KRYXANA 200MG FILM-COATED TABLETS

Indications

• Locally advanced or metastatic breast cancer (specialist use only)
• Hormone receptor-positive, HER2-negative advanced breast cancer
• Combination with fulvestrant for hormone receptor-positive advanced breast cancer after endocrine therapy
• Combination with aromatase inhibitors for postmenopausal women with advanced breast cancer as initial endocrine-based therapy

Dosage

Adults: 600 mg once daily for 21 consecutive days, followed by a 7-day break, to be repeated in 28-day cycles. It should be taken at approximately the same time each day, preferably in the morning.

Mechanism of action

Ribociclib selectively inhibits cyclin-dependent kinases 4 and 6. These kinases, when activated by binding to D-cyclins, facilitate cell cycle progression and proliferation. By inhibiting CDK4/6, ribociclib decreases the phosphorylation of the retinoblastoma protein (pRb), leading to cell cycle arrest in the G1 phase and reduced tumor cell proliferation, particularly in breast cancer models.

Pharmacodynamics

Ribociclib causes concentration-dependent changes in the QTcF interval, necessitating caution in patients taking other QTc-prolonging medications or those with a predisposition to Torsades de Pointes (TdP). Its effects on cell cycle regulation contribute to its therapeutic use in treating certain malignancies, specifically breast cancer.

Pharmacokinetics

Ribociclib is absorbed orally, with peak plasma concentrations typically occurring within 4 to 6 hours post-dose. It is extensively metabolized in the liver, primarily by cytochrome P450 enzymes, with a half-life allowing for once-daily dosing. The pharmacokinetics of ribociclib can be significantly affected by concomitant medications that either induce or inhibit these metabolic pathways.

Contra-indications

• Pre-existing QTc prolongation risk
• Concomitant use of drugs known to prolong QTc interval

Adverse effects

• Alopecia
• Anaemia
• Decreased appetite
• Asthenia
• Back pain
• Constipation
• Cough
• Decreased leucocytes
• Diarrhoea
• Dizziness
• Dry eye
• Dry mouth
• Dyspnoea
• Electrolyte imbalance
• Excessive tearing
• Fever
• Gastrointestinal discomfort
• Headache
• Hepatic disorders
• Increased risk of infection

Interactions

• Ribociclib + alfuzosin: Severe (increases exposure)
• Ribociclib + amiodarone: Severe (increases exposure)
• Ribociclib + quetiapine: Severe (increases exposure)
• Ribociclib + ergotamine: Severe (increases exposure)
• Grapefruit juice + ribociclib: Severe (increases exposure)
• Mitotane + ribociclib: Severe (decreases exposure)
• Ribociclib + pimozide: Severe (increases exposure)
• Ribociclib + alpha blockers: Severe (increases exposure)
• Ribociclib + antiarrhythmics: Severe (increases exposure)
• Ribociclib + second-generation antipsychotics: Severe (increases exposure)

Precautions

• Monitor ECG before initiating treatment, especially in patients with QTcF values <450 milliseconds
• Repeat ECG at approximately day 14 of the first cycle and at the beginning of the second cycle
• Monitor serum electrolytes (potassium, calcium, phosphorus, magnesium) before initiating treatment and periodically during treatment
• Correct any electrolyte abnormalities before starting treatment
• Assess for pulmonary symptoms indicative of interstitial lung disease and pneumonitis

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Ribociclib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

Mechanism of action

Ribociclib is a selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6. These kinases are activated upon binding to D-cyclins and are downstream of signaling 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). Ribociclib has been shown _in vitro_ to decrease pRb phosphorylation, resulting in arrest in the G1 phase of the cell cycle and reduced proliferation in breast cancer-derived models. The inhibition of pRb phosphorylation is correlated with a decrease in the volume of tumor cells.

Pharmacodynamics

Ribociclib causes concentration-dependent changes in QTcF interval. It should be used with caution in patients undergoing treatment with other QTc-prolonging agents, or in patients pre-disposed to the development of Torsades de Pointes (TdP) (e.g. those with long QT syndrome, LQTS).