Ribociclib

Registered South African indications:

• Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer

Contraindications
South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to peanut or soya
• Pregnancy and women of childbearing potential (not using contraception)
• Breastfeeding
• Difficult to control/unstable severe cardiac conditions including dysrhythmias, congestive cardiac failure, recent myocardial infarction and unstable angina pectoris
• Congenital long QT syndrome
• Coadministration with agents that have a known potential to prolong the QTcF interval to ≥500ms, or ≥60ms from the pre-treatment QTcF, increasing the risk to develop serious dysrhythmias (e.g. tamoxifen, moxifloxacin)
• Coadministration with strong CYP3A inhibitors (e.g. ritonavir/lopinavir, itraconazole)
• Coadministration with CYP3A substrates with a narrow therapeutic index (e.g. midazolam, fentanyl)
• Coadministration with strong CYP3A4 inducers (e.g. rifampicin, phenytoin)

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to peanut or soya

Cautions
South African manufacturer recommendations

• 21 days after stopping treatment (for women of childbearing potential)
• Males of reproductive potential
• Severe renal impairment
• Moderate to severe (Child-Pugh class B or C) hepatic impairment
• Pre-existing critical visceral disease
• QTcF values ≥450msec
• Significant risk of developing QTc prolongation
  - Electrolyte abnormalities
• Coadministration with moderate CYP3A4 inducer (efavirenz) (See additional prescribing points)
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy
• Women of childbearing potential and 21 days after stopping treatment
• Breastfeeding
• Males of reproductive potential
• Severe renal impairment
• Moderate to severe (Child-Pugh class B or C) hepatic impairment
• Pre-existing critical visceral disease
• QTcF values ≥450msec
• Significant risk of developing QTc prolongation
  - Long QT syndrome
  - Uncontrolled or significant cardiac disease, including recent myocardial infarction, congestive heart failure, unstable angina and bradyarrhythmias
  - Electrolyte abnormalities
• Coadministration with moderate CYP3A4 inducer (efavirenz) (See additional prescribing points)
• Coadministration with moderate CYP3A4 inhibitor (erythromycin)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: fct

Treatment with ribociclib should be initiated by a medical practitioner experienced in the use of anticancer therapies

Used for the treatment of
Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer (Additional agent (s) required)
- In combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy

• Oral (fct): 600mg (three 200mg fct), dly for 21 consecutive days, followed by 7 days off treatment, resulting in a complete cycle of 28 days

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The treatment should be continued as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs

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In pre-or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist

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Ribociclib can be taken with or without food

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Dose to be taken at approximately the same time each day, preferably in the morning

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

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Treatment of pre-and perimenopausal women with the approved ribociclib combinations should also include a luteinising hormone-releasing hormone (LHRH) agonist in accordance with local clinical practice

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Ribociclib should be used together with 2.5mg letrozole or another aromatase inhibitor or with 500mg fulvestrant

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When ribociclib is used in combination with an aromatase inhibitor, the aromatase inhibitor should be taken orally once daily continuously throughout the 28-day cycle. Please refer to the professional information (PI) of the particular aromatase inhibitor for additional details

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When ribociclib is used in combination with fulvestrant, fulvestrant is administered intramuscularly on days 1, 15 and 29, and once monthly thereafter. Please refer to the professional information (PI) of fulvestrant for additional details

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Consult specialist for dosages and regimens (including dose modifications during the management of adverse reactions)

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Method of administration: See additional prescribing points

Not established for use in children below 18 years

Pregnancy
South African manufacturer recommendations

• Contraindicated
• Ribociclib is teratogenic and contraindicated in pregnancy. There are no adequate and well-controlled studies in pregnant women
• Based on findings in animals, ribociclib can cause foetal harm when administered to a pregnant woman. Ribociclib is contraindicated during pregnancy and in women of childbearing potential not using contraception
• Pregnancy status should be verified prior to starting treatment with ribociclib. Women of childbearing potential who are receiving ribociclib should use effective contraception (e.g. double barrier contraception) during therapy and for at least 21 days after stopping treatment with ribociclib

International manufacturer recommendations

• Caution; not recommended
• There are no adequate and well-controlled studies in pregnant women
• Based on findings in animals, ribociclib can cause foetal harm when administered to a pregnant woman. Ribociclib is not recommended during pregnancy and in women of childbearing potential not using contraception
• Pregnancy status should be verified prior to starting treatment with ribociclib. Women of childbearing potential who are receiving ribociclib should use effective contraception (e.g. double barrier contraception) during therapy and for at least 21 days after stopping treatment with ribociclib

Breastfeeding
South African manufacturer recommendations

• Contraindicated 
• It is not known if ribociclib is present in human milk. There are no data on the effects of ribociclib on the breastfed infant or the effects of ribociclib on milk production. Ribociclib and its metabolites readily passed into the milk of lactating rats
• Mothers on treatment with ribociclib should not breastfeed their infants. Mothers receiving ribociclib should not breastfeed for at least 21 days after the last dose

International manufacturer recommendations

• Caution; not recommended 
• It is not known if ribociclib is present in human milk. There are no data on the effects of ribociclib on the breastfed infant or the effects of ribociclib on milk production
• Ribociclib and its metabolites readily passed into the milk of lactating rats. Patients receiving ribociclib should not breastfeed for at least 21 days after the last dose

Fertility

• There are no clinical data available regarding effects of ribociclib on fertility. Based on animal studies, ribociclib may impair fertility in males of reproductive potential

Renal Impairment
South African manufacturer recommendations

• Mild to moderate: No dose adjustment recommended 
• Severe: Caution; no dose adjustment recommended 
  Monitor signs of toxicity as there is no experience with ribociclib in this population

International manufacturer recommendations

• Mild to moderate: No dose adjustment recommended 
• Severe: Caution; dose adjustment recommended 
  Oral (fct): Initial: 200mg, dly

Hepatic Impairment

• Mild (Child-Pugh class A): No dose adjustment recommended 
• Moderate to severe (Child-Pugh class B or C): Caution; dose adjustment recommended 
  Oral (fct): Initial: 400mg, dly 

Elderly

• No dose adjustment recommended

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Dizziness
• Vertigo
• Fatigue

Cardiovascular Disorders

• Syncope
• Prolonged QT electrocardiogram

Respiratory Disorders

• Dyspnoea
• Cough
• Respiratory tract infections

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Constipation
• Stomatitis
• Abdominal pain
  - Upper abdominal pain
• Dyspepsia
• Dry mouth
• Oropharyngeal pain
• Gastroenteritis

Hepatobiliary Disorders

• Hepatotoxicity
  - Hepatocellular injury
  - Drug-induced liver injury 
  - Hepatotoxicity
  - Hepatic failure
  - Autoimmune hepatitis
• Abnormal liver function tests
  - Increased alanine aminotransferase
  - Incresed aspartate aminotransferase 
  - Increased blood bilirubin

Genitourinary Disorders

• Urinary tract infections
• Increased blood creatinine

Endocrine and Metabolic Disorders

• Decreased appetite
• Hypocalcaemia
• Hypokalaemia
• Hypophosphataemia

Musculoskeletal Disorders

• Back pain

Skin and Subcutaneous Tissue Disorders

• Alopecia
• Rash
  -  Maculopapular rash
  - Pruritic rash
• Pruritus
• Erythema
• Dry skin
• Vitiligo
• Toxic epidermal necrolysis (TEN)

Immune, Blood and Lymphatic System Disorders

• Infections
• Neutropenia
• Leukopenia
• Anaemia
• Lymphopenia
• Thrombocytopenia
• Febrile neutropenia
• Peripheral oedema
• Pyrexia
• Sepsis

Sensory Disorders

• Increased lacrimation
• Dry eye
• Dysgeusia

• Medicinal agents that are known to prolong the QT interval
• Tamoxifen
• Moxifloxacin
• Chloroquine
• Halofantrine
• Clarithromycin
• Ciprofloxacin
• Levofloxacin
• Azithromycin
• Haloperidol
• Methadone
• Bepridil
• Pimozide
• Intravenous ondansetron 
• Strong CYP3A4 inhibitors (See additional prescribing points)
• Ritonavir/lopinavir
• Itraconazole
• Ritonavir
• Clarithromycin
• Indinavir
• Ketoconazole
• Lopinavir
• Nefazodone
• Nelfinavir
• Posaconazole
• Saquinavir
• Telaprevir
• Telithromycin
• Verapamil
• Voriconazole
• CYP3A4 substrates (including those with a narrow therapeutic index)
• Midazolam
• Fentanyl
• Alfentanil
• Ciclosporin
• Everolimus
• Sirolimus 
• Tacrolimus
• Alfuzosin
• Amiodarone
• Cisapride
• Pimozide
• Quinidine
• Ergotamine
• Dihydroergotamine
• Quetiapine
• Lovastatin
• Simvastatin
• Sildenafil
• Triazolam
• Strong CYP3A4 inducers
• Rifampicin
• Phenytoin
• Carbamazepine
• P-glycoprotein (P-gp) substrates
• Breast cancer resistance protein (BCRP) substrates
• Organic anion transporting polypeptide (OATP1B1/1B3) substrates
• Organic cation transporters (OCT1, OCT2) substrates 
• Multi-antimicrobial extrusion protein (MATE1) substrates 
• Bile salt export pump (BSEP) substrates 
• Digoxin
• Pitavastatin
• Pravastatin
• Rosuvastatin 
• Metformin
• Antiarrhythmic medicinal agents
• Disopyramide
• Procainamide
• Sotalol

Other interactions

• Grapefruit or grapefruit juice
• St John's wort (Hypericum perforatum)

• Full blood count (baseline, every 2 weeks for the first 2 cycles, at the beginning of each following 4 cycles and as clinically necessary)
• Hepatic function (baseline, every 2 weeks for the first 2 cycles, at the beginning of each following 4 cycles and as clinically necessary; if grade 2 or higher abnormalities occur, monitor more frequently)
• Electrolytes (before treatment, at the beginning of the first 6 cycles, and as clinically indicated)
• Electrocardiography (before treatment initiation; repeat on day 14 of cycle 1, at the beginning of cycle 2, and as clinically indicated; if QTcF is prolonged at any time during treatment, monitor electrocardiography more frequently)
• Hepatitis B virus (HBV) screening (before beginning or at the beginning of systemic anticancer therapy)
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to hepatitis B surface antigen

Specific cases may require

• Pregnancy status (in patients who could become pregnant)

Additional observations

• Signs/symptoms of
  - Dermatologic toxicity
  - Interstitial lung disease/pneumonitis 
• Adherence

Method of administration

• Ribociclib should be taken orally once daily with or without food. The tablets should be swallowed whole and should not be chewed, crushed or split prior to swallowing. No tablet should be ingested if it is broken, cracked or otherwise not intact

Coadministration with strong CYP3A4 inhibitors

• If treatment with a strong CYP3A4 inhibitor cannot be avoided, the dose should be reduced to: Oral (fct): 400mg, dly 

Coadministration with mild or moderate CYP3A4 inhibitors

• No dose adjustments of ribociclib are required at initiation of treatment with mild or moderate CYP3A4 inhibitors. However, monitoring of ribociclib-related adverse effects is recommended

Coadministration with moderate CYP3A4 inducers

• The effect of a moderate CYP3A4 inducer on ribociclib exposure has not been studied. Physiologically-based pharmacokinetic simulations suggested that a moderate CYP3A4 inducer (efavirenz) may decrease steady-state ribociclib C_max and AUC by 51% and 70%, respectively. The concomitant use of moderate CYP3A4 inducers may therefore lead to decreased exposure and consequently a risk for impaired efficacy, in particular in patients treated with ribociclib at 400mg or 200mg once daily

Coadministration with caffeine (CYP1A2 substrate)

• With multiple doses of ribociclib (400mg) increased the caffeine exposure by 20% (1.20-fold) in healthy subjects, compared with administration of caffeine alone. At the clinically relevant dose of 600mg, simulations using PBPK models predicted only weak inhibitory effects of ribociclib on CYP1A2 substrates (<2-fold increase in AUC)

Ribociclib is a selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6, resulting in 50% inhibition (IC₅₀) values of 0.01 (4.3ng/ml) and 0.039μm (16.9ng/ml) in biochemical assays, respectively. These kinases are activated upon binding to D-cyclins and play a crucial role in signalling pathways which lead to cell cycle progression and cellular proliferation. The cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In vitro, ribociclib decreased pRb phosphorylation, leading to arrest in the G1 phase of the cell cycle, and reduced cell proliferation in breast cancer cell lines. In vivo, treatment with single-agent ribociclib led to tumour regressions which correlated with inhibition of pRb phosphorylation. In vivo studies using patient-derived oestrogen receptor-positive breast cancer xenograft model combinations of ribociclib and antioestrogens (i.e. letrozole) resulted in superior tumour growth inhibition with sustained tumour regression and delayed tumour regrowth after stopping dosing compared to each substance alone. Additionally, in vivo antitumour activity of ribociclib in combination with fulvestrant was assessed in immune-deficient mice bearing the ZR751 ER+ human breast cancer xenografts and the combination with fulvestrant resulted in complete tumour growth inhibition. When tested in a panel of breast cancer cell lines with known ER status, ribociclib demonstrated to be more efficacious in ER+ breast cancer cell lines than in the ER- ones. In the preclinical models tested so far, intact pRb was required for ribociclib activity.

Film coated tablet 200mg

• Kryxana (Norvatis) originator