593458 Uk Kisqali Therapy Management Guide Digital 2018 V3.1

User Manual:

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Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard.

Adverse events should also be reported to Novartis Pharmaceuticals UK Ltd on 01276 698370,

at medinfo.uk@novartis.com or online through the patient safety information tool at https://psi.novartis.com

KISQALI® (ribociclib)

Optimising treatment

for your patients

KISQALI in combination with an aromatase inhibitor is indicated for the treatment of

postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer

as initial endocrine-based therapy.1

HR+/HER- = Hormone-receptor-positive and human epidermal growth factor receptor 2-negative.

Prescribing Information can be found on pages 22 and 23 of this document.

This medicinal product is subject

to additional monitoring.

THERAPY

MANAGEMENT

GUIDE

2 3

KISQALI is a CDK4/6 inhibitor for ﬁrst-line HR+/HER2- locally advanced or metastatic breast

cancer treatment.1

This guide provides information for healthcare professionals about how to use KISQALI,

detailing posology, how to monitor patients, and how to manage important adverse events.

INDICATION1

KISQALI in combination with an aromatase inhibitor is indicated for the treatment of

postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer as

initial endocrine-based therapy.

MECHANISM OF ACTION1

KISQALI is a selective inhibitor of CDK4/6, which play a crucial role in signalling pathways

that lead to cell cycle progression and cellular proliferation.

KISQALI works with an aromatase inhibitor (e.g. letrozole) to induce G1 arrest and delay

disease progression.1

Introduction

CDK4/6 = cyclin-dependent kinases 4 and 6; ER = oestrogen receptor; G1 = gap phase 1.

Contents

CONTENTS ..........................................................................................................................PAGE

DOSING AND ADMINISTRATION ...................................................................4

Pharmaceutical form .................................................................................................................4

Starting dose ...............................................................................................................................4

Dosing schedule ..........................................................................................................................5

Method of administration .........................................................................................................5

DOSE MODIFICATIONS ................................................................................. 6

MONITORING ................................................................................................ 7

AE PROFILE ................................................................................................. 8

MANAGING NEUTROPENIA .........................................................................10

Clinical incidence .......................................................................................................................10

Neutropenia management algorithm .................................................................................... 11

MANAGING HEPATOBILIARY TOXICITY ......................................................12

Clinical incidence .......................................................................................................................12

ALT/AST management algorithm ..........................................................................................13

MANAGING QT PROLONGATION ..................................................................14

Clinical incidence .......................................................................................................................14

QT prolongation management algorithm ............................................................................15

GENERAL AE MANAGEMENT ......................................................................16

Clinical incidence .......................................................................................................................16

General AE management algorithm .....................................................................................16

OTHER SPECIAL WARNINGS AND PRECAUTIONS .......................................18

Effects during pregnancy and lactation, and on fertility .................................................18

Critical visceral disease ............................................................................................................18

Soya lecithin ...............................................................................................................................18

INTERACTIONS: EFFECTS ON KISQALI BY OTHER PRODUCTS ...................19

Strong CYP3A4 inhibitors .......................................................................................................19

Strong CYP3A4 inducers .........................................................................................................19

INTERACTIONS: EFFECTS ON OTHER PRODUCTS BY KISQALI ..................20

CYP3A4 substrates ..................................................................................................................20

Substances that are substrates of transporters ...............................................................20

ANTICIPATED INTERACTIONS ....................................................................21

Medicinal products that may prolong the QT interval ......................................................21

KISQALI PRESCRIBING INFORMATION....................................................... 22

ANDROGEN

OESTROGEN

CYCLIN D1

CDK4/6

AROMATASE

INHIBITOR

KISQALI

4 5

PHARMACEUTICAL FORM1

KISQALI is available as 200 mg ﬁlm-coated tablets.

Diameter: 11.1 mm.

STARTING DOSE1

The recommended starting dose is 600 mg/day (3 x 200 mg tablets).

•A reduced starting dose may be required for special populations.

RECOMMENDED STARTING DOSES OF KISQALI FOR SPECIAL POPULATIONS1

RENAL IMPAIRMENT

MILD

(eGFR 60 to <90 ml/min/1.73 m2)No dose adjustment required.

MODERATE

(eGFR 30 to <60 ml/min/1.73 m2)No dose adjustment required.

SEVERE

(eGFR <30 ml/min/1.73 m2)

Caution should be used in patients with severe renal

impairment with close monitoring of signs of toxicity as there

is no experience with KISQALI in this population.

HEPATIC IMPAIRMENT

MILD

(Child–Pugh class A) No dose adjustment required.

MODERATE

(Child–Pugh class B) The recommended starting dose is 400 mg/day.

SEVERE

(Child–Pugh class C) The recommended starting dose is 400 mg/day.

PAEDIATRIC AND ELDERLY POPULATIONS

PAEDIATRIC POPULATION

(aged <18 years)

The safety and efﬁcacy of KISQALI in children and

adolescents aged below 18 years have not been established

as no data are available.

ELDERLY

(aged >65 years) No dose adjustment required.

Dosing and administration

eGFR = estimated glomerular ﬁltration rate; QTc = Corrected QT interval.

DOSING SCHEDULE1

KISQALI should be taken as part of a 28-day treatment cycle comprising a once-daily dose

of KISQALI for 21 consecutive days followed by 7 consecutive days off treatment. Treatment

with KISQALI should be continued as long as the patient is deriving clinical beneﬁt from

therapy or until unacceptable toxicity occurs.

KISQALI should be used together with 2.5 mg letrozole or another aromatase inhibitor. The

aromatase inhibitor should be taken orally once daily continuously throughout the 28-day

cycle. Please refer to the Summary of Product Characteristics of the aromatase inhibitor for

additional details.

RECOMMENDED DOSING SCHEDULE FOR KISQALI (28-DAY CYCLE)1

WEEK 1 WEEK 2 WEEK 3 WEEK 4

KISQALI

600 mg (3 x 200 mg tablets) once daily for

21 consecutive days followed by 7 days off

treatment.

AROMATASE INHIBITOR

(e.g. 2.5 mg letrozole)

Once daily continuously throughout the

28-day cycle. Please see the Summary of

Product Characteristics for the aromatase

inhibitor for details.

Patients should take their dose at approximately the same time each day, preferably in the

morning. If the patient vomits after taking a 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.

METHOD OF ADMINISTRATION1

KISQALI should be taken orally once daily with or without food. KISQALI 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.

KISQALI can be administered with or without food, but patients should be instructed to avoid

pomegranates, pomegranate juice, grapefruit and grapefruit juice. These are known to inhibit

CYP3A4 enzymes and may increase the exposure to Kisqali.1

The use of KISQALI should be avoided in patients who already have or who are at signiﬁcant

risk of developing QTc prolongation. These include patients with the following:

•long QT syndrome;

•uncontrolled or signiﬁcant cardiac disease, including recent myocardial infarction,

congestive heart failure, unstable angina and bradyarrhythmias;

•electrolyte abnormalities.

A reduced dose of KISQALI may be required when strong CYP3A4 inhibitors are

concomitantly administered.

Dose adjustments with strong CYP3A4 inhibitors are detailed on page 19 of this guide.

6 7

Dose modiﬁcations

DOSE MODIFICATIONS

Management of severe or intolerable adverse events may require temporary dose

interruption, reduction or discontinuation of KISQALI.1

RECOMMENDED STEPWISE DOSE MODIFICATIONS1

RECOMMENDED

STARTING DOSE

FIRST

DOSE REDUCTION

SECOND

DOSE REDUCTION

600 mg/day

(3 x 200 mg tablets) ›

400 mg/day

(2 x 200 mg tablets) ›

200 mg/day

(1 x 200 mg tablet)

If further dose reduction below 200 mg/day is required, the treatment should be

permanently discontinued.

Dose modiﬁcations for speciﬁc adverse events are detailed on pages 10–17 of this guide.

MONITORING

It is recommended that certain blood tests and an ECG assessment be performed prior to and

during treatment with KISQALI.1

RECOMMENDED MONITORING SCHEDULE1

CYCLE 1 CYCLE 2 CYCLES 3–6 THEREAFTER

BLOOD

FBC

LFTs Test prior to initiation. Day 14 Days 1 and 14 Day 1 of each

cycle

As clinically

indicated

Electrolytes

Test prior to initiation.

Correct any

abnormalities before

initiating treatment

with KISQALI.

Day 1 Day 1 Day 1 of each

cycle

As clinically

indicated

CARDIAC

ECG

Test prior to initiation.

KISQALI should only

be initiated in patients

with QTcF <450 msec.

Day 14 Day 1 As clinically

indicated

As clinically

indicated

•More frequent monitoring is recommended in the event of liver enzyme elevations

at grade ≥2 or QTcF prolongation during treatment.

As a result of monitoring, adverse events which require dose modiﬁcation may be identiﬁed.

Dose modiﬁcations for speciﬁc adverse events are detailed on pages 10–17 of this guide.

ECG = electrocardiogram; FBC = full blood count; LFT = liver function test;

QTcF = QT interval corrected using Fridericia’s formula.

Monitoring

8 9

Adverse events proﬁle

Frequencies of adverse events with KISQALI reported in MONALEESA-2, a Phase III clinical

study, are listed below. Frequencies are deﬁned as: 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); and very rare (<1/10,000).1

FREQUENCIES OF ADVERSE EVENTS OBSERVED WITH KISQALI IN MONALEESA-21

AE FREQUENCY

Infections and infestations

Urinary tract infection Very common

Blood and lymphatic system disorders

Neutropenia Very common

Leukopenia Very common

Anaemia Very common

Lymphopenia Very common

Thrombocytopenia Common

Febrile neutropenia Common

Metabolism and nutrition disorders

Decreased appetite Very common

Hypocalcaemia Common

Hypokalaemia Common

Hypophosphataemia Common

Nervous system disorders

Headache Very common

Insomnia Very common

Eye disorders

Lacrimation increased Common

Dry eye Common

Cardiac disorders

Syncope Common

Respiratory, thoracic and mediastinal disorders

Dyspnoea Very common

Epistaxis Common

AE FREQUENCY

Gastrointestinal disorders

Nausea Very common

Diarrhoea Very common

Vomiting Very common

Constipation Very common

Stomatitis Very common

Abdominal pain Very common

Dysgeusia Common

Dyspepsia Common

Hepatobiliary disorders

Hepatotoxicity* Common

Skin and subcutaneous tissue disorders

Alopecia Very common

Rash†Very common

Pruritus Very common

Erythema Common

Musculoskeletal and connective tissue disorders

Back pain Very common

General disorders and administration site conditions

Fatigue Very common

Peripheral oedema Very common

Asthenia Very common

Pyrexia Very common

Investigations

Abnormal liver function tests‡Very common

Blood creatinine increased Common

Weight decreased Common

Electrocardiogram QT prolonged Common

Hepatotoxicity: hepatocellular injury, drug induced liver injury, hepatotoxicity, hepatic failure (single non-fatal case),

autoimmune hepatitis (single case).

†Rash: rash, rash maculopapular.

‡Abnormal liver function tests: alanine aminotransferase increased, aspartate aminotransferase increased,

blood bilirubin increased.AE = adverse event

For a full list of adverse events, please consult the Summary of Product Characteristics

for KISQALI.

10 11

Managing neutropenia

CLINICAL INCIDENCE1

Neutropenia is a very common adverse event associated with KISQALI treatment (occurring

at a frequency of ≥1/10 patients), and was the most frequently reported adverse event in

MONALEESA-2.

NEUTROPENIA* EVENTS REPORTED IN PATIENTS RECEIVING

KISQALI (N=334) IN MONALEESA-21

EVENT†PROPORTION OF PATIENTS WITH

AT LEAST ONE EVENT (%)

Neutropenia at any grade 74 . 3

Neutropenia at grade 3 or 4 59.6

Febrile neutropenia 1.5

TIME TO ONSET AND IMPROVEMENT OF NEUTROPENIA IN MONALEESA-21

*Decrease in neutrophil count, based on laboratory ﬁndings.

†

Grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.032:

grade 3 neutropenia: ANC 500 to 1000/mm3; grade 4 neutropenia: ANC <500/mm3.

ANC = absolute neutrophil count.

NEUTROPENIA MANAGEMENT ALGORITHM1

Full blood counts should be performed before initiating with KISQALI.

After initiation of KISQALI, full blood count 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.

ANC 1000/mm3

to ≤LLN

(Grades 1 or 2*)

ANC

500–1000/mm3

(Grade 3*)

Grade 3*

neutropenia with a

single fever

>38.3°C [or >38°C

for more than

1 hour and/or

concurrent

infection]

(Grade 3* febrile

neutropenia)

ANC <500/mm3

(Grade 4*)

Clinical

description

Dose

modiﬁcation

No dose

adjustment is

required.

Dose interruption

until recovery to

grade ≤2.

Dose interruption

until recovery to

grade ≤2.

Dose interruption

until recovery to

grade ≤2.

If neutropenia

improves to

grade ≤2:

Resume KISQALI

at the same dose

level.

If toxicity recurs at

grade 3:

Dose interruption

until recovery to

grade ≤2, then

resume KISQALI

and reduce by one

dose level.

If neutropenia

improves to

grade ≤2:

Resume KISQALI

and reduce by one

dose level.

If neutropenia

improves to

grade ≤2:

Resume KISQALI

and reduce by one

dose level.

Follow-up

If dose reduction below 200 mg/day is required, the treatment should be permanently

discontinued.

*Grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.2

LLN = lower limit of normal.

Among the patients who had

grade 2, 3 or 4† neutropenia,

the median time to onset was 16 days.

The median time to improvement of grade ≥3†

events with KISQALI (to grade <3) was 15 days

following treatment interruption and/or

reduction and/or discontinuation.

days

12 13

Managing hepatobiliary toxicity

CLINICAL INCIDENCE1

Hepatobiliary toxicity events* are a common adverse event associated with KISQALI

treatment, (occurring at a frequency of ≥1/100 patients, but <1/10 patients). Abnormal liver

function tests are a very common adverse event (occurring at a frequency of ≥1/10 patients).

HEPATOBILIARY TOXICITY EVENTS REPORTED IN PATIENTS RECEIVING KISQALI

(N=334) IN MONALEESA-21

EVENT†PROPORTION OF PATIENTS WITH

AT LEAST ONE EVENT (%)

Any hepatobiliary toxicity event

At any grade

At grade 3 or 4

24.0

11.4

ALT elevations at grade 3 or 4 10.2

AST elevations at grade 3 or 4 6.9

Concurrent elevations in ALT or AST >3 x ULN and total bilirubin >2 x ULN, with normal

alkaline phosphatase, in the absence of cholestasis occurred in 4 (1.2%) patients receiving

KISQALI in MONALEESA-2, all of whom recovered to normal levels within 154 days after

treatment with KISQALI was discontinued.

TIME TO ONSET AND IMPROVEMENT OF LIVER ENZYME ELEVATIONS IN

MONALEESA-2 AND A PHASE IB STUDY OF KISQALI PLUS LETROZOLE1

Based on the severity of the transaminase elevations, treatment with KISQALI may have to be

interrupted, reduced or discontinued as described on the page opposite. In MONALEESA-2,

discontinuation of KISQALI due to abnormal liver function tests or hepatotoxicity occurred in

3.0% and 0.6% of patients respectively.

Recommendations for patients who have grade ≥3 ALT/AST elevation at baseline have not

been established.

Page 12 footnotes:

*Hepatotoxicity included hepatocellular injury, drug-induced liver injury, hepatotoxicity, hepatic failure (of which there was

a single non-fatal case) and autoimmune hepatitis (of which there was a single case).

†Grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.032:

grade 3 ALT/AST elevation: >5–20 x ULN; grade 3 ALT/AST elevation: >20 x ULN.

ULN = upper limit of normal.

ALT/AST MANAGEMENT ALGORITHM1

Liver function tests should be performed before initiating treatment with KISQALI.

After initiation, liver function tests 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.

No dose

adjustment is

required.

>ULN to 3 x ULN

(Grade 1*)

If grade 2 at

baseline:

No dose

adjustment is

required.

>3-5 x ULN

(Grade 2*)

If grade <2 at

baseline:

Dose

interruption

until recovery

to ≤ baseline

grade.

If ALT/AST

elevations improve

to ≤ baseline grade:

Resume KISQALI

at the same dose

level.

If toxicity recurs at

grade 2:

Resume KISQALI

and reduce by one

dose level.

If ALT/AST

elevations improve

to ≤ baseline grade:

Resume KISQALI

and reduce by one

dose level.

If toxicity recurs at

grade 3:

Discontinue

KISQALI.

Dose

interruption of

KISQALI until

recovery to ≤

baseline grade.

>5-20 x ULN

(Grade 3*)

Discontinue

KISQALI.

>20 x ULN

(Grade 4*)

Clinical

description

Dose

modiﬁcations

for ALT and/or

AST elevations

from baseline,

without

increase in

total bilirubin

above 2 x ULN

Follow-up

If patients develop ALT and/or AST >3 x ULN along with total bilirubin >2 x ULN

irrespective of baseline grade, discontinue KISQALI.

If dose reduction below 200 mg/day is required, the treatment should be permanently

discontinued.

*Grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.2

The majority (83.8%) of grade 3 or 4† ALT/

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 57 days.

days

The median time to improvement

(to grade ≤2) was 24 days.

days

14 15

Managing QT prolongation

CLINICAL INCIDENCE1

QT prolongation is a common adverse event associated with KISQALI treatment (occurring at

a frequency of ≥1/100 patients, but fewer than 1/10 patients).

QT INTERVAL PROLONGATION REPORTED IN PATIENTS RECEIVING KISQALI

(N=334) IN MONALEESA-21

EVENT PROPORTION OF PATIENTS WITH

AT LEAST ONE EVENT (%)

Any QT interval prolongation

(including ECG QT prolonged

and syncope)

7. 5

QTcF interval >500 msec 0.3

QTcF interval >480 msec 3.3

QTcF increase >60 msec

from baseline 2.7

7.5% of patients had at least one event of QT interval prolongation (including ECG QT

prolonged and syncope) with KISQALI. There were no reported cases of torsade de pointes.

Dose interruptions/adjustments due to ECG QT prolongation and syncope were reported in

0.9% of patients who were receiving KISQALI.

TIME TO ONSET OF QT INTERVAL PROLONGATION IN MONALEESA-21,3

QTcF interval prolongation >480 msec with

KISQALI mostly occurred within the ﬁrst 4 weeks

of treatment.

weeks

Amongst the patients who had QTcF prolongation

>480 msec, the median time to onset was

15 days, and these changes were reversible with

dose interruption and/or dose reduction.

days

Based on the severity of QT interval prolongation, treatment with KISQALI may have to be

interrupted, reduced or discontinued as described on the page opposite.

QT PROLONGATION MANAGEMENT ALGORITHM1

ECG should be assessed before initiating treatment. Treatment with KISQALI should be

initiated only in patients with QTcF values <450 msec. After initiation, 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.

ECGs with QTcF

>480 msec

Dose interruption

until recovery to

<481 msec

If QTcF is greater

than 500 msec on at

least two separate

ECGs:

Interrupt KISQALI

until QTcF is

<481 msec

If QTcF improves to

<481 msec:

Resume KISQALI

at the same dose

level.

If QTcF

prolongation recurs

at ≥481 msec:

Dose interruption

until QTcF improves

to <481 msec and

then resume

KISQALI and

reduce by one dose

level.

If QTcF improves to

<481 msec:

Resume KISQALI

and reduce by one

dose level.

ECGs with QTcF >500 msec

If QTcF interval prolongation to greater than

500 msec or greater than 60 msec change

from baseline occurs

in combination with

torsade de pointes or polymorphic

ventricular tachycardia or signs/symptoms of

serious arrhythmia:

Permanently discontinue KISQALI.

Clinical

description

Dose

modiﬁcation

Follow-up

If dose reduction below 200 mg/day is required, the treatment should be permanently

discontinued.

16 17

General adverse events management

CLINICAL INCIDENCE1

The most common adverse events of any grade (reported in ≥20% of patients) for which the

frequency for KISQALI plus letrozole exceeds the frequency for placebo plus letrozole were:

•neutropenia

•leukopenia

•headache

•back pain

•nausea

•fatigue

•diarrhoea

•vomiting

•constipation

•alopecia

•rash

The most common adverse events at grade 3 or 4 (reported in ≥2% of patients) for which the

frequency for KISQALI plus letrozole exceeds the frequency for placebo plus letrozole were:

•neutropenia

•leukopenia

•abnormal liver

function test

•lymphopenia

•hypophosphataemia

•vomiting

•nausea

•fatigue

•back pain

Management of severe or intolerable adverse events with KISQALI may require temporary

dose interruption, reduction or discontinuation, as described on the page opposite.

GENERAL ADVERSE EVENTS MANAGEMENT ALGORITHM1

No dose adjustment

is required.

Initiate appropriate

medical therapy

and monitor as

clinically indicated.

Dose interruption

until recovery to

grade ≤1.

Discontinue

KISQALI.

Dose

modiﬁcation

If AE improves to grade ≤1:

Resume KISQALI at the same dose level.

If toxicity recurs at grade 3:

Resume KISQALI and reduce by one dose level.

Follow-up

Management of severe or intolerable adverse events with KISQALI may require temporary dose

interruption, reduction or discontinuation.

Grade 1 or 2* Grade 3* Grade 4*

Clinical

description

If dose reduction below 200 mg/day is required, the treatment should be permanently

discontinued.

*Grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.2

ADL = activities of daily living; BSA = body surface area; LLN = lower limit of normal; N/A = grade is not available;

TPN = total parenteral nutrition.

AE GRADES 1 & 2 GRADE 3 GRADE 4

Vomiting 1–5 episodes separated by

5 minutes) in 24 hours

≥6 episodes (separated

by 5 minutes) in 24 hours;

tube feeding, TPN or

hospitalisation indicated

Life-threatening

consequences; urgent

intervention indicated

Headache Mild or moderate pain;

limiting instrumental ADL

Severe pain;

limiting self-care ADL N/A

Back pain Mild or moderate pain;

limiting instrumental ADL

Severe pain;

limiting self-care ADL N/A

Fatigue

Fatigue relieved by rest, or

fatigue not relieved by rest;

limiting instrumental ADL

Fatigue not relieved by rest,

limiting self-care ADL N/A

Nausea

Loss of appetite without

alteration in eating habits,

or oral intake decreased

without signiﬁcant weight

loss, dehydration or

malnutrition

Inadequate oral caloric or

ﬂuid intake; tube feeding,

TPN, or hospitalisation

indicated

N/A

Diarrhoea

Increase of <7 stools per

day over baseline; mild

to moderate increase in

ostomy output compared

to baseline

Increase of ≥7 stools per day

over baseline; incontinence;

hospitalisation indicated;

severe increase in ostomy

output compared to baseline;

limiting self-care ADL

Life-threatening

consequences; urgent

intervention indicated

Constipation

Occasional or intermittent

symptoms; occasional use

of stool softeners, laxatives,

dietary modiﬁcation, or

enema, or Persistent

symptoms with regular use

of laxatives or enemas;

limiting instrumental ADL

Obstipation with manual

evacuation indicated;

limiting self-care ADL

Life-threatening

consequences; urgent

intervention indicated

Alopecia

Any hair loss that is

abnormal for that

individual

N/A N/A

Rash

(maculopapular)

Macules/papules covering

<30% BSA with or without

symptoms (e.g. pruritus,

burning, tightness); limiting

instrumental ADL

Macules/papules covering

>30% BSA with or without

associated symptoms;

limiting self-care ADL

N/A

Hypophosphataemia <LLN to 2.0 mg/dL;

<LLN to 0.6 mmol/L

<2.0–1.0 mg/dL;

<0.6–0.3 mmol/L

<1.0 mg/dL;

<0.3 mmol/L; life-

threatening consequences

Leukopenia <LLN to 2000/mm3;

<LLN to 2.0 x 109/L

<2000–1000/mm3;

<2.0–1.0 x 109/L <1000/mm3; <1.0 x 109/L

Lymphopenia <LLN to 500/mm3;

<LLN to 0.5 x 109/L

<500–200/mm3;

<0.5–0.2 x 109/L <200/mm3; <0.2 x 109/L

Adapted from Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.2

18 19

Interactions: effects on KISQALI by other products

EFFECTS DURING PREGNANCY AND LACTATION, AND ON FERTILITY

KISQALI is indicated for use in postmenopausal women, but please note the following

effects of its active ingredient during pregnancy and lactation and on fertility.

Pregnancy status should be veriﬁed prior to starting treatment with KISQALI.

Based on ﬁndings in animals, KISQALI can cause foetal harm when administered to a

pregnant woman.

CRITICAL VISCERAL DISEASE

The efﬁcacy and safety of KISQALI have not been studied in patients with critical

visceral disease.

SOYA LECITHIN

KISQALI contains soya lecithin. Patients who are hypersensitive to peanut or soya should

not take KISQALI.

Other special warnings and precautions

KISQALI is primarily metabolised by CYP3A4. Therefore, medicinal products that can

inﬂuence CYP3A4 enzyme activity may alter the pharmacokinetics of KISQALI.

STRONG CYP3A4 INHIBITORS1

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

•Voriconazole

Alternative concomitant medicinal products with less potential to inhibit CYP3A4 should be

considered and patients should be monitored for adverse events.

•If co-administration of KISQALI with a strong CYP3A4 inhibitor cannot be avoided, the

dose of KISQALI should be reduced to 400 mg; however, there are no clinical data with

this dose adjustment.

•In patients who have had their dose reduced to 400 mg 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 and

in whom initiation of co-administration of a strong CYP3A4 inhibitor cannot be avoided,

KISQALI treatment should be interrupted.

•Due to inter-patient variability, the recommended dose adjustments may not be optimal

in all patients; therefore, close monitoring for adverse events is recommended. In the

event of toxicity related to KISQALI, the dose should be modiﬁed or treatment should be

interrupted until toxicity is resolved. If the strong inhibitor is discontinued, the KISQALI

dose should be resumed (after at least ﬁve half-lives of the CYP3A4 inhibitor) at the

dose used prior to the initiation of the strong CYP3A4 inhibitor.

•Patients should be instructed to avoid pomegranates, pomegranate juice, grapefruit

and grapefruit juice. These are known to inhibit CYP3A4 enzymes and may increase the

exposure to KISQALI.

STRONG CYP3A4 INDUCERS1

The concomitant use of strong CYP3A4 inducers, including but not limited to the following,

should be avoided:

•Phenytoin

•Rifampin

•Carbamazepine

•St John’s wort (Hypericum perforatum)

Alternative concomitant medicinal products with no or minimal potential to induce CYP3A4

should be considered and patients should be monitored for adverse events.

For a full list of potential interactions, please consult the Summary of Product

Characteristics for KISQALI.

20 21

Interactions: effects on other products by KISQALI Anticipated interactions

CYP3A4 SUBSTRATES1

KISQALI 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.

Caution is recommended when KISQALI is administered 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 the following, may need to be reduced as

KISQALI can increase their exposure:

•Alfentanil

•Ciclosporin

•Everolimus

•Fentanyl

•Sirolimus

•Tacrolimus

Concomitant administration of KISQALI 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

When KISQALI is co-administered with other medicinal products, the Summary of Product

Characteristics of the other medicinal product must be consulted for the recommendations

regarding co-administration with CYP3A4 inhibitors.

SUBSTANCES THAT ARE SUBSTRATES OF TRANSPORTERS1

KISQALI 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 the following:

•Digoxin

•Pitavastatin

•Pravastatin

•Rosuvastatin

•Metformin

MEDICINAL PRODUCTS THAT MAY PROLONG THE QT INTERVAL1

Co-administration of KISQALI with anti-arrhythmic medicinal products with a known

potential to prolong the QT interval, including, but not limited to, the following, should

be avoided:

•Amiodarone

•Disopyramide

•Procainamide

•Quinidine

•Sotalol

Co-administration of KISQALI with other medicinal products with a known potential to

prolong the QT interval, including but not limited to the following, should be avoided:

•Chloroquine

•Halofantrine

•Clarithromycin

•Haloperidol

•Methadone

•Moxiﬂoxacin

•Bepridil

•Pimozide

• Intravenous ondansetron

For a full list of potential interactions, please consult the Summary of Product

Characteristics for KISQALI.

22 23

PRESCRIBING INFORMATION

Kisqali® (ribociclib succinate)

(Please refer to the SmPC before prescribing

Kisqali)

Presentation: Film-coated tablet containing

ribociclib succinate, equivalent to 200 mg

ribociclib. Indication: Kisqali, in combination

with an aromatase inhibitor, is indicated for

the treatment of 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.

Dosage: The recommended dose is 600 mg once

daily; taken orally with or without food at the

same time every day for 21 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. Kisqali should be used together with

2.5 mg letrozole or another aromatase inhibitor

(AI). The AI should be taken orally once daily

continuously throughout the 28-day cycle. If the

patient vomits after taking the dose or misses

a dose, an additional dose should not be taken.

The next prescribing dose should be taken at the

usual time. Dose Modiﬁcation: Management of

severe or intolerable adverse drug reactions may

require temporary dose interruption, reduction

or discontinuation of Kisqali (See Special

Warnings & Precautions). Dose reduction should

be achieved by decrements of 200 mg daily. If

further dose reduction below 200 mg/day is

required, the treatment should be permanently

discontinued. Full blood counts (FBC) should

be performed before and after initiating Kisqali

treatment. FBC 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. For neutropenia, no dose

modiﬁcations required for grade 1 or 2. For grade

3, interrupt the dose until recovery to grade ≤2,

then resume at same dose level. If toxicity recurs

at grade 3, interrupt the dose until recovery,

then resume Kisqali and reduce by 1 dose level.

For grade 3 febrile neutropenia interrupt the

dose until recovery to grade ≤2, resume Kisqali

and reduce by 1 dose level. For grade 4 interrupt

the dose until recovery to grade ≤2, resume

Kisqali and reduce by 1 dose level. Liver function

tests (LFTs) should be performed before and

after initiating Kisqali 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. No dose adjustment

is required for grade 1. For grade 2: if baseline at

grade <2, interrupt until recovery to ≤ baseline

grade, then resume Kisqali at same dose, and if

grade 2 recurs, resume Kisqali at next lower dose

level; if baseline at grade 2, no dose interruption.

For grade 3: interrupt Kisqali until recovery

to ≤ baseline grade then resume at next lower

dose level. If grade 3 recurs, discontinue Kisqali.

For grade 4: discontinue Kisqali. If patients

develop ALT and/or AST >3xULN along with total

bilirubin >2xULN irrespective of baseline grade,

discontinue Kisqali. ECG should be assessed

before and after initiating treatment with Kisqali.

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.

ECGs with QTcF >480 msec the dose should be

interrupted. If the QTcF resolves to <481 msec,

resume the treatment at same dose level and if

QTcF >481 msec recurs, interrupt the dose until

QTcF resolves to <481 and then resume Kisqali

at the next lower dose level. If QTcF >500 msec

on at least 2 separate ECGs, interrupt Kisqali

until QTcF <481 msec then resume Kisqali at next

lower dose level. If QTcF >500 msec or >60 msec

change from baseline occurs in combination with

torsade de pointes or polymorphic ventricular

tachycardia or signs/symptoms of serious

arrhythmia, permanently discontinue Kisqali. For

other toxicities no dose adjustment required for

grade 1 or 2, initiate appropriate medical therapy

and monitor as clinically indicated. For grade 3,

interrupt until recovery to grade ≤1, then resume

Kisqali at the same dose. If grade 3 recurs, resume

Kisqali at the next lower dose level. For grade 4,

discontinue Kisqali. 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 Kisqali dose should be reduced to 400 mg

once daily. Contraindications: Hypersensitivity

to the active substance or to peanut, soya or

any other listed excipients. Special Warnings

and Precautions: 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, Kisqali treatment may have to be

interrupted, reduced or discontinued. QT Interval

prolongation: Treatment with Kisqali should

be initiated only in patients with QTcF values

less than 450 msec. 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

Kisqali. The use of Kisqali with medicinal products

known to prolong QTc interval and/or strong

CYP3A4 inhibitors should be avoided as this

may lead to clinically meaningful prolongation

of the QTcF interval. Kisqali should be avoided

in patients with long QT syndrome, signiﬁcant

cardiac disease and electrolyte abnormalities.

Hepatobiliary toxicity, CYP3A4 substrates, soya

lecithin: see other sections. Based on ﬁndings in

animals, ribociclib can cause foetal harm when

administered to a pregnant woman. Kisqali may

have a minor inﬂuence on the ability to drive

and use machinery; patients should be cautious

in case they experience fatigue. Undesirable

Effects: Very common: abdominal pain,

abnormal liver function tests (ALT, AST & blood

bilirubin increased), alopecia, anaemia, asthenia,

back pain, constipation, decreased appetite,

diarrhoea, dyspnoea, fatigue, headache,

insomnia, leukopenia, lymphopenia, nausea,

neutropenia, peripheral oedema, pruritus,

pyrexia, rash, stomatitis, urinary tract infection

and vomiting. Common: decreased weight, dry

eye, dysgeusia, dyspepsia, electrocardiogram

QT prolonged, epistaxis, erythema, febrile

neutropenia, hepatotoxicity, hypocalcaemia,

hypokalaemia, hypophosphataemia, increased

lacrimation, increased blood creatinine, syncope

and thrombocytopenia. Interactions: Ribociclib

is primarily metabolised by CYP3A4. Medicinal

products that can inﬂuence CYP3A4 enzyme

activity may alter the pharmacokinetics of

ribociclib. 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

Kisqali with medicinal products with a known

potential to prolong the QT interval such as

anti-arrhythmic medicinal products and other

medicinal products that are known to prolong

the QT interval should be avoided. Please refer

to the SmPC for other possible interactions.

Basic NHS Cost: 21 tablets = £983.33, 42 tablets

= £1,966.67, 63 tablets = £2,950.00.

Marketing Authorisation (MA) Holder:

Novartis Europharm Ltd, Frimley Business Park,

Camberley, GU16 7SR, UK.

MA Number: EU/1/17/1221/001-012

Legal category: POM

Further information is available from Novartis

Pharmaceuticals UK Ltd, Frimley Business Park,

Frimley, Camberley, Surrey, GU16 7SR, UK. Tel:

01276 692255.

Date of Preparation: July 2017

KIS17-C022

Adverse events should be reported. Reporting

forms and information can be found at

www.mhra.gov.uk/yellowcard.

Adverse events should also be reported to

Novartis on 01276 698370, at

medinfo.uk@novartis.com or online through the

patient safety information tool at

https://psi.novartis.com

Prescribing information

July 2018

References:

1. KISQALI Summary of Product Characteristics.

2. US Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE) version

4.03. 2010. Available at: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010–06–14_QuickReference_5x7.pdf

(Accessed July 2017).

3. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as ﬁrst-line therapy for HR-positive, advanced breast cancer.

NEJM. 2016; 375(18); 1738–1748.

593458 Uk Kisqali Therapy Management Guide Digital 2018 V3.1

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