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ribociclib

( rye-boe-SYE-klib )
Funding:
Exceptional Access Program
  • ribociclib - First-line treatment of hormone receptor positive, human epidermal growth factor receptor 2 (HER 2)-negative unresectable locally advanced breast cancer or metastatic breast cancer, with specific criteria
Other Name(s): Kisqali™
Appearance: Tablet.    
A - Drug Name

ribociclib

COMMON TRADE NAME(S):   Kisqali™

 
B - Mechanism of Action and Pharmacokinetics

Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6.  The cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb).  Inhibition of pRb phosphorylation arrests the cell cycle in the G1 phase, suppressing DNA synthesis and inhibiting cancer cell growth.



Absorption
Effects with food

No clinically significant effect

Peak plasma levels

Achieved between 1 and 4 hours

Time to reach steady state

8 days


Distribution
PPB

70%

Distribution Sites

Equally distributed between red blood cells and plasma

Cross blood brain barrier?

Relatively low brain penetration observed in animals with intact blood brain barriers.

Metabolism

  • Ribociclib undergoes extensive hepatic metabolism mainly via CYP3A4. 
  • No major metabolite was considered to have clinically relevant contribution to efficacy and safety.

Elimination

Ribociclib is eliminated mainly via the feces, with a small contribution from the renal route.

Half-life

 32 hours

Feces

69% (total dose); 17% unchanged

Urine

23% (total dose); 12% unchanged

 
C - Indications and Status
Health Canada Approvals:

Ribociclib is indicated for use in combination with letrozole for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer as an initial endocrine-based therapy.



 
D - Adverse Effects

Emetogenic Potential:  

Minimal – No routine prophylaxis; PRN recommended

The adverse effects reported below were based on the phase III study of postmenopausal women with breast cancer, receiving ribociclib plus letrozole or placebo plus letrozole, where the incidence was ³ 2% more than placebo.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular QT interval prolonged (5%) E
Venous thromboembolism (3%) E
Dermatological Alopecia (33%) E
Rash, pruritus (20%) I  E
Gastrointestinal Abdominal pain (11%) E
Anorexia, weight loss (19%) E
Constipation (25%) E
Diarrhea (35%) E
Dyspepsia (7%) I  E
Mucositis (12%) E
Nausea, vomiting (52%) I
General Edema (15%) E
Fatigue (37%) E
Fever (13%) I  E
Hematological Myelosuppression ± infection, bleeding (60%) (maybe severe) E
Hepatobiliary ↑ LFTs (46%) (10% severe) D
Metabolic / Endocrine ↓ Ca (5%) E
↓ K (11%) E
↓ PO4 (13%) E
Musculoskeletal Musculoskeletal pain (20%) E
Nervous System Dysgeusia (9%) E
Headache (22%) E
Insomnia (12%) E
Ophthalmic Dry eye (6%) E
Watering eyes (7%) E
Renal Creatinine increased (20%) (< 1% severe) E
Respiratory Dyspnea (12%) E


* "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 ribociclib include myelosuppression ± infection, bleeding, nausea/vomiting, ↑ LFTs, fatigue, diarrhea, alopecia, constipation, headache, musculoskeletal pain and creatinine increased.

Within the phase III clinical trial, most of the severe LFT elevation events occurred within the first 6 months of treatment (median onset 57 days). Most were reported without concurrent increases in bilirubin. Median time to recovery to Grade ≤ 2 was 24 days.

Median time to onset of QTcF > 480 msec was 15 days and these changes were reversible with withholding the dose or modification.

 
E - Dosing

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

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



Adults:

Oral: 600 mg/day on Days 1 to 21, q28 days

Refer to LETRRIBO regimen monograph for information on ribociclib use with letrozole.


Dosage with Toxicity:

Dose Level

Ribociclib Dose

Starting dose

600 mg/day

First dose reduction

400 mg/day

Second dose reduction

200 mg/day

Third dose reduction

Discontinue

 

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.

 



Dosage with Hepatic Impairment:

Hepatic Impairment

Starting Dose

Mild (Child-Pugh class A)

No change

Moderate (Child-Pugh class B)

400 mg once daily; only if benefit outweighs risk

Severe (Child-Pugh class C)

400 mg once daily; only if benefit outweighs risk



Dosage with Renal Impairment:

Creatinine clearance

Starting Dose

≥ 30 mL/min

No change

< 30 mL/min

No data; use only if benefit outweighs risk

 



Dosage in the elderly:

  • No adjustment of the starting dose is required.

  • No overall differences in safety or effectiveness were observed between patients over 65 years of age and younger patients.



Dosage based on gender:

No clinically relevant effects of gender on ribociclib pharmacokinetics parameters.



Dosage based on ethnicity:

 No clinically relevant effects of race on ribociclib pharmacokinetics parameters.



Children:

The safety and efficacy of ribociclib in pediatric patients has not been established.



 
F - Administration Guidelines

  • 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.

  • Avoid grapefruit or pomegranate, grapefruit juice or pomegranate juice, or grapefruit or pomegranate - containing products (Refer to Interactions).

  • 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 in original package to protect from moisture.

  • Do not store ribociclib above 30°C.



 

 

 
G - Special Precautions
Contraindications:

  • Patients with hypersensitivity to this drug or to any ingredient in the formulation.

  • 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).

Other Warnings/Precautions:

  • 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 use in patients with uncorrected hypokalemia, hypomagnesemia, or hypocalcemia and other risk factors.

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


Other Drug Properties:

  • Carcinogenicity: Unknown

     

     

  • Phototoxicity: Unlikely

     

     

Pregnancy and Lactation:
  • Embryotoxicity: Documented in animals

    Ribociclib is indicated for use in postmenopausal women and is not recommended for use in pregnancy. Women of reproductive potential should use effective contraception during therapy and for at least 3 weeks after the last dose and undergo pregnancy testing prior to starting ribociclib.

     

  • Genotoxicity: No

     

     

  • Fertility effects: Unknown

    Animal data suggests that ribociclib may affect male fertility.

     

  • Breastfeeding: Unknown

    Ribociclib is excreted into milk in animals and is not recommended in breastfeeding during therapy or for at least 3 weeks after the last dose.

 
H - Interactions

  • There is no interaction with letrozole.
     
  • Ribociclib is primarily metabolized by CYP3A4. Therefore, medicinal products which can influence CYP3A4 enzyme activity may alter the pharmacokinetics of ribociclib and ribociclib can affect the pharmacokinetics of co-administered CYP3A substrates. Ribociclib has weak inhibitory effects on CYP1A2 substrates though no induction of CYP1A2 or CYP3A4 was observed in vitro.
     
  • Ribociclib may inhibit BCRP, OCT2, Multidrug and Toxic Compound Extrusion Protein-1 (MATE1) and human Bile Salt Export Puup (BSEP). Monitor patients closely when co-administering ribociclib and substrates of these transporters.

AGENT EFFECT MECHANISM MANAGEMENT
CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, pomegranate, Seville oranges or starfruit) ↑ ribociclib exposure ↓ metabolism of CYP3A4 Substrates Avoid use with strong CYP3A4 inhibitors when possible; if avoidance is not possible, reduce ribociclib dose to 200mg and monitor closely.
CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) ↓ plasma exposure of ribociclib ↑ metabolism of CYP3A4 Substrates Avoid concomitant use of strong CYP3A4 inducers.
CYP3A4 substrates with narrow therapeutic index (e.g. alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, midazolam, pimozide, quinidine, sirolimus and tacrolimus) ↑ CYP3A4 Substrate exposure ↓ metabolism of CYP3A4 Substrate Avoid co-administration with CYP3A4 substrates with a narrow therapeutic index. If avoidance is not possible, consider reducing dose of substrate.
Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) Avoid coadministration to the extent possible.
Drugs that disrupt electrolyte levels (i.e. loop/thiazide diuretics, laxatives, amphotericin B, high dose corticosteroids) serum electrolyte imbalance decrease electrolyte levels Avoid to the extent possible.
Drugs that reduce heart rate (i.e. beta blockers, calcium channel blockers, digoxin) may increase risk of arrhythmia Avoid to the extent possible.
 
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

Monitor Type Monitor Frequency

CBC

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

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.

ECG

At baseline, 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.

Electrolytes, including potassium, magnesium, calcium, and phosphorous 

At baseline, at regular intervals during steady-state treatment in later cycles, and whenever clinically indicated (for example patients with QTc prolongation).

Clinical toxicity assessment of infection, bleeding, thromboembolism (close monitoring in patients at risk), gastrointestinal and skin effects, and fatigue

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



 
J - Supplementary Public Funding

Exceptional Access Program (EAP Website)

  • ribociclib - First-line treatment of hormone receptor positive, human epidermal growth factor receptor 2 (HER 2)-negative unresectable locally advanced breast cancer or metastatic breast cancer, with specific criteria

 
K - References

Kasqali (ribociclib) product monograph. Doraval, Quebec: Novartis Pharmaceuticals; March 2018.

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


June 2020 Edited EAP description in supplementary public funding

 
L - Disclaimer

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.

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