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ruxolitinib
Ruxolitinib is a Janus kinase (JAK) inhibitor, with selectivity for JAK1 and JAK2 which mediate the signaling of cytokines and growth factors for hematopoiesis and immune function. In myelofibrosis and polycythemia vera, JAK1/2 activity is dysregulated. Ruxolitinib interrupts JAK-STAT signaling and inhibits cell proliferation.
Rapidly absorbed; dose proportional pharmacokinetics
| Bioavailability | 95% or greater, no significant effects with food administration |
| Peak plasma levels | 1 hour |
Rapidly and widely distributed
| PPB | 97%, mostly to albumin |
| Cross blood brain barrier? | No |
Metabolized mainly in the liver by CYP3A4, and to a lesser extent by CYP2C9
| Active metabolites |
Yes |
| Urine | 74% (< 1% unchanged) |
| Feces | 22% (< 1% unchanged) |
| Half-life |
3 hours for ruxolitinib alone 5.8 hours for ruxolitinib + metabolites |
- Myelofibrosis (MF)
- Polycythemia vera (PV)
- Graft-versus-host disease (GVHD)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
The following side effect information is based on two pivotal phase II studies (COMFORT I and II) and one phase II supporting study involving myelofibrosis (MF) patients. Side effect information specific to polycythemia vera (PV) patients is derived from a pivotal phase III study (RESPONSE) and a supporting phase II study. This table also includes severe or life-threatening adverse effects from other sources.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Angina (4%-MF) | E D | |||
| Bradycardia (3%- MF, 7%-PV) | E | ||||
| Endocarditis infective (rare) | E D | ||||
| Hypertension (5%-PV) | E D | ||||
| Palpitations (5%) (MF) | E | ||||
| PR interval prolonged (12%) | E D | ||||
| Venous thromboembolism (rare) | E | ||||
| Gastrointestinal | Constipation (8%-PV) | E D | |||
| Diarrhea (15%-PV) | E D | ||||
| Nausea (6%-PV) | E D | ||||
| Weight gain (11%-MF, 5%-PV) | E D | ||||
| General | Fever (15%) (MF) | E | |||
| Hematological | Myelosuppression ± infection, bleeding (82%-MF, 44%-PV) (may be severe, includes viral reactivation, opportunistic/atypical infections such as tuberculosis) | E | |||
| Other - Withdrawal/rebound syndrome (MF) | E | ||||
| Hepatobiliary | ↑ LFTs (28%) (MF) | E | |||
| Metabolic / Endocrine | Hyperlipidemia (17%-MF, 30%-PV) | E | |||
| Musculoskeletal | Musculoskeletal pain (Muscle spasms, back pain) (12%-PV) | E D | |||
| Neoplastic | Secondary malignancy (Non-melanoma skin cancers) | E D | |||
| Nervous System | Dizziness (19%-MF; 12%-PV) | E | |||
| Headache (16%) (MF) | E | ||||
| Leukoencephalopathy (PML) (rare) | E | ||||
| Other -Tinnitis (6%-PV) | E D | ||||
| Respiratory | Cough, dyspnea (10%-PV) | E D | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for ruxolitinib include myelosuppression ± infection, bleeding, hyperlipidemia, ↑ LFTs, dizziness, headache, diarrhea, musculoskeletal pain, weight gain and cough.
Major adverse cardiovascular events (MACE), arterial/venous thrombosis, and/or malignancy, including fatal outcomes, have been reported with the JAK inhibitor tofacitinib. Consider the benefits and risks prior to initiating, or continuing, therapy of JAK inhibitors, especially in patients > 65 years, who are current or past smokers, or with other cardiovascular, thrombosis or malignancy risk factors.
Bradycardia and PR interval prolongation have been reported in the phase 3 clinical trials. Significant QTc increases were observed with ruxolitinib in a phase 3 clinical trial when compared with best available therapy, but no difference was demonstrated in another clinical trial which compared ruxolitinib to placebo.
Venous thromboembolism (VTE), including fatal cases, has been reported with the use of JAK inhibitors. Based on case reports, there is a possible link between ruxolitinib and VTE; however, patients also had blood disorders that may increase the risk of VTE.
Lipid abnormalities, including increases in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides have been reported. Patients should be monitored and treated according to guidelines.
Increases in systolic pressure by 20 mmHg or more from baseline were reported in some trials but are of unclear significance.
Dose-related myelosuppression can occur, including anemia, neutropenia and thrombocytopenia. Median time of onset of myelosuppression is 6 - 12 weeks as observed in the phase 3 trials. Patients with low platelet counts at baseline (< 200 x 109/L) are at higher risk of experiencing thrombocytopenia during treatment.
Bleeding events reported in the phase 3 clinical trials include intracranial, gastrointestinal, bruising, epistaxis, post-procedural hemorrhage and hematuria (and may be severe).
Herpes zoster infections have been reported in phase 3 clinical trials. Prompt treatment is required when signs and symptoms of this infection present. PML (JC virus) has been reported and may be life-threatening. Ruxolitinib should be held if PML is suspected and discontinued if it is confirmed.
Hepatitis B viral load increases have been reported in patients with chronic HBV infections taking ruxolitinib. These patients should be treated and monitored according to clinical guidelines.
Tuberculosis has been reported, including fatal cases, with patients receiving ruxolitinib.
Visual disorders, including loss of vision, secondary to eye infection is a risk with ruxolitinib. Other severe infections have also been reported, including fungal, as well as sepsis and endocarditis
Withdrawal effects may occur following interruption or discontinuation of ruxolitinib in patients with myelofibrosis, which may include symptoms of myelofibrosis returning, or septic shock-like symptoms within 1 week. Gradual tapering of ruxolitinib should be considered; however, the benefit of this practice is unproven.
Non-Melanoma Skin Cancers (NMSC’s), including basal cell, squamous cell, and Merkel cell carcinoma have been reported in patients treated with ruxolitinib, although a causal relationship has not been established. Most of the patients had previous extended hydroxyurea use or pre-malignant skin lesions. Patients are advised to minimize risk factors, such as UV exposure, and periodically examine skin (especially those who have other skin cancer risk factors).
Refer to protocol by which patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Perform tuberculosis skin test and/or Interferon-gamma release assay before treatment initiation. Caution with interpreting results in severely immunocompromised patients due to possible false negatives.
Starting dose is based on indication, platelet and neutrophil counts, and degree of hepatic or renal impairment.
Treatment should not be started until neutrophils are ≥ 1 x 109/L and platelets ≥ 50 x 109/L.
Refer to product monograph for GVHD dosing information.
Refer to Interactions section for dosing recommendations when co-administered with CYP3A4 inhibitors.
Other supportive care:
- Patients should minimize exposure to risk factors for skin cancer such as exposure to sunlight.
Starting Dose
|
ANC ( x109/L)
|
Platelet Count ( x109/L) |
Starting Dose Myelofibrosis |
Starting Dose Polycythemia vera |
|
> 1 |
> 200 |
20 mg PO twice daily |
10 mg PO twice daily |
| > 1 | 100 - 200 |
15 mg PO twice daily |
10 mg PO twice daily |
| > 1 | 75 - 99 | 10 mg PO twice daily | 5 mg PO twice daily |
|
> 1 |
50 - 74 |
5 mg PO twice daily |
5 mg PO twice daily |
| ≤ 1 | < 50 | Do not use | Do not use |
Titration of Dose
If response to treatment is inadequate (for MF or PV), escalation may proceed as detailed below. The maximum dose is 25 mg PO BID.
The starting dose should not be increased during the first 4 weeks of treatment (for patients with MF) and 8 weeks of treatment (for PV).
Discontinue after 6 months if no improvement in symptoms or spleen size (MF) or after 16 months if no clinical benefit (PV).
|
ANC
|
|
Platelets (x 109/L)
|
At 4 weeks (MF), |
Every 2 weeks (or more) thereafter |
|
>0.75
|
AND
|
> 125 (and nadir >100)
|
↑ by 5mg bid
|
↑ by 5mg bid, if blood counts criteria are met. |
|
≤0.75
|
OR
|
≤ 125 (or nadir < 100 )
|
Do not escalate.
|
Do not escalate.
|
MF or PV:
|
Toxicity (x 109/L)
|
Action
|
| Hb < 80 g/L (PV pts only) | Hold; when Hb recovers, may restart at 5 mg PO twice daily and titrate gradually. |
| Hb < 120 g/L (PV pts only) | Consider dose reduction, especially if Hb < 100 g/L. |
| Platelets < 50 or ANC < 0.5 |
Hold; when platelet and ANC counts above these levels, may restart at 5 mg PO twice daily and titrate gradually.
|
| Platelets 50 to < 125 (MF pts only) | Refer to Dose Modification for Thrombocytopenia table below to minimize holds. May titrate gradually if appropriate. |
| PML, active tuberculosis, severe infection | Hold and investigate; discontinue if confirmed. |
| Bleeding requiring intervention (regardless of platelet count) | Hold until event is resolved; consider restart at previous dose if cause of bleeding controlled. If the underlying cause persists, consider restart at a lower dose. |
Dose Modification for Thrombocytopenia (MF)
|
|
Dose at Time of Platelet Decline |
||||
|
Platelet count |
25 mg BID
|
20 mg BID
|
15 mg BID
|
10 mg BID
|
5 mg BID
|
|
|
New dose
|
New dose
|
New dose
|
New dose
|
New dose
|
|
100 to < 125
|
20 mg BID |
15 mg BID |
No change |
No change |
No change |
|
75 to < 100
|
10 mg BID |
10 mg BID |
10 mg BID |
No change |
No change |
|
50 to < 75
|
5 mg BID |
5 mg BID |
5 mg BID |
5 mg BID |
No change |
Avoid use in patients with hepatic impairment and platelets < 100 x 109/L.
|
Hepatic impairment
|
Ruxolitinib Dose (MF or PV)
|
|
None
|
No adjustment required.
|
|
Any degree
|
Start at 50% of usual dose*. Monitor carefully and adjust as appropriate. |
*round up to the nearest dosage strength, if necessary.
Avoid use in patients with moderate to severe renal impairment if platelets < 100 x 109/L.
Hemodialysis is not expected to enhance the elimination of ruxolitinib.
|
Renal Impairment
|
Ruxolitinib Dose (MF or PV)
|
|
Mild
|
No adjustment required. |
|
Moderate (CrCl 30-50 mL/min)
|
Start at 50% of usual dose*. Monitor closely for toxicity. Avoid if platelets < 100 x 109/L. |
|
Severe (CrCl < 30 mL/min)
|
|
|
Patients on hemodialysis |
Single dose given only after each dialysis session based on platelet count. MF: 15 mg for platelets 100-200 x 109/L; 20mg for platelets > 200 x 109/L PV: 10 mg |
*round up to the nearest dosage strength, if necessary
No dosage adjustments required. No overall differences in safety or effectiveness were observed between patients > 65 years of age and younger patients with MF or PV.
Female MF patients may be at a higher risk of anemia than male patients. Ruxolitinib clearance in women with MF was lower compared to men, however, no specific dose adjustment has been recommended.
Safety and effectiveness of ruxolitinib in pediatric patients with MF or PV have not been established.
- Administer with or without food with a glass of water.
- The tablets should be swallowed whole; do not cut, break, dissolve, crush or chew the tablets.
- Avoid grapefruit, starfruit, Seville oranges, their juices or products during treatment.
- If a dose is missed, skip this dose and take the next dose as scheduled. Do not double the dose to make up for the missed one.
- Store at room temperature (15-25°C).
- Patients who have a hypersensitivity to this drug or any of its components
- Patients who have/had progressive multifocal leukoencephalopathy (PML)
- Major adverse cardiovascular events (MACE), arterial/venous thrombosis, and/or malignancy, including fatal outcomes, have been reported with the JAK inhibitor tofacitinib. Consider the benefits and risks prior to initiating, or continuing, therapy of JAK inhibitors, especially in patients > 65 years, who are current or past smokers, or with other cardiovascular, thrombosis or malignancy risk factors.
- Ruxolitinib can cause bradycardia and prolongation of PR interval; use with caution in patients on drugs with similar effects or with history of cardiovascular disease including bradycardia, syncope or arrhythmia, sick sinus syndrome, sinoatrial block, atrioventricular (AV) block, ischemic heart disease, or congestive heart failure.
- Serious bacterial, mycobacterial, fungal, and viral infections including viral reactivation and opportunistic infections (in some cases fatal) have been reported. Do not administer ruxolitinib in patients with active tuberculosis or active serious infections.
- Contains lactose and should not be used in patients with hereditary lactase/glucose or galactose disorders.
Other Drug Properties:
-
Carcinogenicity:
Unknown
-
Embryotoxicity:
Documented in animals
-
Fetotoxicity:
Documented in animals
-
Mutagenicity:
No
-
Clastogenicity:
No
-
Teratogenicity:
Unknown
-
Crosses placental barrier:
Yes
Ruxolitinib is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose (general recommendation).
-
Excretion into breast milk:
Documented in animals
Breastfeeding is not recommended during treatment and for 2 weeks after the last dose. -
Fertility effects:
Probable
Concurrent use of hematopoietic growth factors or cytoreductive agents and ruxolitinib has not been studied.
Monitor more frequently for cytopenias (e.g., twice a week) when starting a strong CYP3A4 inhibitor or combined moderate CYP2C9 and CYP3A4 inhibitors. Avoid concomitant use if platelet < 100.
Refer to product monograph for management in GVHD.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir) | ↑ ruxolitinib concentration and/or toxicity (↑ 91% in AUC) | ↓ metabolism of ruxolitinib | For MF and PV, ↓ ruxolitinib by 50% with concomitant use of strong CYP3A4 inhibitors. Monitor for cytopenias. Avoid concomitant use if platelet < 100. |
| Moderate CYP3A4 inhibitors (e.g., erythromycin, ciprofloxacin, fruit or juice from grapefruit, Seville oranges or starfruit) | ↑ ruxolitinib concentration and/or toxicity (↑ 27% in AUC) | ↓ metabolism of ruxolitinib | Monitor for cytopenias. |
| Combined moderate CYP2C9 and CYP3A4 inhibitors (e.g., fluconazole) | ↑ ruxolitinib concentration and/or toxicity (↑ 232% in AUC) | ↓ metabolism of ruxolitinib | ↓ ruxolitinib by 50%; avoid fluconazole doses > 200 mg daily. Monitor for cytopenias. Avoid concomitant use if platelet < 100. |
| Drugs that decrease heart rate and/or prolong the PR interval (ie. antiarrhythmics, beta blockers, digitalis glycosides, cholinesterase inhibitors, HIV protease inhibitors, non-dihydropyridine calcium channel blockers) | ↑ risk of bradycardia and/or ↑ PR interval | Additive | Avoid if possible. |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline, every 2 - 4 weeks until doses are stabilized, and then as clinically indicated. Monitor more frequently for cytopenias (e.g., twice a week) when starting a strong CYP3A4 inhibitor or combined moderate CYP2C9 and CYP3A4 inhibitors. |
Liver and renal function tests |
Baseline and as clinically indicated |
Lipids (total cholesterol, LDL, triglycerides) |
Prior to starting, 4 weeks after starting, then as clinically indicated |
Pulse rate and blood pressure |
Baseline and as clinically indicated |
ECG |
Baseline and as clinically indicated |
Clinical toxicity assessment for cardiovascular effects, infections (including ocular), bleeding, thrombosis, skin effects (including malignancies) and withdrawal syndrome (if applicable) |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Exceptional Access Program (EAP Website)
- ruxolitinib - For patients with intermediate to high risk symptomatic myelofibrosis, or patients with symptomatic splenomegaly, according to specific criteria
- ruxolitinib - For the treatment of patients with polycythemia vera according to criteria.
Harrison C, Kiladjian J, Kathrin Al-Ali H, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012;366-787-98.
Health Professional Risk Communication. Janus Kinase Inhibitors and the Risk of Major Adverse Cardiovascular Events, Thrombosis (Including Fatal Events) and Malignancy. Health Canada. November 2022.
Prescribing information: Jakafi® (ruxolitinib). Incyte Corporation (US), September 2021.
Product monograph: Jakavi® (ruxolitinib). Novartis Pharmaceuticals Canada Incorporated, June 8, 2022.
Summary Safety Review - Xeljanz and Xeljanz XR (tofacitinib), and Jakavi (ruxolitinib) - Janus Kinase (JAK) inhibitors - Health Canada. June 2020.
Tefferi A and Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clinic Proceedings 2011;86(12):1188-91.
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012;366:799-807.
February 2023 Updated Mechanism of Action, Indications, Adverse Effects, Dosing, Administration Guidelines, Special Precautions, Interactions, and Monitoring sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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