainly eliminated through metabolism. The mean elimination half-life of ruxolitinib is approximately 3 hours. Following a single oral dose of [14C]-labelled ruxolitinib in healthy adult subjects, elimination was predominately through metabolism, with 74% of radioactivity excreted in urine and 22% via faeces. Unchanged parent substance accounted for less than 1% of the excreted total radioactivity.

Linearity/non-linearity

Dose proportionality was demonstrated in the single and multiple dose studies.

Special populations

Effects of age, gender or race

In healthy subjects, no significant differences in ruxolitinib pharmacokinetics were observed with regard to gender and race. In a population pharmacokinetic evaluation in myelofibrosis patients, no relationship was apparent between oral clearance and patient age or race. The predicted oral clearance was 17.7 l/h in women and 22.1 l/h in men, with 39% inter-subject variability.

Paediatric population

The safety and effectiveness of Jakavi in paediatric patients have not been established (see section 5.1, “Paediatric population”).

Renal impairment

Renal function was determined using both Modification of Diet in Renal Disease (MDRD) and urinary creatinine. Following a single ruxolitinib dose of 25 mg, the exposure of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites tended to increase with increasing severity of renal impairment, and were most markedly increased in the subjects with severe renal impairment. It is unknown whether the increased metabolite exposure is of safety concern. A dose modification is recommended in patients with severe renal impairment and end-stage renal disease (see section 4.2). Dosing only on dialysis days reduces the metabolite exposure, but also the pharmacodynamic effect, especially on the days between dialysis.

Hepatic impairment

Following a single ruxolitinib dose of 25 mg in patients with varying degrees of hepatic impairment, the mean AUC for ruxolitinib was increased in patients with mild, moderate and severe hepatic impairment by 87%, 28% and 65%, respectively, compared to patients with normal hepatic function. There was no clear relationship between AUC and the degree of hepatic impairment based on Child-Pugh scores. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). A dose reduction of approximately 50% is recommended for patients with hepatic impairment (see section 4.2).

5.3 Preclinical safety data

Ruxolitinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity and reproductive toxicity studies and in a carcinogenicity study. Target organs associated with the pharmacological action of ruxolitinb in repeated dose studies include bone marrow, peripheral blood and lymphoid tissues. Infections generally associated with immunosuppression were noted in dogs. Adverse decreases in blood pressure along with increases in heart rate were noted in a dog telemetry study, and an adverse decrease in minute volume was noted in a respiratory study in rats. The margins (based on unbound Cmax) at the non-adverse level in the dog and rat studies were 15.7-fold and 10.4-fold greater, respectively, than the maximum human recommended dose of 25 mg twice daily. No effects were noted in an evaluation of the neuropharmacological effects of ruxolitinib.

Ruxolitinib decreased foetal weight and increased post-implantation loss in animal studies. There was no evidence of a teratogenic effect in rats and rabbits. However, the exposure margins compared to the highest clinical dose were low and the results are therefore of limited relevance for humans. No effects were noted on fertility. In a pre- and post-natal development study, a slightly prolonged gestation period, reduced number of implantation sites, and reduced number of pups delivered were observed. In the pups, decreased mean initial body weights and short period of decreased mean body weight gain were observed. In lactating rats, ruxolitinib and/or its metabolites were excreted into the milk with a concentration that was 13-fold higher than the maternal plasma concentration. Ruxolitinib was not mutagenic or clastogenic. Ruxolitinib was not carcinogenic in the Tg.rasH2 transgenic mouse model.

6. Pharmaceutical particulars
6.1 List of excipients

Cellulose, microcrystalline

Magnesium stearate

Silica, colloidal anhydrous

Sodium starch glycolate (Type A)

Povidone

Hydroxypropylcellulose

Lactose monohydrate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Blisters

2 years

Bottles

2 years

After first-opening: 1 month

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

PVC/PCTFE/Aluminium blister packs containing 14 or 56 tablets or multipacks containing 168 (3 packs of 56) tablets.

HDPE bottle with induction seal and child-resistant closure containing 60 tablets.

Not all pack sizes or types may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

8. Marketing authorisation number(s)

EU/1/12/773/001 Jakavi 5 mg

EU/1/12/773/004 Jakavi 5 mg

EU/1/12/773/005 Jakavi 5 mg

EU/1/12/773/006 Jakavi 5 mg

EU/1/12/773/002 Jakavi 15 mg

EU/1/12/773/007 Jakavi 15 mg

EU/1/12/773/008 Jakavi 15 mg

EU/1/12/773/009 Jakavi 15 mg

EU/1/12/773/003 Jakavi 20 mg

EU/1/12/773/010 Jakavi 20 mg

EU/1/12/773/011 Jakavi 20 mg

EU/1/12/773/012 Jakavi 20 mg

9. Date of first authorisation/renewal of the authorisation

23 August 2012

10. Date of revision of the text

13 November 2013

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Legal category

POM

Company contact details

Novartis Pharmaceuticals UK Ltd

Company image
Address

Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR

Fax

+44 (0)1276 698 449

Medical Information e-mail
Telephone

+44 (0)1276 692 255

Medical Information Direct Line

+44 (0)1276 698 370

Customer Care direct line

+44 (0)845 741 9442

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Active ingredients

ruxolitinib phosphate

Legal categories

POM - Prescription Only Medicine

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