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RUXO

Cancer Type: Hematologic, Myeloproliferative Neoplasms (MPNs)  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
    ruxolitinib - For patients with intermediate to high risk symptomatic myelofibrosis, or patients with symptomatic splenomegaly, according to specific criteria
Exceptional Access Program
    ruxolitinib - For the treatment of patients with polycythemia vera according to criteria.
A - Regimen Name

RUXO Regimen
Ruxolitinib


Disease Site
Hematologic - Myeloproliferative Neoplasms (MPNs)

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

For the treatment of splenomegaly and/or its associated symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis.

For the control of hematocrit in adult patients with polycythemia vera (PV) resistant to or intolerant of a cytoreductive agent.

 

 

 

 


Supplementary Public Funding

ruxolitinib
Exceptional Access Program (ruxolitinib - For patients with intermediate to high risk symptomatic myelofibrosis, or patients with symptomatic splenomegaly, according to specific criteria) (EAP Website)

ruxolitinib
Exceptional Access Program (ruxolitinib - For the treatment of patients with polycythemia vera according to criteria.) (EAP Website)

 
B - Drug Regimen

ruxolitinib

Starting dose is based on platelet and neutrophil counts, indication being treated, as well as degree of hepatic and renal impairment.  Treatment should not be started until neutrophils are ≥ 1 x 109/L and platelets ≥ 50 x 109/L.

ANC ( x109/L)
Platelet Count ( x109/L)
Starting Dose Myelofibosis
Starting Dose Polycthemia 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
50 - 100
Use with extreme caution; 5 mg PO twice daily
5 mg PO twice daily
≤ 1 < 50 Do not use Do not use

 

Refer to section E for dose titrations, if applicable.
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C - Cycle Frequency

CONTINUOUS TREATMENT

Until disease progression or unacceptable toxicity; must be discontinued after 6 months if no evidence of improvement in symptoms or spleen size (MF) or after 16 months if no clinical benefit (PV).

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered.

Titration of Dose

If response to treatment is inadequate, escalation may proceed as detailed below. The maximum dose is 25 mg PO BID

The starting dose should not be increased within the first 4 weeks of treatment (for patients with MF) and 8 weeks of treatment (for PV).  In patients with MF, ruxolitinib should be discontinued after 6 months if no improvement in spleen size or symptoms has been documented.  In patients with PV, discontinue after 16 months if no clinical benefit

 

ANC
 
Platelets (x 109/L) 
At 4 weeks
Every 2 weeks thereafter
>0.75
AND
>125 (and nadir >100)
 
↑ by 5mg bid
↑ by 5mg bid, if counts criteria in the first column are met.
≤0.75
OR
 ≤ 125 (or nadir < 100 )
Do not escalate
Do not escalate

 

 

 

Dosage with toxicity

Table A:

Toxicity (x 109/L)
Action
Hb* <80 g/L  (PV pts only) Hold; when recovered, 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 Follow dose modification table (Table B) 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.

* for PV patients only

 

Table B:

 

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

 

 



Hepatic Impairment

Avoid use in patients with hepatic impairment and platelets < 100 x 109/L.

Hepatic impairment
Starting Dose
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.  


Renal Impairment

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
Starting Dose
Mild

No adjustment required

Moderate (CrCl 30-50 mL/min)

Avoid if platelets < 100 x 109/L. Start at 50% of  usual dose*

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

Dosage in the elderly:

No dosage adjustments required.

Dosage based on gender:

Female MF patients may be at a higher risk of anemia than male patients.  No specific dose adjustment has been recommended.


 
F - Adverse Effects

Refer to drug monograph(s) for additional details of adverse effects


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Myelosuppression ± infection, bleeding (83%) (may be severe, includes atypical infections (fungal, viral, TB), viral reactivation and endocarditis)
  • ↑ LFTs
  • Dizziness
  • Hyperlipidemia
  • Headache
  • Diarrhea
  • Musculoskeletal pain
  • Weight gain
  • Cough, dyspnea
  • Angina
  • Bradycardia
  • Prolonged QT interval
  • Secondary malignancy
  • Withdrawal syndrome
 
G - Interactions

Refer to ruxolitinib drug monograph(s) for additional details


  • CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges, starfruit or pomegranate) can decrease metabolism and increase concentration fo ruxolitinib.
  • Do not use strong CYP3A4 inhibitors with ruxolitinib if platelets < 100. Avoid strong CYP3A4 inhibitors in general; if must use, ↓ ruxolitinib by 50% . Caution when using mild and moderate inhibitors. Monitor for cytopenias and other toxicity
  • Decrease ruxolitinib dose by 50% if used with moderate CYP2C9 and CYP3A4 inhibitors (e.g fluconazole); avoid fluconazole at doses > 200mg daily
  • If possible, avoid drugs that decrease heart rate and/or prolong the PR interval due to increased risk of bradycardia
 
H - Drug Administration and Special Precautions

Refer to ruxolitinib drug monograph(s) for additional details


Administration:

  • Prescribed dose should be administered orally on an empty stomach or with food with a large 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 (15-30°C).

Special Precautions

Contraindications:

  • Patients who have a hypersensitivity to this drug or any of its components
  • Patients with active tuberculosis or active serious infections
  • Patients who have/had progressive multifocal encephalopathy (PML)

Other Warnings/Precautions:

  • Serious bacterial, mycobacterial, fungal, and viral infections including viral reactivation and opportunistic infections (in some cases fatal) have been reported.
  • Contains lactose and should not be used in patients with hereditary lactase/glucose or galactose disorders
  • 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
  • Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose (general recommendation)
  • Breastfeeding is not recommended
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

  • CBC; baseline and regular; Should be monitored every 2 - 4 weeks until doses are stabilized, and then as clinically indicated
  • ECG; baseline and periodic
  • Liver and renal function tests; baseline and periodic
  • Lipid monitoring; prior to starting, 4 weeks after starting, then periodic
  • Pulse rate and blood pressure; baseline and regular
  • Tuberculosis skin test and/or Interferon-gamma release assay; caution with interpreting results in severely immunocompromised patients due to possible false negatives; baseline;
  • Clinical toxicity assessment for cardiovascular, infections (including ocular),  bleeding symptoms; at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Outpatient prescription for home administration


 
K - References

Ruxolitinib drug monograph, Cancer Care Ontario.

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.

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.

June 2019 Updated emetic risk category


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.