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LETRRIBO

Cancer Type: Breast  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
    For the treatment of breast cancer according to clinical criteria
ODB Limited Use
    letrozole - Treatment of metastatic breast cancer in hormone receptor positive postmenopausal women
A - Regimen Name

LETRRIBO Regimen
Letrozole - Ribociclib


Disease Site
Breast

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 first-line treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative unresectable locally advanced or metastatic breast cancer

 


Supplementary Public Funding

ribociclib
Exceptional Access Program (For the treatment of breast cancer according to clinical criteria)

letrozole
ODB Limited Use (letrozole - Treatment of metastatic breast cancer in hormone receptor positive postmenopausal women)

 
B - Drug Regimen

letrozole
2.5 mg PO Daily
ribociclib
600 mg PO Days 1 to 21

 

Note: Must be given together with GnRH agonist if patient is premenopausal

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C - Cycle Frequency

Letrozole: Continuous

Ribociclib: Repeat every 28 days (3 weeks on, 1 week off)

 

Until disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended


Febrile Neutropenia Risk:

Low

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

 
E - Dose Modifications

  • Hypokalemia, hypomagnesemia and hypocalcaemia should be corrected prior to starting or continuing ribociclib.

  • Ribociclib should be started only in patients with QTcF < 450 msec.

Dosage with toxicity

Letrozole: No dosage adjustment necessary for hematological and/or non-hematological toxicities.

Dose Level

Ribociclib dose (mg/day) for 3 out of 4 weeks

Letrozole dose (mg/day) continuous

Starting dose

600

2.5

First dose reduction

400

2.5

Second dose reduction

200

2.5

Third dose reduction

Discontinue

2.5



 

Worst Toxicity from Previous Cycle

 

Grade

Ribociclib Dose

Neutrophils

 

Grade 3

Hold* until Grade 2. Restart at the same dose level.

If Grade 3 recurs hold until recovery to Grade 2, then ↓ 1 dose level.

 

Grade 4 or febrile neutropenia

Hold* until Grade 2. Restart by 1 dose level ↓.

QTcF

 

> 480 msec

Hold*;

If QTcF resolves to < 481 msec, restart at the same dose level.

If recurs, hold* until QTcF resolves to < 481 msec, then restart by 1 dose level ↓.

 

> 500 msec

Hold* if QTcF > 500 msec on at least 2 separate ECGs (within the same visit).

If QTcF resolves to < 481 msec, restart by 1 dose level ↓.

Torsade de Pointes, or
Polymorphic ventricular tachycardia,

or

Signs/symptoms of serious arrhythmia

 

Any

Discontinue.

Bilirubin 2x ULN

 

 

 

 

 

 

 

 

 

 

 

 

and

Grade 2 AST and/or ALT

Baseline Grade 2 – Continue.

Baseline Grade 0-1:

Hold* until ≤ baseline, then restart at same dose. If Grade 2 recurs, restart with 1 dose level ↓.

and

Grade 3 AST and/or ALT

Hold* until ≤ baseline, then restart with 1 dose level ↓.

If Grade 3 recurs, discontinue.

and

 

Grade 4 AST and/or ALT

Discontinue.

Bilirubin > 2 x ULN,
in the absence of cholestasis

and

Grade ³ 2 ALT and/or AST irrespective of baseline

Discontinue.

Other related toxicity

 

Grade 3

Hold* until Grade 1 then restart at same dose.

If Grade 3 recurs, restart by 1 dose level ↓.

 

Grade 4

Discontinue.

*Hold until ANC ≤ grade 2, QTcF ≤ 480 ms, other toxicities recovered to recovery to parameters as described in table above.



Hepatic Impairment

Hepatic Impairment

Ribociclib Dose

Letrozole Dose

Mild (Child-Pugh class A)

No dosage adjustment needed

No dosage adjustment needed

Moderate – Severe (Child-Pugh class B and class C)

400 mg once daily; only if benefit outweighs risk

No data in severe hepatic impairment. Monitor closely and consider dose modification.


Renal Impairment

Creatinine Clearance

Ribociclib Dose

Letrozole Dose

≥ 30 mL/min

No dosage adjustment needed

No dosage adjustment needed

< 30 mL/min

No data; use only if benefit outweighs risk

No data; use only if benefit outweighs risk

 


Dosage in the Elderly

No adjustment of the starting dose is required.  Older patients have an increased risk of osteoporosis and fracture with letrozole.
 

Dosage based on gender and ethnicity

No clinically relevant effects of gender or race on ribociclib pharmacokinetics parameters.


 
F - Adverse Effects

Refer to ribociclib , letrozole 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
  • Nausea, vomiting
  • Estrogen deprivation symptoms
  • Fatigue
  • ↑ LFTs (maybe severe)
  • Diarrhea
  • Alopecia
  • Constipation
  • Musculoskeletal pain
  • Edema
  • Headache
  • Creatinine increased
  • Rash, pruritus (maybe severe)
  • Electrolyte disturbances
  • Anorexia, weight loss
  • Fever
  • Dyspnea
  • Insomnia
  • Mucositis
  • Abdominal pain
  • Increased cholesterol
  • Osteoporosis, fracture
  • Arterial and venous thromboembolism
  • Arrhythmia
  • Cardiotoxicity
  • Hypersensitivity
  • Eye disorders
  • QT interval prolonged

 

 
G - Interactions

Refer to ribociclib , letrozole drug monograph(s) for additional details


  • Avoid concomitant use of ribociclib with strong CYP3A inhibitors. If strong inhibitors cannot be avoided, ribociclib dose should be reduced to 200mg.

  • Avoid concomitant use of ribociclib with strong CYP3A inducers.

  • Consideration should be given to reducing the dose of CYP3A4 substrates with narrow therapeutic indices when given concurrently with ribociclib.

  • Avoid concomitant use of drugs known to prolong QT, disrupt electrolyte levels and/or reduce heart rate.

  • Avoid concomitant use with tamoxifen and other anti-estrogens or estrogen-containing therapies.

  • Avoid grapefruit or pomegranate, grapefruit juice or pomegranate juice, or grapefruit or pomegranate - containing products which may increase ribociclib levels

 
H - Drug Administration and Special Precautions

Refer to ribociclib , letrozole drug monograph(s) for additional details


Administration: ribociclib

  • Can be taken with or without food.

  • Should be taken approximately at the same time each day, preferably in the morning.

  • Tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). Tablets that are broken, cracked, or otherwise not intact should not be ingested.

  • If the patient vomits or misses a dose, an additional dose should not be taken that day. The next dose should be taken the next day at the usual time.

  • Ribociclib should be stored at temperatures below 30°C and in original package to protect from moisture.

 

Administration: letrozole

  • Tablets should be taken with a glass of water, with or without food, at around the same time every day.

  • Do not crush or chew the tablets.

  • Missed doses should be taken as soon as possible, but should be skipped if within a few hours of the next planned dose.  Do not double the dose due to over-proportionality of exposure at doses above 2.5 mg daily.

  • Store tablets at room temperature (15-30°C).


Contraindications

  • Patients with hypersensitivity to ribociclib or letrozole, or any components in their formulation, or other aromatase inhibitors.

  • Patients with untreated congenital long QT syndrome, a QTcF interval of ≥450 msec at baseline, and those who are at significant risk of developing QTc prolongation (for example, uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina and bradyarrhythmia).

  • Premenopausal women and patients under 18 years of age.

  • Pregnancy or lactation.

  • Not indicated in hormone-receptor negative disease.
     

Other Warnings/Precautions:

  • Patients should exercise caution when driving or operating machinery as fatigue, dizziness and somnolence have been reported with ribociclib and letrozole.

  • Ribociclib is associated with concentration-dependent QTc prolongation, with expected maximal QTc prolongation during steady state treatment between days 8 and 21 of the 28-day cycle.

  • Avoid ribociclib use in patients with uncorrected hypokalemia, hypomagnesemia, or hypocalcemia.

  • Use ribociclib in caution in patients at risk of thromboembolic events.

  • Some brands of letrozole contain lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.

Pregnancy and Lactation:

  • Letrozole is contraindicated in pregnancy and lactation.
  • Ribociclib is not recommended for use in pregnancy. If treatment is used in women of childbearing potential, adequate contraception should be used by both sexes during treatment, and for at least 3 weeks after the last dose.
  • Ribociclib is not recommended in breastfeeding during therapy or for at least 3 weeks after the last dose.
  • Based on animal studies, ribociclib may impair male fertility.

 

 
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: At baseline, every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles and as clinically necessary.

  • ECG: Prior to treatment initiation, repeat on day 14 of cycle 1, at the beginning of cycle 2, at regular intervals thereafter (at approximately day 14 of the cycle) and as clinically indicated.

  • Liver function tests: At baseline, every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles and as clinically necessary. More frequent monitoring required in patients with ≥ grade 2 LFTs.

  • Electrolytes, including potassium, magnesium, calcium, and phosphorous: Prior to treatment, at regular intervals during steady-state treatment in later cycles, and whenever clinically indicated.

  • Bone mineral density; Baseline and regular.

  • Serum cholesterol and lipids evaluation; Baseline and regular.

  • Clinical toxicity assessment of infection, bleeding, thromboembolism, fatigue, estrogen withdrawal symptoms, eye problems and cardiac, bone,  gastrointestinal, skin and musculoskeletal effects; 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

Ribociclib and letrozole drug monographs, Cancer Care Ontario.

Hortobagyi, G. N. et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. New Engl. J. Med. 375, 1738–1748 (2016).

Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol 2018;29:1541-1547.

Tripathy D, Im S, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial.

September 2019 Updated EAP funding (for ribociclib) and rationale/uses section


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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.
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