Kisqali 200 mg

/ Novartis

The recommended dose is 600 mg (three 200 mg film-coated tablets) of ribociclib once daily for 21 consecutive days followed by 7 days off treatment, resulting in a complete cycle of 28 days. The treatment should be continued as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs.
The drug should be used together with 2.5 mg letrozole or another non steroidal aromatase inhibitor or with 500 mg fulvestrant.
When ribociclib is used in combination with a non-steroidal aromatase inhibitor, the non steroidal aromatase inhibitor should be taken orally once daily continuously throughout the 28-day cycle, Please refer to the Prescribing information of the non-steroidal aromatase inhibitor for additional details.
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 Prescribing information of fulvestrant for additional details.
Treatment of pre- and perimenopausal women with the approved ribociclib combinations should also include an LHRH agonist in accordance with local clinical practice.
Ribociclib can be taken with or without food. Patients should be encouraged to take their dose at approximately the same time each day, preferably in the morning. 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.
ECG should be assessed before initiating treatment with ribociclib.
Treatment with ribociclib should be initiated only in patients with QTcF values less than 450 msec. After initiating treatment, ECG should be repeated at approximately day 14 of the first cycle, then as clinically indicated. In case of QTcF prolongation during treatment, more frequent ECG monitoring is recommended.
Dose modifications: Management of severe or intolerable adverse drug reactions (ADRs) may require temporary dose interruption, reduction or discontinuation of Ribociclib. If dose reduction is required, the recommended
dose reduction guidelines are listed in Table 1 at the attached doctor’s leaflet.
Renal impairment: No dose adjustment is necessary in patients with mild or moderate renal impairment.
Caution should be used in patients with severe renal impairment with close monitoring of signs of toxicity as there is no experience with ribociclib in this population.
Hepatic impairment: Based on a pharmacokinetic study in healthy subjects and non-cancer subjects with impaired hepatic function, no dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). Patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) can have increased (less than 2-fold) exposure to ribociclib and the starting dose of 400 mg ribociclib once daily is recommended. Ribociclib has not been studied in breast cancer patients with moderate and severe hepatic impairment.
Paediatric population: ribociclib is not indicated for use in children and adolescents.
Elderly: No dose adjustment is required in patients over 65 years of age.
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.
See prescribing information for full details.

Indicated in combination with a non steroidal aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer as initial endocrine-based therapy; or
fulvestrant for the treatment of men and postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy or following disease progression on endocrine therapy.

Hypersensitivity to the active substance or to peanut, soya or any of the excipients.

Critical visceral disease: The efficacy and safety of ribociclib have not been studied in patients with critical visceral disease.
Neutropenia: Based on the severity of the neutropenia, treatment with Ribociclib may have to be interrupted, reduced or discontinued.
Based on the severity of the transaminase elevations, treatment with Ribociclib may have to be interrupted, reduced or discontinued.
QT interval prolongation: In study E2301 (MONALEESA-7), a QTcF interval increase >60 msec from baseline was observed in 14/87 (16.1%) patients receiving Kisqali plus tamoxifen and in 18/245 (7.3%) patients receiving Kisqali plus a non-steroidal aromatase inhibitor (NSAI). Kisqali is not recommended to be used in combination with tamoxifen. ECG should be assessed before initiating treatment. Treatment with Ribociclib should be initiated only in patients with QTcF values less than 450 msec. ECG should be repeated at approximately day 14 of the first cycle and at the beginning of the second cycle, then as clinically indicated.
Appropriate monitoring of serum electrolytes (including potassium, calcium, phosphorus and magnesium) should be performed before initiating treatment, at the beginning of the first 6 cycles and then as clinically indicated. Any abnormality should be corrected before initiating treatment with Ribociclib and during treatment with Ribociclib.
The use of this drug  should be avoided in patients who already have or who are at significant risk of developing QTc prolongation. This includes  patients with long QT syndrome; with uncontrolled or significant cardiac disease, including recent myocardial infarction, congestive heart failure, unstable angina and bradyarrhythmias; with electrolyte abnormalities.
Thromboembolic events: Caution is advised in patients with risk factors for thromboembolic events while receiving the combination of Ribociclib  with endocrine treatment. Monitor patients for signs and symptoms of thromboembolism and treat as medically approprriate.
CYP3A4 substrates: Ribociclib is a strong CYP3A4 inhibitor at the 600 mg dose and a moderate CYP3A4 inhibitor at the 400 mg dose. Thus, ribociclib may interact with medicinal products which are metabolised via CYP3A4, which may lead to increased serum concentrations of CYP3A4 substrates. Caution is recommended in case of concomitant use with sensitive CYP3A4 substrates with a narrow therapeutic index and the Prescribing information of the other product should be consulted for the recommendations regarding co-administration with CYP3A4 inhibitors.
Women of childbearing potential: Women of childbearing potential should be advised to use an effective method of contraception while taking Kisqali and for at least 21 days after the last dose.
Severe cutaneous reactions: Toxic epidermal necrolysis (TEN) has been reported with Kisqali treatment. If signs and symptoms suggestive of severe cutaneous reactions (e.g. progressive widespread skin rash often with blisters or mucosal lesions) appear, Kisqali should be discontinued immediately.
See prescribing information for full details.

The most common ADRs and the most common grade 3/4 ADRs (reported at a frequency ≥20% and ≥2%, respectively) in the pooled dataset for which the frequency for Kisqali plus any combination exceeds the frequency for placebo plus any combination were infections, neutropenia, leukopenia, headache, cough, nausea, fatigue, diarrhoea, vomiting, constipation, alopecia and rash, and infections, neutropenia, leukopenia, anaemia, abnormal liver function tests, lymphopenia, hypophosphataemia, and vomiting, respectively.
See prescribing information for full details.

Substances that may increase ribociclib plasma concentrations: Ribociclib is primarily metabolised by CYP3A4. Therefore, medicinal products that can influence CYP3A4 enzyme activity may alter the pharmacokinetics of ribociclib. Co-administration of the strong CYP3A4 inhibitor ritonavir (100 mg twice daily for 14 days) with a single 400 mg dose of ribociclib increased ribociclib exposure (AUCinf) and the peak concentration (Cmax) in healthy subjects 3.2 and 1.7-fold, respectively, relative to a single 400 mg ribociclib dose given alone. Cmax and AUClast for LEQ803 (a prominent metabolite of ribociclib accounting for less than 10% of parent exposure) decreased by 96% and 98%, respectively.
The concomitant use of strong CYP3A4 inhibitors including, but not limited to, the following must be avoided: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, verapamil and voriconazole. Alternative concomitant medicinal products with less potential to inhibit CYP3A4 should be considered and patients should be monitored for ribociclib-related AEs.
Substances that may decrease ribociclib plasma concentrations: Co-administration of the strong CYP3A4 inducer rifampicin (600 mg daily for 14 days) with a single 600 mg dose of ribociclib decreased the ribociclib AUCinf and Cmax by 89% and 81%, respectively, relative to a single 600 mg ribociclib dose given alone in healthy subjects. LEQ803 Cmax increased 1.7-fold and AUCinf decreased by 27%, respectively. The concomitant use of strong CYP3A4 inducers may therefore lead to decreased exposure and consequently a risk for lack of efficacy. The concomitant use of strong CYP3A4 inducers should be avoided, including, but not limited to, phenytoin, rifampicin, carbamazepine and St John’s Wort (Hypericum perforatum). An alternative concomitant medicinal product with no or minimal potential to induce CYP3A4 should be considered.
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 Cmax 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 400 mg or 200 mg once daily.
See prescribing information for full details.

Pregnancy: Pregnancy status should be verified prior to starting treatment with Ribociclib. Women of childbearing potential who are receiving Kisqali should use effective contraception (e.g. double-barrier contraception) during therapy and for at least 21 days after stopping treatment with Kisqali. Kisqali is not recommended during pregnancy and in women of childbearing potential not using contraception.
Lactation: It is not known if ribociclib is present in human milk. There are no data on the effects of ribociclib on the breast-fed infant or the effects of ribociclib on milk production. Ribociclib and its metabolites readily passed into the milk of lactating rats. Patients receiving Kisqali should not breast-feed for at least 21 days after the last dose.

There is only limited experience with reported cases of over-dosage with Ribociclib . In the event of an overdose, symptoms such as nausea and vomiting may occur. In addition, haematological (e.g. neutropenia, thrombocytopenia) toxicity and possible QTc prolongation may occur. General supportive care should be initiated in all cases of overdosage as necessary.