Les renseignements du Formulaire de médicaments s’adressent aux professionnels de la santé. Il ne s’agit pas d’un avis médical. Certains des renseignements, y compris ceux sur le financement des médicaments anticancéreux, ne s’appliquent pas à tous les patients. Les plans de traitement du cancer sont propres à chaque patient. Si vous êtes un patient, veuillez parler avec votre équipe soignante pour comprendre comment ces renseignements s’appliquent à vous.
FLOX
Small bowel and appendix
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.
Adjuvant treatment of stage III and high risk stage II colorectal cancer
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oxaliplatin 1
| 85 mg /m² | IV in 500mL D5W over 120 minutes | Days 1, 15 and 29 |
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leucovorin 1
| 500 mg /m² | IV diluted in D5W over 120 minutes (after oxaliplatin infusion on days 1, 15, and 29) | Days 1, 8, 15, 22, 29 and 36 |
| fluorouracil | 500 mg /m² | IV as bolus, 1 hour after leucovorin infusion has begun | Days 1, 8, 15, 22, 29, 36 |
1 Oxaliplatin and leucovorin were not given concurrently in the trial.
REPEAT EVERY 56 DAYS
For a maximum total of 3 cycles unless disease progression or unacceptable toxicity occurs
Moderate (Days 1, 15, 29)
Low (Days 8, 22, 36)
Moderate
Other Supportive Care:
Also refer to CCO Antiemetic Recommendations.
Doses should be modified according to the protocol by which the patient is being treated.
Patients should be tested for DPD deficiency before starting treatment with fluorouracil. Refer to the DPD Deficiency Guidance for Clinicians for more information.
In patients with unrecognized DPD deficiency, acute, life-threatening toxicity may occur; if acute grade 2-4 toxicity develops, treatment should be stopped immediately and permanent discontinuation considered based on clinical assessment of the toxicities.
Dosage with toxicity
No dose adjustments required for leucovorin.
Neurotoxicity was graded based on the following scales in some adjuvant colorectal cancer trials.
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Neurotoxicity Grade |
Adjuvant
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1
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No change or none |
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2
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Mild paresthesias, loss of deep tendon reflexes |
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3
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Mild or moderate objective sensory loss, moderate paresthesias |
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4
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Severe objective sensory loss or paresthesias that interfere with function |
Dose Modifications:
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Toxicity Grade |
Oxaliplatin^ |
Fluorouracil^ |
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Persistent(1) Grade 2 Neurotoxicity |
↓ from 85 → 75 mg/m2
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No change |
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Transient(1) Grade 3 Neurotoxicity |
↓ from 85 → 75 mg/m2
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No change |
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Persistent(1) ≥ Grade 3 Neurotoxicity or any Grade 4 Neurotoxicity |
Discontinue
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No change |
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≥ Grade 3 GI toxicity (after prophylaxis) OR Grade 3 or 4 Platelets OR Grade 3 or 4 Neutropenia (including febrile neutropenia)* |
↓ from 85 → 75 mg/m2 *
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Reduce by 20% * |
| Sepsis / septic shock | Discontinue | Discontinue4 |
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Other ≥ grade 3 related organ toxicity(2)
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↓ from 85 → 75 mg/m2
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Reduce by 20% |
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Pharyngolaryngeal dysesthesia
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Hold; then increase duration of infusion to 6 hours(3) |
No change
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Pneumonitis
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Hold, investigate; discontinue permanently if confirmed4 |
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PRES or hemolytic uremic anemia or any signs of microangiopathic hemolytic anemia
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Discontinue permanently4
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^Do not re-treat until the ANC ≥ 1.5 x 109/L and the platelets ≥ 100 x 109/L, GI and neurotoxicities have resolved and other non-hematologic toxicities ≤ grade 1.
1 Transient = 7-14 days; persistent = ≥ 14 days
2 For skin toxicity, reduce 5FU dose only
3 If oxygen saturation is normal, an anxiolytic agent may be given.
4 Do not give leucovorin if fluorouracil is omitted.
* Discontinue if septic shock.
Hepatic Impairment
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Bilirubin
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AST/ALT
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oxaliplatin (% previous dose) |
fluorouracil (% previous dose) |
leucovorin (% previous dose) |
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1-2 x ULN |
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No change |
Caution
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No change |
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>2-4 x ULN |
And/or
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2-4 x ULN |
No change |
Caution
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No change |
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>4 x ULN |
And/or
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4 x ULN
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No data available |
OMIT if Bilirubin > 4 x ULN |
OMIT if 5FU omitted |
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ANY
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Or
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> 4 X ULN |
No data available |
OMIT if Bilirubin > 4 x ULN |
OMIT if 5FU omitted |
Renal Impairment
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Creatinine Clearance (mL/min)
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oxaliplatin
(% previous dose)
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fluorouracil (% prevoius dose) |
leucovorin (% prevoius dose) |
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50 - 80
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No change
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No change | No change |
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30 - <50
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Caution
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No change; monitor | No change |
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<30
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Discontinue
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Consider dose ↓ | No change |
Dosage in the Elderly
Patients ≥ 65 years had a higher incidence of GI toxicity, myelosuppression, syncope and fatigue. No dose adjustments were needed but caution should be exercised.
Dosage based on gender:
Women may be at higher risk of severe (grades 3-4) neutropenia in adjuvant treatment of colorectal cancer.
Refer to oxaliplatin, leucovorin, fluorouracil drug monograph(s) for additional details of adverse effects
| Most Common Side Effects |
Less Common Side Effects, but may be |
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Refer to oxaliplatin, leucovorin, fluorouracil drug monograph(s) for additional details
- Avoid concomitant use of drugs affecting hepatic metabolism (i.e. cimetidine) due to increased serum concentrations and toxicity of fluorouracil
- Avoid metronidazole use as it may decrease the clearance of fluorouracil
- Fluorouracil may increase phenytoin levels and toxicity; monitor levels and patient
- Avoid thiazide diuretics as they may decrease renal excretion of fluorouracil
- Warfarin clearance may be reduced. Monitor INR closely and adjust warfarin dose as necessary
Refer to oxaliplatin, leucovorin, fluorouracil drug monograph(s) for additional details
Drug Administration
Oxaliplatin:
- Oxaliplatin should always be administered before fluorouracil.
- May be mixed in 250-500 mL bag (D5W only - not NS, chloride containing or alkaline solutions, and should not be mixed with fluorouracil) and given by slow infusion. Concentration must be between 0.2 to 0.7 mg/mL
- Infuse IV over 2 hours. Increasing infusion time to 6 hours may decrease acute toxicity such as pharyngolaryngeal dysesthesia.
- Do not use with injection equipment containing aluminum, as this can degrade platinum compounds.
- Unopened vials should be stored at 15-30°C; protect from light.
Leucovorin:
- Leucovorin should be given prior to fluorouracil
- Dilute in D5W and infuse IV over 120 minutes
Fluorouracil:
- Slow push through sidearm of free-flowing IV (5% Dextrose, Normal Saline)
- May be mixed in 50mL minibag (NS or D5W); infuse over 15 min.
- Protect from light
Contraindications
- Severe myelosuppression induced by prior chemotherapy or radiotherapy
- Patients with poor nutritional state
- Patients with potentially serious infections
- Oxaliplatin is contraindicated in patients with hypersensitivity to the drug or to other platinum agents (e.g. cisplatin, carboplatin) and in patients with severe renal impairment (Clcr < 30 mL/min).
- Fluorouracil is contraindicated in patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) activity. Refer to the DPD Deficiency Guidance for Clinicians for more information.
Other Warnings/Precautions
- Patients should be warned about cold avoidance prior to treatment and ice for mucositis prophylaxis should not be used.
- Oxaliplatin may result in dizziness or visual disturbrances (including transient vision loss) in some patients; patients should exercise caution in driving or operating machinery.
- Use with extreme caution in patients who have undergone recent major surgery, with renal or hepatic impairment, widespread bone marrow involvement, or are suspected to have DPD deficiency. Refer to the DPD Deficiency Guidance for Clinicians for more information.
- Avoid live vaccines; use may result in serious infections in immunocompromised patients.
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 before each treatment
- Electrolytes, including magnesium; baseline and before each cycle
- INR, if patient on anticoagulants; as clinically indicated
- Liver function tests; baseline and before each cycle
- Renal function tests; baseline and before each cycle
- Clinical assessment of GI effects, neurotoxicity, infection, bleeding, stomatitis, diarrhea, skin effects, thromboembolism, hypersensitivity, local reactions, respiratory or ophthalmic effects; at each visit
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Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
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Fluorouracil, oxaliplatin, leucovorin drug monographs, Cancer Care Ontario.
Kuebler JP, Wieand S, O’Connel MJ et al. Oxaliplatin Combined With Weekly Bolus Fluorouracil and Leucovorin As Surgical Adjuvant Chemotherapy for Stage II and III Colon Cancer: Results From NSABP C-07. JCO 25(16) June 2007: 2198-2204.
April 2023 Updated DPD deficiency information in the Dose Modifications and Special Precautions sections and fluorouracil antidote information in the Other Notes section.
Antidote for Fluorouracil Overdose:
Uridine triacetate is a prodrug of uridine and is a specific antidote for treating fluorouracil overdose or severe early onset toxicities. If available, consider administering as soon as possible (i.e. within 96 hours) for suspected overdose. If not available, treatment is symptomatic and supportive.
For usage approval and supply, contact Health Canada’s Special Access Program (SAP) (Phone: 613-941-2108. On-call service is available for emergencies). Uridine triacetate (Vistogard®) is supplied by its manufacturer in the United States (Wellstat Therapeutics).
The recommended dosing and administration for uridine triacetate in patients ≥18 years is:
- 10 grams (1 packet of coated granules) orally every 6 hours for 20 doses in total, without regards to meals.
- Granules should not be chewed. They should be mixed with 3 to 4 ounces of soft foods such as applesauce, pudding or yogurt.
- The dose should be ingested within 30 minutes of preparation, followed by at least 4 ounces of water.
- Refer to the prescribing information on dose preparation for NG-tube or G-tube use.
Additional resources on the management of fluorouracil infusion overdose:
- Management of Fluorouracil Infusion Overdose Guideline (Alberta Health Services)
- Management of Fluorouracil Infusion Overdose at the BCCA - Interim Guidance (BC Cancer Agency)
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.