Ribociclib

Oral
Hormone receptor positive, HER2-negative metastatic carcinoma of breast, Hormone receptor positive, HER2-negative locally advanced carcinoma of breast
Adult: In combination with an aromatase inhibitor as initial endocrine-based therapy; or in combination with fulvestrant in postmenopausal women, as initial endocrine-based therapy or following disease progression on endocrine therapy: 600 mg once daily preferably in the morning for 21 days, followed by 7 days off treatment to complete a 28-day cycle. Continue until disease progression or unacceptable toxicity. Pre-/perimenopausal women should also be treated with luteinising hormone-releasing hormone (LHRH) agonist. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety or tolerability (refer to detailed product guideline).
Hepatic impairment: Moderate or severe (Child-Pugh class B or C): Reduce initial dose to 400 mg once daily for 21 days, followed by 7 days off treatment, to complete a 28-day cycle.

Special Populations: Patient taking strong CYP3A4 inhibitors: Reduce dose to 400 mg once daily for 21 days, followed by 7 days off treatment, to complete a 28-day cycle. Further reduce to 200 mg once daily in those who already had their dose decreased to 400 mg once daily due to adjustments for individual safety or tolerability.

Tab: May be taken with or without food.

Pregnancy and lactation.

Patient with QTc prolongation or significant risk factors for developing QTc prolongation (e.g. electrolyte abnormalities, long QT syndrome; uncontrolled or significant cardiac disease, including recent MI, CHF, unstable angina and bradyarrhythmias). Initiate treatment only in patients with QTcF values <450 milliseconds. Not recommended to be used with tamoxifen. Patients taking concomitant strong CYP3A4 inhibitors. Severe renal and moderate to severe hepatic impairment. Patient Counselling This drug may cause fatigue, dizziness or vertigo, if affected, do not drive or operate machinery. Monitoring Parameters Evaluate pregnancy status (in females of reproductive potential) prior to treatment initiation. Hepatitis B virus screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen is recommended before or at the beginning of systemic anticancer therapy. Obtain CBC and LFTs prior to treatment, every 2 weeks for the 1st 2 cycles, at the start of each subsequent 4 cycles, then as clinically indicated; renal function tests at baseline; serum electrolytes (including K, Mg, Ca, and phosphorus) before treatment, at the beginning of the 1st 6 cycles, and as clinically necessary. Correct electrolyte disturbances prior to therapy initiation. Perform ECG before beginning treatment, repeated on day 14 of the 1st cycle and at the start of the 2nd cycle, then as clinically indicated. Check ECG more frequently if QTcF is prolonged at any time during therapy. Monitor for signs and symptoms of dermatologic toxicity and interstitial lung disease/pneumonitis.

Significant: Bone marrow suppression (e.g. neutropenia, anaemia, lymphopenia, thrombocytopenia), hepatobiliary toxicity (e.g. increased ALT and/or AST), QT prolongation (concentration-dependent). Blood and lymphatic system disorders: Leucopenia, febrile neutropenia. Ear and labyrinth disorders: Vertigo. Eye disorders: Increased lacrimation, dry eye. Gastrointestinal disorders: Nausea, diarrhoea, vomiting, constipation, stomatitis, abdominal pain, dry mouth, dyspepsia, oropharyngeal pain, gastroenteritis, dysgeusia. General disorders and administration site conditions: Fatigue, peripheral oedema, asthenia, pyrexia. Investigations: Abnormal LFTs, increased blood creatinine and gamma-glutamyltransferase. Metabolism and nutrition disorders: Decreased appetite, hypocalcaemia, hypokalaemia, hypophosphataemia. Musculoskeletal and connective tissue disorders: Back pain, arthralgia. Nervous system disorders: Headache, dizziness. Psychiatric disorders: Insomnia. Renal and urinary disorders: Urinary tract infection. Respiratory, thoracic and mediastinal disorders: Dyspnoea, cough, respiratory tract infection. Skin and subcutaneous tissue disorders: Alopecia, rash, pruritus, erythema, dry skin, vitiligo. Vascular disorders: Syncope.
Potentially Fatal: Interstitial lung disease, pneumonitis; severe cutaneous adverse reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms).

Symptoms: Nausea, vomiting, thrombocytopenia, neutropenia, and possible QTc prolongation. Management: Symptomatic and supportive treatment.

Increased risk of QT interval prolongation with tamoxifen, antiarrhythmics (e.g. amiodarone, disopyramide, quinidine, sotalol) and other known QT-prolonging agents (e.g. chloroquine, ciprofloxacin, azithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide). May increase ribociclib plasma concentration with strong CYP3A4 inhibitors (e.g. clarithromycin, telithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nefazodone, nelfinavir, telaprevir, verapamil). May decrease plasma concentration and efficacy with CYP3A4 inducers (e.g. phenytoin, rifampicin, carbamazepine). May elevate the serum concentrations of CYP3A4 substrates (e.g. midazolam, alfentanil, fentanyl, ciclosporin, tacrolimus, ergotamine, dihydroergotamine, alfuzosin, cisapride, quetiapine, simvastatin).

May increase the ribociclib systemic exposure with grapefruit or grapefruit juice. May decrease serum concentration with St. John's wort.

Ribociclib is a selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6. It blocks the phosphorylation of retinoblastoma protein and prevents progression through the cell cycle, thereby leading to arrest at the G1 phase.
Absorption: Time to peak plasma concentration: 1-4 hours.
Distribution: Volume of distribution: 1,090 L. Plasma protein binding: Approx 70%.
Metabolism: Extensively metabolised in the liver mainly by CYP3A4 isoenzyme via oxidation to major metabolites M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide).
Excretion: Via faeces (69%; 17% as unchanged drug, 14% as M4 metabolite, ≤3% as other metabolites); urine (23%; 12% as unchanged drug, 4% as M4 metabolite, ≤3% as other metabolites). Terminal elimination half-life: Approx 30-55 hours.

Oral: Store below 30°C. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration and disposal.

Targeted Cancer Therapy

L01EF02 - ribociclib