Ruxolitinib Phosphate

Ruxolitinib Phosphate is a janus-associated kinase inhibitor indicated to treat bone marrow cancer, specifically intermediate or high-risk myelofibrosis. FDA approved on November 16, 2011.

Myelofibrosis (MF): Ruxolitinib Phosphate 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): Ruxolitinib Phosphate is indicated for the treatment of adult patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea.

Ruxolitinib Phosphate is used to treat intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Myelofibrosis is a life-threatening bone marrow problem which is manifested by the following symptoms: enlarged spleen (splenomegaly), severe itching, fever, night sweats, weight loss, bone pain, or unusual tiredness or weakness. Ruxolitinib Phosphate is also used to treat polycythemia vera in patients who have had received hydroxyurea without success.

Ruxolitinib Phosphate is available only with your doctor's prescription.

Myelofibrosis

The recommended starting dose of Ruxolitinib Phosphate is based on platelet count (Table 1). A complete blood count (CBC) and platelet count must be performed before initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. Doses may be titrated based on safety and efficacy.

Table 1: Ruxolitinib Phosphate Starting Doses for Myelofibrosiss

Method Of Administration

Ruxolitinib Phosphate is dosed orally and can be administered 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.

When discontinuing Ruxolitinib Phosphate therapy for reasons other than thrombocytopenia, gradual tapering of the dose of Ruxolitinib Phosphate may be considered, for example by 5 mg twice daily each week.

For patients unable to ingest tablets, Ruxolitinib Phosphate can be administered through a nasogastric tube (8 French or greater) as follows:

• Suspend one tablet in approximately 40 mL of water with stirring for approximately 10 minutes.
• Within 6 hours after the tablet has dispersed, the suspension can be administered through a nasogastric tube using an appropriate syringe.

The tube should be rinsed with approximately 75 mL of water. The effect of tube feeding preparations on Ruxolitinib Phosphate exposure during administration through a nasogastric tube has not been evaluated.

How supplied

Dosage Forms And Strengths

5 mg tablets -round and white with “INCY” on one side and “5” on the other.

10 mg tablets -round and white with “INCY” on one side and “10” on the other.

15 mg tablets -oval and white with “INCY” on one side and “15” on the other.

20 mg tablets -capsule-shaped and white with “INCY” on one side and “20” on the other.

25 mg tablets -oval and white with “INCY” on one side and “25” on the other.

Storage And Handling

Ruxolitinib Phosphate (Ruxolitinib Phosphate) Tablets are available as follows:

Ruxolitinib Phosphate Trade Presentationss

Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Manufactured for: Incyte Corporation, Wilmington, DE 19803. Revised: March 2016

See also:
What is the most important information I should know about Ruxolitinib Phosphate?

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to Ruxolitinib Phosphate or any component of the formulation or container; history of or current progressive multifocal leukoencephalopathy

Use Ruxolitinib Phosphate as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Ruxolitinib Phosphate. Talk to your pharmacist if you have questions about this information.
• Take Ruxolitinib Phosphate by mouth with or without food. If you cannot take Ruxolitinib Phosphate by mouth, talk to your doctor.
• Do not eat grapefruit or drink grapefruit juice while you use Ruxolitinib Phosphate without first checking with your doctor.
• Do not stop taking Ruxolitinib Phosphate without talking with your doctor. If you need to stop Ruxolitinib Phosphate, your doctor may gradually lower your dose.
• Continue to take Ruxolitinib Phosphate even if you feel well. Do not miss any doses.
• If you miss a dose of Ruxolitinib Phosphate, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Ruxolitinib Phosphate.

This medication is used to treat certain bone marrow disorders (myelofibrosis, polycythemia vera). It works by blocking your body from producing substances called growth factors. Growth factors cause cells to grow and divide, and cause the blood cell and spleen problems found in these disorders. Ruxolitinib Phosphate belongs to a class of drugs known as JAK inhibitors. Though not a cure for these disorders, Ruxolitinib Phosphate may help with some of the symptoms, including abdominal discomfort, pain under left ribs, early feelings of fullness from meals, night sweats, itching, and bone/muscle pain.

How to use Ruxolitinib Phosphate

Read the Patient Information Leaflet if available from your pharmacist before you start taking Ruxolitinib Phosphate and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth with or without food as directed by your doctor, usually twice daily. If you are unable to swallow the tablets, ask your doctor about other ways to take this medication.

The dosage is based on your medical condition, laboratory test results, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Avoid eating grapefruit or drinking grapefruit juice while using this medication unless your doctor or pharmacist says you may do so safely. Grapefruit can increase the chance of side effects with this medicine. Ask your doctor or pharmacist for more details.

To reduce your risk of side effects, your doctor may direct you to start this medication at a low dose and gradually increase your dose. Follow your doctor's instructions carefully. Do not increase your dose or use this drug more often or for longer than prescribed. Your condition will not improve any faster, and your risk of side effects will increase.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day.

Do not stop taking Ruxolitinib Phosphate without consulting your doctor. Some conditions may become worse when this drug is suddenly stopped. Also, you may experience symptoms such as fever, trouble breathing, dizziness, and unusual bleeding/bruising. To prevent these symptoms while you are stopping treatment with this drug, your doctor may reduce your dose gradually. Consult your doctor or pharmacist for more details. Report any new or worsening symptoms right away.

Tell your doctor if your symptoms do not improve or if they worsen.

See also:
What other drugs will affect Ruxolitinib Phosphate?

Agents that May Alter Plasma Concentration of Ruxolitinib Phosphate: Strong CYP3A4 Inhibitors: In healthy subjects receiving ketoconazole, a strong CYP3A4 inhibitor, at 200 mg twice daily for four days, the AUC of Ruxolitinib Phosphate increased by 91% and the half-life was prolonged from 3.7 to 6.0 hours.

When administering Ruxolitinib Phosphate with strong CYP3A4 inhibitors the total daily dose of Ruxolitinib Phosphate should be reduced by approximately 50%.

Patients should be closely monitored for cytopenias and dose titrated based on safety and efficacy.

Mild or Moderate CYP3A4 Inhibitors: In healthy subjects receiving erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for four days, there was a 27% increase in the AUC of Ruxolitinib Phosphate.

No dose adjustment is recommended when Ruxolitinib Phosphate is co administered with mild or moderate CYP3A4 inhibitors (e.g. erythromycin). Patients should be closely monitored for cytopenias when initiating therapy with a moderate CYP3A4 inhibitor.

CYP3A4 Inducers: Upon initiation of a CYP3A4 inducer, no dose adjustment is recommended. Gradual dose increases of Ruxolitinib Phosphate may be considered if the effectiveness of therapy is diminished during treatment with a CYP3A4 inducer.

In healthy subjects receiving rifampin, a potent CYP3A4 inducer, at 600 mg once daily for ten days, the AUC of Ruxolitinib Phosphate following a single dose decreased by 71% and the half-life decreased from 3.3 to 1.7 hours. The relative amount of active metabolites increased in relation to parent compound.

P-glycoprotein and Other Transporters: No dose adjustment is recommended when Ruxolitinib Phosphate is co-administered with substances that interact with P-gp and other transporters.

Other Drug Interactions Studied: CYP3A4 Substrates: A study in healthy subjects indicated that Ruxolitinib Phosphate had no clinically significant pharmacokinetic interaction with midazolam (CYP3A4 substrate).

Oral Contraceptives:

See also:
What are the possible side effects of Ruxolitinib Phosphate?

Summary of the Safety Profile: The safety assessment was based on a total of 855 patients (with MF or PV) receiving Ruxolitinib Phosphate 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 Ruxolitinib Phosphate 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: As expected with an extended follow-up period, the cumulative frequency of some adverse events increased in the evaluation of the 3-year follow-up safety data (median duration of exposure of 33.2 months in COMFORT-I and COMFORT-II for patients initially randomised to Ruxolitinib Phosphate) from 457 patients with myelofibrosis treated with Ruxolitinib Phosphate during the randomised and extension periods of the two pivotal phase 3 studies. This evaluation included data from patients that were initially randomised to Ruxolitinib Phosphate (N=301) and patients that received Ruxolitinib Phosphate after crossing over from control treatment arms (N=156). With these updated data, therapy discontinuation due to adverse events was observed in 17.1% of patients treated with Ruxolitinib Phosphate.

Polycythaemia Vera: The safety of Ruxolitinib Phosphate was assessed in 110 patients with PV in an open-label, randomised, controlled phase 3 RESPONSE study. The adverse drug reactions listed as follows reflect the initial study period (up to week 32) with equivalent exposure to Ruxolitinib Phosphate and Best Available Therapy (BAT), corresponding to a median duration of exposure to Ruxolitinib Phosphate of 7.8 months. The mean age of patients receiving Ruxolitinib Phosphate was around 60 years.

Discontinuation due to adverse events, regardless of causality, was observed in 3.6% of patients treated with Ruxolitinib Phosphate and 1.8% of patients treated with best available therapy.

Haematological adverse reactions (any CTCAE grade) included anaemia (43.6%) and thrombocytopenia (24.5%). Anaemia or thrombocytopenia CTCAE grade 3 and 4 were reported in respectively 1.8% or 5.5%.

The three most frequent non-haematological adverse reactions were dizziness (15.5%), constipation (8.2%) and herpes zoster (6.4%).

The three most frequent non-haematological laboratory abnormalities (any CTCAE grade) were hypercholesterolaemia (30.0%), raised alanine aminotransferase (22.7%) and raised aspartate aminotransferase (20.9%). These were all CTCAE grade 1 and 2 with the exception of one CTCAE grade 3 raised alanine aminotransferase event.

Long-term safety: Patients had a median duration of exposure to Ruxolitinib Phosphate of 18.6 months (range 0.3 to 35.9 months). With longer exposure, frequency of adverse events increased; however no new safety findings emerged. When adjusted for exposure, the adverse event rates were generally comparable with those observed during the initial study period.

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 3) 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).

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

Description of Selected Adverse Drug Reactions: Anaemia: In phase 3 clinical studies in MF, 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 Ruxolitinib Phosphate mean decreases in haemoglobin reached a nadir of approximately 10 g/L below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 5 g/L 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 Ruxolitinib Phosphate-treated MF patients and 37.7% of placebo-treated MF 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 Ruxolitinib Phosphate arm and 41.1% in the best available therapy arm.

In the randomised period of the pivotal studies, anaemia was less frequent in PV patients than in MF patients (43.6% versus 82.4%). In the PV population, the CTCAE grade 3 and 4 events were reported in 1.8%, while in the MF patients the frequency was 42.56%.

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 Ruxolitinib Phosphate and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of patients receiving Ruxolitinib Phosphate and 0.9% of patients receiving control regimens. Patients with a platelet count of 100,000/mm³ to 200,000/mm³ before starting Ruxolitinib Phosphate had a higher frequency of grade 3 or 4 thrombocytopenia compared to patients with platelet count >200,000/mm³ (64.2% vs 38.5%).

In the randomised period of the pivotal studies, the rate of patients experiencing thrombocytopenia was lower in PV (24.5%) patients compared to MF (69.8%) patients. The frequency of severe (i.e. CTCAE grade 3 and 4) thrombocytopenia was lower in PV (5.5%) than in MF (11.6%) patients.

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% of patients, and 0.3% of patients discontinued treatment because of neutropenia.

In the randomised period of the pivotal study in PV patients, neutropenia was reported in two patients (1.8%) of which one patient developed CTCAE grade 4 neutropenia.

Bleeding: In the phase 3 pivotal studies in MF bleeding events (including intracranial and gastrointestinal, bruising and other bleeding events) were reported in 32.6% of patients exposed to Ruxolitinib Phosphate 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 Ruxolitinib Phosphate or reference treatments (4.7% vs 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 Ruxolitinib Phosphate compared with the reference treatments (21.3% vs 11.6%). Intracranial bleeding was reported in 1% of patients exposed to Ruxolitinib Phosphate and 0.9% exposed to reference treatments. Gastrointestinal bleeding was reported in 5% of patients exposed to Ruxolitinib Phosphate 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 Ruxolitinib Phosphate and 10.3% treated with reference treatments.

In the randomised period of the pivotal study in PV patients, bleeding events (including intracranial and gastrointestinal, bruising and other bleeding events) were reported in 20% of patients treated with Ruxolitinib Phosphate and 15.3% patients receiving best available therapy. Bruising was reported in similar frequencies in Ruxolitinib Phosphate and BAT arms (10.9% versus 8.1%). No intracranial bleeding or gastrointestinal haemorrhage events were reported in patients receiving Ruxolitinib Phosphate. One patient treated with Ruxolitinib Phosphate experienced a grade 3 bleeding event (post-procedural bleeding); no grade 4 bleeding was reported. Other bleeding events (including events such as epistaxis, post-procedural haemorrhage, gingival bleeding) were reported in 11.8% of patients treated with Ruxolitinib Phosphate and 6.3% treated with best available therapy.

Infections: In the phase 3 pivotal studies in MF, grade 3 or 4 urinary tract infection was reported in 1.0% of patients, herpes zoster in 4.3% and tuberculosis in 1.0%. In phase 3 clinical studies sepsis was reported in 3.0% of patients. An extended follow-up of patients treated with Ruxolitinib Phosphate showed no trends towards an increase in the rate of sepsis over time.

In the randomised period of the pivotal study in PV patients, one (0.9%) CTCAE grade 3 and no grade 4 urinary tract infection was reported. The rate of herpes zoster was slightly higher in PV (6.4%) patients than in MF (4.0%) patients. There was one report of CTCAE grade 3 post-herpetic neuralgia amongst the PV patients.

Increased Systolic Blood Pressure: In the phase 3 pivotal clinical studies in MF 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 (MF patients) the mean increase from baseline in systolic BP was 0-2 mmHg on Ruxolitinib Phosphate versus a decrease of 2-5 mmHg in the placebo arm. In COMFORT-II mean values showed little difference between the Ruxolitinib Phosphate-treated and the control-treated MF patients.

In the randomised period of the pivotal study in PV patients, the mean systolic blood pressure increased by 0.65 mmHg in the Ruxolitinib Phosphate arm versus a decrease of 2 mmHg in the BAT arm.

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.