Ribociclib

Ribociclib is a selective inhibitor of cyclin-dependent kinases 4 and 6, with IC50 values of 0.01 µM for CDK4 and 0.039 µM for CDK6 in biochemical assays. These kinases are activated by D-cyclins and drive the signalling pathways that lead to cell-cycle progression and proliferation.

Mechanism of Action

• Cell-cycle control: the cyclin D–CDK4/6 complex regulates progression through the cell cycle by phosphorylating the retinoblastoma protein (pRb).
• Inhibition: in breast cancer models ribociclib decreased pRb phosphorylation, which arrested cells in the G1 phase, reduced proliferation and produced a senescent phenotype. Single-agent treatment caused tumour regression in vivo.
• With endocrine therapy: in patient-derived oestrogen receptor-positive xenografts, ribociclib with letrozole gave superior tumour growth inhibition to either alone, and with fulvestrant it gave complete inhibition in a mouse model. Ribociclib may also have immunomodulatory effects, lowering regulatory T cells.
• Tumour sensitivity: it was more effective in oestrogen receptor-positive than receptor-negative cell lines, and intact pRb was required for its activity in preclinical models.
• QT interval: ribociclib causes concentration-dependent increases in the QTc interval, larger at 600 mg than at 400 mg.

Pharmacokinetics

• Absorption: absolute bioavailability 65.8%; peak concentrations after 1 to 4 hours. Steady state is reached after about 8 days, with an accumulation ratio of about 2.5. A high-fat meal does not change absorption, so tablets can be taken with or without food.
• Distribution: about 70% bound to plasma proteins, independent of concentration; equally distributed between blood cells and plasma. The apparent volume of distribution at steady state is about 1,090 L.
• Metabolism: eliminated mainly by hepatic metabolism through CYP3A4 (oxidation, then conjugation). Unchanged ribociclib is the main circulating compound, and its activity comes almost entirely from the parent drug.
• Elimination: effective half-life about 32 hours and apparent clearance about 25.5 L/h at 600 mg in advanced cancer. After a radiolabelled dose, 69.1% was recovered in faeces and 22.6% in urine; unchanged drug was 17.3% of the dose in faeces and 12.1% in urine.
• Special populations: age, body weight and sex have no clinically relevant effect. In a single-dose study, exposure (AUC) rose 1.6-fold, 1.9-fold and 2.7-fold in mild, moderate and severe renal impairment, although in patients with breast cancer mild or moderate impairment had no clinically meaningful effect. Exposure rose by less than 2-fold in moderate or severe hepatic impairment; mild impairment has no effect.

Ribociclib is always used with endocrine therapy.

• Early breast cancer (adjuvant treatment): in combination with an aromatase inhibitor, for patients with hormone receptor (HR)-positive, HER2-negative early breast cancer at high risk of recurrence (selection criteria are given in the SmPC). In pre- or perimenopausal women, or in men, the aromatase inhibitor should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.
• Advanced or metastatic breast cancer: women with HR-positive, HER2-negative locally advanced or metastatic breast cancer, in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with an LHRH agonist.

• Hypersensitivity to ribociclib or to peanut, soya or any of the excipients.

In the early breast cancer study (2,525 patients) the most common reactions (≥20%) were neutropenia, infections, nausea, headache, fatigue, leukopenia and abnormal liver function tests; the most common grade 3 or 4 reactions (≥2%) were neutropenia, abnormal liver function tests and leukopenia. In advanced or metastatic disease (1,065 patients) the most common were neutropenia, infections, nausea, fatigue, diarrhoea, leukopenia, vomiting, headache, constipation, alopecia, cough, rash, back pain, anaemia and abnormal liver function tests. Dose reductions for adverse events occurred in 22.8% of patients in early and 39.5% in advanced disease, and permanent discontinuation in 19.7% and 8.7%.

Very common (≥1/10): infections, neutropenia, leukopenia, headache, cough, nausea, diarrhoea, constipation, abdominal pain, alopecia, fatigue, asthenia, pyrexia, abnormal liver function tests. In advanced or metastatic disease also anaemia, lymphopenia, decreased appetite, dizziness, dyspnoea, vomiting, stomatitis, dyspepsia, rash, pruritus, back pain and peripheral oedema.

Common (≥1/100 to <1/10): thrombocytopenia, hypocalcaemia, hypokalaemia, interstitial lung disease or pneumonitis, hepatotoxicity, oropharyngeal pain, increased blood creatinine, prolonged QT interval on ECG. In early breast cancer also anaemia, lymphopenia, decreased appetite, dizziness, dyspnoea, vomiting, stomatitis, rash, pruritus and peripheral oedema. In advanced or metastatic disease also febrile neutropenia, hypophosphataemia, vertigo, increased lacrimation, dry eye, syncope, dysgeusia, dry skin, erythema, vitiligo and dry mouth.

Uncommon (≥1/1,000 to <1/100): febrile neutropenia (early breast cancer).

Rare (≥1/10,000 to <1/1,000): erythema multiforme (advanced or metastatic disease).

Not known: toxic epidermal necrolysis.

Neutropenia occurred in 62.5% of patients with early and 75.4% with advanced disease (grade 3 or 4 neutrophil decreases in 45.1% and 62.0%). Hepatobiliary events were more frequent than with placebo or aromatase inhibitor alone, and most grade 3 or 4 transaminase rises occurred in the first 6 months. QT prolongation events occurred in 5.3% (early) and 9.3% (advanced) of patients; no torsade de pointes was reported in the advanced-disease studies.

Ribociclib is metabolised mainly by CYP3A4. It is a strong CYP3A4 inhibitor at 600 mg and a moderate one at 400 mg.

• Strong CYP3A4 inhibitors (clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, verapamil, voriconazole): must be avoided; ritonavir raised ribociclib exposure (AUC) 3.2-fold. Consider an alternative; if unavoidable, reduce the ribociclib dose (see Administration and Dosage). Mild or moderate inhibitors need no adjustment, but monitor for adverse reactions.
• Grapefruit and grapefruit juice: inhibit CYP3A4 and may raise exposure, so avoid them.
• Strong CYP3A4 inducers (phenytoin, rifampicin, carbamazepine, St John’s wort): avoid, as rifampicin cut exposure (AUC) by 89%. Moderate inducers such as efavirenz may lower exposure considerably, especially at 400 or 200 mg.
• CYP3A4 substrates: ribociclib raised midazolam exposure 3.8-fold at 400 mg. Avoid alfuzosin, amiodarone, cisapride, pimozide, quinidine, ergotamine, dihydroergotamine, quetiapine, lovastatin, simvastatin, sildenafil, midazolam and triazolam. For narrow-index substrates such as alfentanil, ciclosporin, everolimus, fentanyl, sirolimus and tacrolimus, the dose may need reducing.
• QT-prolonging medicines (for example amiodarone, disopyramide, procainamide, quinidine, sotalol, chloroquine, halofantrine, clarithromycin, ciprofloxacin, levofloxacin, azithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide, intravenous ondansetron): avoid.
• Transporter substrates: caution with narrow-index substrates such as digoxin, pitavastatin, pravastatin, rosuvastatin and metformin.
• Endocrine partners: no interaction with letrozole, anastrozole or fulvestrant. Tamoxifen exposure roughly doubled with ribociclib, and the combination is not recommended. Studies with oral contraceptives have not been done.

Treatment is started by a physician experienced in the use of anticancer therapies. HR and HER2 status are assessed with a CE-marked in vitro diagnostic device or, if none is available, another validated test. The tablets are taken once daily, with or without food, at about the same time each day (preferably in the morning), and swallowed whole: not chewed, crushed or split, and not if broken or cracked.

Recommended Dose

• Early breast cancer: 400 mg (two 200 mg tablets) once daily for 21 consecutive days, then 7 days off, in 28-day cycles, for 3 years or until recurrence or unacceptable toxicity.
• Advanced or metastatic breast cancer: 600 mg (three 200 mg tablets) once daily on the same 21/7 schedule, for as long as the patient benefits or until unacceptable toxicity.
• With an aromatase inhibitor: taken orally once daily, continuously through the 28-day cycle. With fulvestrant: intramuscularly on days 1, 15 and 29, then monthly.
• LHRH agonist: pre- or perimenopausal women need one with either combination; in early breast cancer, men taking an aromatase inhibitor need one too.

Dose Adjustments

• Dose levels: early disease 400 mg, then 200 mg per day; advanced disease 600 mg, then 400 mg, then 200 mg per day. Below 200 mg per day, treatment is stopped.
• Monitoring: blood counts and liver tests before starting, every 2 weeks for the first 2 cycles, at the start of each of the next 4 cycles, then as indicated. ECG before starting (start only if QTcF is below 450 msec), at about day 14 of cycle 1, then as indicated. Serum electrolytes (potassium, calcium, phosphorus, magnesium) before starting and at the start of the first 6 cycles; abnormalities are corrected.
• Neutropenia: none for grade 1 or 2. For grade 3, interrupt until grade 2 or less and resume at the same dose (one level lower if grade 3 recurs); for febrile neutropenia or grade 4, interrupt and resume one level lower.
• Liver toxicity: for AST/ALT grade 2, interrupt until back to baseline grade and resume (one level lower if it recurs; no interruption if grade 2 was present at baseline); for grade 3, interrupt then resume one level lower, and stop if it recurs; stop at grade 4, or if ALT/AST exceed 3 times the upper limit of normal with bilirubin above 2 times in the absence of cholestasis.
• QT prolongation: for QTcF 481–500 msec, interrupt until below 481 msec, then resume at the same dose in early disease or one level lower in advanced disease; for above 500 msec, interrupt and resume one level lower, and stop if it recurs. Stop permanently if QTcF is above 500 msec, or rises by more than 60 msec, together with torsade de pointes, polymorphic ventricular tachycardia or signs of serious arrhythmia.
• Interstitial lung disease or pneumonitis: none for grade 1; for grade 2, interrupt until grade 1 or less and resume one level lower after a benefit-risk assessment; stop at grade 3 or 4.
• Other toxicities: for grade 3, interrupt until grade 1 or less and resume (one level lower if it recurs); stop at grade 4.
• With a strong CYP3A4 inhibitor that cannot be avoided: reduce 600 mg to 400 mg and 400 mg to 200 mg; interrupt treatment if already on 200 mg. Return to the previous dose after at least 5 half-lives of the inhibitor.

Special Populations

• Elderly: no dose adjustment over 65 years.
• Renal impairment: no adjustment in mild or moderate impairment; a starting dose of 200 mg in severe impairment (not studied in patients with breast cancer).
• Hepatic impairment: no adjustment in early breast cancer. In advanced disease, none in mild impairment (Child-Pugh A); a starting dose of 400 mg in moderate or severe impairment (Child-Pugh B or C).
• Children and adolescents: safety and efficacy below 18 years have not been established.

Missed or Vomited Dose

Do not take an extra dose that day. Take the next dose at the usual time.

QT Interval Prolongation

Avoid ribociclib in patients who already have, or are at significant risk of, QTc prolongation: long QT syndrome, uncontrolled or significant heart disease (recent myocardial infarction, congestive heart failure, unstable angina, bradyarrhythmias) or electrolyte abnormalities. Medicines that prolong the QT interval and strong CYP3A4 inhibitors should be avoided. It is not recommended with tamoxifen: a QTcF rise of more than 60 msec occurred in 16.1% of patients taking tamoxifen against 7.3% taking a non-steroidal aromatase inhibitor.

Neutropenia and Liver Toxicity

Neutropenia and raised transaminases may require interruption, dose reduction or discontinuation. Patients should report any fever promptly. Recommendations for patients with AST/ALT grade 3 or higher at baseline have not been established.

Skin, Lung and Kidney Findings

• Severe skin reactions: toxic epidermal necrolysis has been reported; stop ribociclib immediately if a progressive widespread rash with blisters or mucosal lesions appears.
• Interstitial lung disease or pneumonitis: may be fatal; patients are monitored for hypoxia, cough and dyspnoea.
• Blood creatinine: ribociclib inhibits the renal transporters OCT2 and MATE1 and may raise creatinine; assess renal function further to exclude renal impairment.
• Critical visceral disease: time to response was longer with ribociclib plus a non-steroidal aromatase inhibitor than with combination chemotherapy, which should be considered in these patients.

Pregnancy, Breastfeeding and Fertility

• Contraception: check pregnancy status before starting. Women of childbearing potential should use effective contraception (for example double-barrier) during treatment and for at least 21 days after the last dose.
• Pregnancy: no adequate studies; animal findings indicate foetal harm. Not recommended in pregnancy or in women of childbearing potential not using contraception.
• Breastfeeding: not known whether it passes into human milk (it did in rats). Do not breastfeed during treatment and for at least 21 days after the last dose.
• Fertility: no clinical data; animal studies suggest it may impair male fertility.

Excipients with Known Effect

The tablets contain soya lecithin (0.344 mg per tablet). Patients who are hypersensitive to peanut or soya must not take them.

Effect on Driving

Ribociclib may have a minor influence on the ability to drive and use machines. Patients should be careful if they feel tired, dizzy or have vertigo.

The tablets need no special temperature conditions. Keep them in the original package to protect them from moisture. Blister packs hold 14 or 21 tablets, in unit packs of 21 to 189 tablets and multipacks of 63, 126 or 189; not all pack sizes may be marketed.

2 years. Do not use after the expiry date.

Prescription only (Rx), started by a physician experienced in anticancer therapy. Ribociclib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.