Ribociclib

Co-administration of ribociclib with medicinal products with a known potential to prolong the QT interval such as anti-arrhythmic medicinal products (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine and sotalol), and other medicinal products that are known to prolong the QT interval (including, but not limited to, chloroquine, halofantrine, clarithromycin, ciprofloxacin, levofloxacin, azithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide and intravenous ondansetron) should be avoided.

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 400 mg or 200 mg once daily.

Patients should be instructed to avoid grapefruit or grapefruit juice. These are known to inhibit cytochrome CYP3A4 enzymes and may increase the exposure to ribociclib.

In vitro evaluations indicated that ribociclib has a potential to inhibit the activities of drug transporters P-gp, BCRP, OATP1B1/1B3, OCT1, OCT2, MATE1 and BSEP. Caution and monitoring for toxicity are advised during concomitant treatment with sensitive substrates of these transporters which exhibit a narrow therapeutic index, including but not limited to digoxin, pitavastatin, pravastatin, rosuvastatin and metformin.

Concomitant use of strong CYP3A4 inhibitors should be avoided and an alternative concomitant medicinal product with less potential to inhibit CYP3A4 inhibition should be considered. If patients must be given a strong CYP3A4 inhibitor concomitantly with ribociclib, the ribociclib dose should be reduced to 400 mg once daily.

In patients who have had their dose reduced to 400 mg ribociclib daily and in whom initiation of co-administration of a strong CYP3A4 inhibitor cannot be avoided, the dose should be further reduced to 200 mg.

In patients who have had their dose reduced to 200 mg ribociclib daily and in whom initiation of co-administration of a strong CYP3A4 inhibitor cannot be avoided, ribociclib treatment should be interrupted.

Due to inter-patient variability, the recommended dose adjustments may not be optimal in all patients, therefore close monitoring of signs of toxicity is recommended. If the strong inhibitor is discontinued, the ribociclib dose should be changed to the dose used prior to the initiation of the strong CYP3A4 inhibitor after at least 5 half-lives of the strong CYP3A4 inhibitor.

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 (AUC_inf) and the peak concentration (C_max) in healthy subjects 3.2 and 1.7-fold, respectively, relative to a single 400 mg ribociclib dose given alone. C_max and AUC_last 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.

If co-administration of ribociclib with a strong CYP3A4 inhibitor cannot be avoided, the dose of ribociclib should be reduced as described. However, there are no clinical data with these dose adjustments. Due to inter-patient variability, the recommended dose adjustments may not be optimal in all patients, therefore close monitoring for ribociclib-related AEs is recommended. In the event of ribociclib-related toxicity, the dose should be modified or treatment should be interrupted until toxicity is resolved. If the strong CYP3A4 inhibitor is discontinued, and after at least 5 half-lives of the CYP3A4 inhibitor, ribociclib should be resumed at the same dose used prior to the initiation of the strong CYP3A4 inhibitor.

Physiologically-based pharmacokinetic simulations suggested that at a 600 mg dose of ribociclib, a moderate CYP3A4 inhibitor (erythromycin) may increase ribociclib steady-state C_max and AUC 1.2-fold and 1.3-fold, respectively. For patients who had their ribociclib dose reduced to 400 mg once daily, the increase of the steady-state C_max and AUC was estimated to be 1.4- and 2.1-fold, respectively. The effect at the 200 mg once-daily dose was predicted to be a 1.7- and 2.8-fold increase, respectively. No dose adjustments of ribociclib are required at initiation of treatment with mild or moderate CYP3A4 inhibitors. However, monitoring of ribociclib-related AEs is recommended.

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 C_max by 89% and 81%, respectively, relative to a single 600 mg ribociclib dose given alone in healthy subjects. LEQ803 C_max 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.

A starting dose of 400 mg is recommended in patients with severe renal impairment. Caution should be used in patients with severe renal impairment with close monitoring for signs of toxicity.

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 is a moderate to strong CYP3A4 inhibitor and may interact with medicinal substrates that are metabolised via CYP3A4, which can lead to increased serum concentrations of the concomitantly used medicinal product.

Co-administration of midazolam (CYP3A4 substrate) with multiple doses of ribociclib (400 mg) increased the midazolam exposure by 280% (3.80-fold) in healthy subjects, compared with administration of midazolam alone. Simulations using physiologically-based pharmacokinetic models suggested that ribociclib given at the clinically relevant dose of 600 mg is expected to increase the midazolam AUC by 5.2-fold. Therefore, in general, when ribociclib is co-administered with other medicinal products, the SmPC of the other medicinal product must be consulted for the recommendations regarding co-administration with CYP3A4 inhibitors. Caution is recommended in case of concomitant use with sensitive CYP3A4 substrates with a narrow therapeutic index. The dose of a sensitive CYP3A4 substrate with a narrow therapeutic index, including but not limited to alfentanil, ciclosporin, everolimus, fentanyl, sirolimus and tacrolimus, may need to be reduced as ribociclib can increase their exposure.

Concomitant administration of ribociclib at the 600 mg dose with the following CYP3A4 substrates should be avoided: alfuzosin, amiodarone, cisapride, pimozide, quinidine, ergotamine, dihydroergotamine, quetiapine, lovastatin, simvastatin, sildenafil, midazolam, triazolam.

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

Data from a clinical study in patients with breast cancer indicated that tamoxifen exposure was increased approximately 2-fold following co-administration of ribociclib and tamoxifen.

ECG should be assessed before initiating treatment with ribociclib. After initiating treatment, ECG should be repeated at approximately day 14 of the first cycle and at the beginning of the second cycle, then as clinically indicated. In case of QTcF prolongation during treatment, more frequent ECG monitoring is recommended.

Dose modification and management – QT prolongation:

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 ribociclib 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.

* Excluding neutropenia, hepatotoxicity and QT interval prolongation.

Complete blood counts (CBC) should be performed before initiating treatment with ribociclib. After initiating treatment CBC should be monitored every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, then as clinically indicated.

Dose modification and management – Neutropenia:

* Grading according to CTCAE Version 4.03 (CTCAE = Common Terminology Criteria for Adverse Events).
** Grade 3 neutropenia with a single fever >38.3°C (or above 38°C for more than one hour and/or concurrent infection).
ANC = absolute neutrophil count; LLN = lower limit of normal

Toxic epidermal necrolysis (TEN) has been reported with ribociclib treatment. If signs and symptoms suggestive of severe cutaneous reactions (e.g. progressive widespread skin rash often with blisters or mucosal lesions) appear, ribociclib should be discontinued immediately.

Liver function tests (LFTs) should be performed before initiating treatment with ribociclib. After initiating treatment LFTs should be performed every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, then as clinically indicated. If grade ≥2 abnormalities are noted, more frequent monitoring is recommended.

Dose modification and management – Hepatobiliary toxicity:

* Grading according to CTCAE Version 4.03 (CTCAE = Common Terminology Criteria for Adverse Events)
** Baseline = prior to treatment initiation
ULN = upper limit of normal

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.

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 ribociclib should not breast-feed for at least 21 days after the last dose.

Women of childbearing potential / 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.

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.

Ribociclib may have minor influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines in case they experience fatigue, dizziness or vertigo during treatment with ribociclib.

Summary of the safety profile

The most common ADRs and the most common grade ¾ ADRs (reported at a frequency ≥20% and ≥2%, respectively) in the pooled dataset for which the frequency for ribociclib 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.

Dose reduction due to adverse events, regardless of causality, occurred in 37.3% of patients receiving ribociclib in the phase III clinical studies regardless of the combination and permanent discontinuation was reported in 7.0% of patients receiving ribociclib and any combination in the phase III clinical studies.

List of adverse reactions

The overall safety evaluation of ribociclib is based on the pooled dataset from 1,065 patients who received ribociclib in combination with endocrine therapy (N=582 in combination with an aromatase inhibitor and N=483 in combination with fulvestrant) and who were included in the randomised, double-blind, placebo-controlled phase III clinical studies (MONALEESA-2, MONALEESA-7 NSAI subgroup and MONALEESA-3) in HR-positive, HER2-negative advanced or metastatic breast cancer. Additional ADRs were identified post-marketing.

The median duration of exposure to ribociclib treatment across the pooled phase III studies dataset was 21.7 months, with 61.7% patients exposed ≥12 months.

Adverse drug reactions from the phase III clinical studies are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available data).

Adverse drug reactions observed in the three phase III clinical studies and during post-marketing experience:

Infections and infestations

Very common: Infections¹

Blood and lymphatic system disorders

Very common: Neutropenia, leukopenia, anaemia, lymphopenia

Common: Thrombocytopenia, febrile neutropenia

Metabolism and nutrition disorders

Very common: Decreased appetite

Common: Hypocalcaemia, hypokalaemia, hypophosphataemia

Nervous system disorders

Very common: Headache, dizziness

Common: Vertigo

Eye disorders

Common: Lacrimation increased, dry eye

Cardiac disorders

Common: Syncope

Respiratory, thoracic and mediastinal disorders

Very common: Dyspnoea, cough

Gastrointestinal disorders

Very common: Nausea, diarrhoea, vomiting, constipation, stomatitis, abdominal pain², dyspepsia

Common: Dysgeusia

Hepatobiliary disorders

Common: Hepatotoxicity³

Skin and subcutaneous tissue disorders

Very common: Alopecia, rash⁴, pruritus

Common: Erythema, dry skin, vitiligo

Not known: Toxic epidermal necrolysis (TEN)*

Musculoskeletal and connective tissue disorders

Very common: Back pain

General disorders and administration site conditions

Very common: Fatigue, peripheral oedema, asthenia, pyrexia

Common: Dry mouth, oropharyngeal pain

Investigations

Very common: Abnormal liver function tests⁵

Common: Blood creatinine increased, electrocardiogram QT prolonged

¹ Infections: urinary tract infections, respiratory tract infections, gastroenteritis, sepsis (<1%).
² Abdominal pain: abdominal pain, abdominal pain upper.
³ Hepatotoxicity: hepatocellular injury, drug-induced liver injury (<1%), hepatotoxicity, hepatic failure, autoimmune hepatitis (single case).
⁴ Rash: rash, rash maculopapular, rash pruritic.
⁵ Abnormal liver function tests: ALT increased, AST increased, blood bilirubin increased.
* Adverse reactions reported during post-marketing experience. These are derived from spontaneous reports for which it is not always possible to reliably establish frequency or a causal relationship to exposure to the medicinal product.

Description of selected adverse drug reactions

Neutropenia

Neutropenia was the most frequently reported adverse drug reaction (73.7%) and a grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) was reported in 58.6% of patients receiving ribociclib plus any combination in the phase III studies.

Among the patients who had grade 2, 3 or 4 neutropenia, the median time to onset was 16 days, for those patients who had an event. The median time to resolution of grade ≥3 (to normalisation or grade <3) was 12 days in the ribociclib plus any combination arms following treatment interruption and/or reduction and/or discontinuation. Febrile neutropenia was reported in about 1.4% of patients exposed to ribociclib in the phase III studies. Patients should be instructed to report any fever promptly.

Based on its severity, neutropenia was managed by laboratory monitoring, dose interruption and/or dose modification. Treatment discontinuation due to neutropenia was low (0.8%).

Hepatobiliary toxicity

In the phase III clinical studies, hepatobiliary toxicity events occurred in a higher proportion of patients in the ribociclib plus any combination arms compared with the placebo plus any combination arms (23.2% versus 16.5%, respectively), with more grade ¾ adverse events reported in the patients treated with ribociclib plus any combination (11.4% versus 5.4%, respectively). Increases in transaminases were observed. Grade 3 or 4 increases in ALT (9.7% versus 1.5%) and AST (6.7% versus 2.1%) were reported in the ribociclib and placebo arms, respectively. Concurrent elevations in ALT or AST greater than three times the upper limit of normal and total bilirubin greater than two times the upper limit of normal, with normal alkaline phosphatase, in the absence of cholestasis occurred in 6 patients (4 patients in Study A2301 [MONALEESA-2], whose levels recovered to normal within 154 days and 2 patients in Study F2301 [MONALEESA-3], whose levels recovered to normal in 121 and 532 days, respectively, after discontinuation of ribociclib). There were no such cases reported in Study E2301 (MONALEESA-7).

Dose interruptions and/or adjustments due to hepatobiliary toxicity events were reported in 10.4% of ribociclib plus any combination treated patients, primarily due to ALT increased (6.9%) and/or AST increased (6.1%). Discontinuation of treatment with ribociclib plus any combination due to abnormal liver function tests or hepatotoxicity occurred in 2.3% and 0.4% of patients respectively.

In the phase III clinical studies, 83.2% (89/107) of grade 3 or 4 ALT or AST elevation events occurred within the first 6 months of treatment. Among the patients who had grade 3 or 4 ALT/AST elevation, the median time to onset was 85 days for the ribociclib plus any combination arms. The median time to resolution (to normalisation or grade ≤2) was 22 days in the ribociclib plus any combination arms.

QT prolongation

In study E2301 (MONALEESA-7), the observed mean QTcF increase from baseline was approximately 10 msec higher in the tamoxifen plus placebo subgroup compared with the NSAI plus placebo subgroup, suggesting that tamoxifen alone had a QTcF prolongation effect which can contribute to the QTcF values observed in the ribociclib plus tamoxifen group. In the placebo arm, a QTcF interval increase of >60 msec from baseline occurred in 6/90 (6.7%) patients receiving tamoxifen and in no patients receiving a NSAI. A QTcF interval increase of >60 msec from baseline was observed in 14/87 (16.1%) patients receiving ribociclib plus tamoxifen and in 18/245 (7.3%) patients receiving ribociclib plus a NSAI. ribociclib is not recommended to be used in combination with tamoxifen.

In the phase III clinical studies 8.4% of patients in the ribociclib plus aromatase inhibitor or fulvestrant arms and 3.2% in the placebo plus aromatase inhibitor or fulvestrant arms had at least one event of QT interval prolongation (including ECG QT prolonged and syncope). Review of ECG data showed 14 patients (1.3%) had >500 msec post-baseline QTcF value, and 59 patients (5.6%) had a >60 msec increase from baseline in QTcF intervals. There were no reported cases of torsade de pointes. Dose interruptions/adjustments were reported in 2.3% of ribociclib plus aromatase inhibitor or fulvestrant treated patients due to electrocardiogram QT prolonged and syncope.

The analysis of ECG data showed 52 patients (4.9%) and 11 patients (1.4%) with at least one >480 msec post-baseline QTcF for the ribociclib plus aromatase inhibitor or fulvestrant arms and the placebo plus aromatase inhibitor or fulvestrant arms, respectively. Amongst the patients who had QTcF prolongation >480 msec, the median time to onset was 15 days regardless of the combination and these changes were reversible with dose interruption and/or dose reduction.