Consumer medicine information

Kisqali

Ribociclib

BRAND INFORMATION

Brand name

Kisqali

Active ingredient

Ribociclib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kisqali.

SUMMARY CMI

KISQALI®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Kisqali?

Kisqali contains the active ingredient ribociclib (as succinate). Kisqali is used to treat certain types of breast cancer.

For more information, see Section 1. Why am I using Kisqali? in the full CMI.

2. What should I know before I use Kisqali?

Do not use if you have ever had an allergic reaction to ribociclib, cyclin dependent kinase inhibitors, soy lecithin or any of the ingredients listed at the end of the CMI. Do not use Kisqali if you have a QT prolongation heart problem.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Kisqali? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Kisqali and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Kisqali?

  • Kisqali is taken in repeating cycles of 28 days, each day for 21 days followed by a 7 day treatment break. Kisqali is used in combination with a second medicine (either an aromatase inhibitor or fulvestrant), which are used as hormonal anticancer therapies.

More instructions can be found in Section 4. How do I use Kisqali? in the full CMI.

5. What should I know while using Kisqali?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Kisqali.
  • Keep all your doctor appointments as regular tests on your blood, heart and lung function are needed.
Things you should not do
  • Do not take Kisqali if you are pregnant or breastfeeding.
  • Do not eat grapefruit (or grapefruit juice), pomelo, star fruit or Seville oranges.
Driving or using machines
  • Treatment with Kisqali may make you feel tired or dizzy.
Looking after your medicine
  • Store the tablets in a cool dry place below 30°C.

For more information, see Section 5. What should I know while using Kisqali? in the full CMI.

6. Are there any side effects?

There can be serious side effects that need immediate medical attention. These include allergic reactions, severe skin reactions, infections, liver and heart problems.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

KISQALI®

Active ingredient: ribociclib (as succinate)


Consumer Medicine Information (CMI)

This leaflet provides important information about using Kisqali. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Kisqali.

Where to find information in this leaflet:

1. Why am I using Kisqali?
2. What should I know before I use Kisqali?
3. What if I am taking other medicines?
4. How do I use Kisqali?
5. What should I know while using Kisqali?
6. Are there any side effects?
7. Product details

1. Why am I using Kisqali?

Kisqali contains the active ingredient ribociclib. Kisqali is believed to work by blocking the effects of types of enzymes, called cyclin dependent kinases (CDK) that chemically signal cancer cells to grow and multiply. By blocking these enzymes, Kisqali may delay the growth of breast cancer.

Kisqali is used to treat hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that is locally advanced or may have also spread to other parts of the body (metastatic).

It is used in combination with a second medicine (either an aromatase inhibitor or fulvestrant), which are used as hormonal anticancer therapies.

If Kisqali is used in women who have not reached menopause and in combination with an aromatase inhibitor, a third medicine must also be used from the group of luteinising hormone-releasing hormone (LHRH) agonists. This medicine controls the function of your ovaries, by reducing the amount of oestrogen (a hormone) that is produced by your body.

2. What should I know before I use Kisqali?

Warnings

Do not take Kisqali if:

  • you are allergic to ribociclib, any cyclin dependent kinase inhibitor, soya lecithin, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
  • you have a heart problem known as QT prolongation.
This is caused by a change in the electrical activity of the heart, and is seen by your doctor on an ECG (electrocardiogram), or
  • you have conditions which put you at risk of getting QT prolongation,
    such as: a slow heartbeat, low potassium, magnesium, calcium or phosphorous levels in your blood, a family history of QT prolongation, or
  • you take other medicines which prolong the QT interval.

Women of child-bearing age who recently became postmenopausal or peri menopausal should not commence treatment with Kisqali until your post-menopausal status is fully established.

Check with your doctor if you:

  • have any other medical conditions, including:
    - fever, sore throat or mouth ulcers due to infections (signs of low level of white blood cells)
    - problems with your liver or previously had any type of liver disease
    - heart failure, heart attack, heart disorders or heart rhythm disorders, such as an irregular heartbeat, including a condition called prolonged QT syndrome (QT interval prolongation)
    - low levels of potassium, magnesium, calcium, or phosphorous in your blood
  • are still having periods
  • take any other medicines or supplements.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. Kisqali may harm your unborn baby if you are pregnant. Women who are able to become pregnant should have a negative pregnancy test result before starting treatment and use effective birth control during treatment and for at least 21 days after stopping Kisqali.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is not known if Kisqali is present in breast milk.

Your doctor will discuss with you the potential risks of taking Kisqali during pregnancy or when breast feeding.

Men taking Kisqali

Kisqali may reduce fertility in male patients.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Kisqali and affect how it works. In particular, these include medicines used to treat:

  • fungal infections, such as ketoconazole, itraconazole, voriconazole or posaconazole
  • bacterial infections, such as erythromycin, clarithromycin, azithromycin, moxifloxacin, levofloxacin, norfloxacin, and ciprofloxacin
  • HIV/AIDS, such as: ritonavir, saquinavir, idinavir, lopinavir, nelfinavir, telaprevir and efavirenz
  • seizures or fits, anti-epileptics such as carbamazepine, phenytoin, rifampin and midazolam
  • heart rhythm problems, such as amiodarone, disopyramide, procainamide, quinidine and sotalol
  • depression, anxiety, sleep problems, or other conditions with a herbal product called St John's Wort (also known as Hypericum perforatum).

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Kisqali.

4. How do I use Kisqali?

How much to take

Kisqali is taken is repeating cycles of 28 days (4 weeks). It is taken each day for 21 days, followed by a treatment break of 7 days when Kisqali tablets are not taken.

  • Days 1 to 21 (of repeating 28 day cycle)
    - The usual starting dose is 600 mg (3 Kisqali 200 mg tablets). Your doctor will tell you exactly how many tablets to take.
  • Days 22 to 28 (of repeating 28 day cycle)
    - Do not take any Kisqali tablets this week.
    - The 7 day break when you do not take Kisqali tablets will help your body to recover and decrease the risks of getting any potentially serious side effects or an infection.
    - If you take Kisqali with an aromatase inhibitor, keep taking the aromatase inhibitor each day as directed by your doctor.
  • Start taking Kisqali again the following week on days 1 to 21 as a new 28 day cycle begins.

When to take Kisqali

  • Kisqali should be taken at about the same time each day, preferably in the morning on days 1 to 21 of a 28 day cycle.
  • Kisqali tablet packs have a fifth flap to help you keep track of your doses during each treatment cycle. Write in the days of the week starting with the first day of your treatment. Cross off a circle after each tablet that you take, in each week of the cycle, as shown in the pack example.

How to take Kisqali

Swallow Kisqali tablets whole with a glass of water or other liquid.

Do not chew, crush or split the tablets prior to swallowing.

Taking Kisqali in combination with an aromatase inhibitor or fulvestrant

These other medicines are supplied separately. Your doctor will tell you how much and when to take the aromatase inhibitor or fulvestrant, and LHRH agonist if prescribed.

Keep taking theses medicines as directed by your doctor.

Taking with food or drinks

Kisqali tablets can be taken with or without food.

However, do not eat grapefruit (or drink grapefruit juice), pomelos, star-fruit, or Seville oranges during your treatment with Kisqali. These foods may change the way Kisqali is absorbed into your body.

How long to keep taking Kisqali

This is a long-term treatment, which may continue for many months or years.

Continue taking Kisqali once a day on days 1 to 21, of repeating 28 day cycles, for as long as your doctor tells you to. Your doctor will regularly check your condition to ensure that Kisqali treatment is having the desired effect on you.

If you forget to use Kisqali

Kisqali should be taken regularly at the same time each day on days 1 to 21.

If you miss a dose during days 1 to 21, skip the missed dose and take your next dose at your regular time on the next day.

Do not take a double dose to make up for the dose you missed.

If you have trouble remembering when to take or skip Kisqali, keep a treatment diary, or ask your doctor, nurse or pharmacist for some hints.

If you take too much Kisqali

If you think that you have taken too much Kisqali, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Kisqali?

Things you should do

Follow your doctor's instructions carefully. Your treatment may not help or you may have unwanted side effects if you do not follow the instructions.

Keep all your doctor's appointments to check your progress:

  • You will have regular blood tests before and during treatment with Kisqali to monitor how your liver is working, the amount of blood cells, and electrolytes (blood salts including potassium, calcium, magnesium and phosphate) in your body.
  • The electrical activity of your heart will be checked before and during treatment (with a test called an electrocardiogram or ECG). These test results can change when taking Kisqali.
  • Your lung function will be checked.
  • If necessary, additional tests to check how your kidneys are working will be done.

If necessary, your doctor may decide to stop Kisqali for a short time or reduce your Kisqali dose to allow your liver, kidneys, blood cells, electrolytes, lungs or heart activity to recover. Your doctor may also decide to stop treatment permanently.

Call your doctor straight away if you:

  • Become pregnant – you should not take this medicine while you are pregnant.

Remind any doctor, dentist or pharmacist you visit that you are using Kisqali.

Things you should not do

  • If you take Kisqali with an aromatase inhibitor, do not skip the aromatase inhibitor on any day. It must be taken every day as directed in the 28 day cycle
  • Do not use Kisqali to treat any other complaint unless your doctor says you can
  • Do not give this medicine to anyone else.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Kisqali affects you.

Kisqali may cause tiredness, dizziness or vertigo in some people.

Drinking alcohol

Be careful drinking alcohol until you know how Kisqali affects you.

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place below 30°C, away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Very common side effects

Very common side effectsWhat to do
  • Tiredness, fatigue, pale skin, feeling weak
  • Respiratory tract problems
    - Sore throat
    - Runny nose, blocked nose
    - Sneezing
    - Feeling of pressure or pain in the cheeks or forehead with or without fever,
    - Cough, hoarseness, weak voice or voice loss
  • Mouth, stomach or bowel problems
    - Reduced appetite
    - Nausea, vomiting
    - Diarrhea, constipation
    - Mouth sores or ulcers with gum inflammation
    - Stomach pain
    - Painful and frequent urination
  • Back pain
  • Hair loss or thinning
  • Rash, itching
  • Headache
  • Swollen hands, ankles or feet
  • Dizziness or lightheadedness
Speak to your doctor if you have any of these very common side effects and they worry you.

Common side effects

Common side effectsWhat to do
  • Mouth, stomach or bowel problems
    - Abdominal pain, nausea, vomiting, diarrhoea, swelling or bloating of the abdomen and feeling sick
    - Strange taste in the mouth, dry mouth
    - Sore throat
    - Upset stomach, indigestion, heartburn
  • Watering or tearing of the eyes, dry eye
  • Skin reddening
  • Loss of skin colour in patches
  • Dry skin.
Speak to your doctor if you have any of these common side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Allergic reactions
    - severe itching of the skin, with a red rash, or raised bumps;
    - swelling of the face, lips, tongue, throat, or other parts of the body;
    - difficulty in breathing or swallowing
    - dizziness.
  • Infections showing signs of:
    - fever, sweats or chills, cough, flu like symptoms, weight loss, shortness of breath, blood in your phlegm, sores on your body, warm or painful areas on your body, diarrhoea or stomach pain, feeling very tired
    - fever, sore throat or mouth ulcers
    - increased heart rate, shortness of breath or rapid breathing, fever and chills (these may be signs of a sepsis which is an infection in the blood system which may be life threatening)
  • Heart problems
    - chest pain or discomfort
    - changes in heart beat (fast, slow or irregular), palpitations,
    - light headedness, fainting, dizziness
    - lips turning blue colour
    - shortness of breath
    - swelling (oedema) of your lower limbs or skin.
  • Severe skin reactions:
    - blistering peeling skin with painful raw areas, fever, flu-like symptoms
    - rash, blisters or lesions.
  • Signs of liver problems
    - tiredness
    - itchy yellow skin or yellowing of the whites of your eyes
    - nausea or vomiting, loss of appetite
    - pain in the upper right side of the belly (abdomen)
    - dark or brown urine
    - bleeding or bruising more easily than normal.
  • Other serious side effects:
    - sore throat or mouth ulcers with a single episode of fever greater than 38.3°c, or above 38°c for more than one hour and/or with infection
    - shortness of breath, cough, anxiety, confusion and restlessness.
Stop taking Kisqali and call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Some side effects can only be found when your doctor does tests to check your progress. It is very common for Kisqali to affect certain blood and liver function tests, and common for Kisqali to affect heart test results.

Your doctor will discuss with you what to do if any of your test results are affected.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Kisqali contains

Active ingredient
(main ingredient)
Each tablet contains 200 mg ribociclib, as the succinate salt.
Other ingredients
(inactive ingredients)
  • Magnesium stearate (vegetable source) (E572)
  • Microcrystalline cellulose (E460(i))
  • Hyprolose (E463)
  • Crospovidone (E1202)
  • Colloidal silicon dioxide
  • Polyvinyl alcohol (partially hydrolysed) (E1203)
  • Titanium dioxide (E171)
  • Iron oxide black CI77499 (E172)
  • Iron oxide red CI77491 (E172)
  • Iron oxide yellow CI77492 (E172)
  • Purified talc (E553b)
  • Lecithin (soy) (E322)
  • Xanthan gum (E415).
Potential allergensSoy lecithin

Do not take this medicine if you are allergic to any of these ingredients.

Kisqali does not contain sucrose, lactose, gluten, tartrazine, azo dyes, or any animal products.

What Kisqali looks like

Kisqali film coated tablets are light greyish violet, unscored, round, curved with bevelled edges, debossed with "RIC" on one side and "NVR" on the other side (Aust R 280246).

The tablets are supplied in packs containing either 63, 42, or 21 tablets. All packs contain three blister strips in each carton.

  • 63 tablets: this pack is for patients taking 600 mg (as three 200 mg tablets) ribociclib once each day for 3 weeks. Each blister strip contains 21 tablets.
  • 42 tablets: this pack is for patients taking 400 mg (as two 200 mg tablets) ribociclib once each day for 3 weeks. Each blister strip contains 14 tablets.
  • 21 tablets: this pack is for patients taking the lowest ribociclib daily dose of 200 mg (one tablet) once each day. Each blister strip contains 7 tablets.

Who distributes Kisqali

Novartis Pharmaceuticals Australia Pty Limited
(ABN 18 004 244 160)
54 Waterloo Road
Macquarie Park NSW 2113
Telephone 1 800 671 203
Website: www.novartis.com.au

® = Registered trademark
© Copyright 2022

This leaflet was prepared in March 2022.

Internal document code
(kis070322c is based on PI kis070322i).

Published by MIMS April 2022

BRAND INFORMATION

Brand name

Kisqali

Active ingredient

Ribociclib

Schedule

S4

 

1 Name of Medicine

Ribociclib.

2 Qualitative and Quantitative Composition

Active substance.

Each film coated tablet contains ribociclib succinate equivalent to 200 mg ribociclib.

Excipients.

Excipients with known effect.

Each film-coated tablet contains 0.344 mg soya lecithin.
For full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Light greyish violet, unscored, round (approx. diameter: 11.1 mm), curved film-coated tablet with bevelled edges; debossed with "RIC" on one side and "NVR" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Kisqali is indicated for the treatment of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor or fulvestrant, as initial endocrine-based therapy or following prior endocrine therapy.
In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.

4.2 Dose and Method of Administration

Treatment with Kisqali should be initiated by a physician experienced in the use of anticancer therapies.
Monitoring for adverse drug reactions (ADRs) is required, including full blood counts, LFTs, serum electrolytes, and ECG; dose modification (delay, reduction) or cessation may be required (see Tables 1-5).

Dose.

Kisqali.

The recommended dose of Kisqali is 600 mg (three 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days, followed by 7 days off treatment, resulting in a complete cycle of 28 days. Kisqali may be taken with or without food (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Treatment should be continued as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs.

Aromatase inhibitor.

When co-administered with Kisqali, the aromatase inhibitor is taken daily throughout the 28-day cycle. Please refer to the full Product Information for the aromatase inhibitor dosing regimen.
Patients should be encouraged to take their dose of Kisqali and aromatase inhibitor at approximately the same time each day, preferably in the morning.

Fulvestrant.

When co-administered with Kisqali, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, 29, and once monthly thereafter. Please refer to the full Product Information of fulvestrant.

Luteinising hormone-releasing hormone (LHRH) agonist.

In pre- or perimenopausal women, the endocrine therapy should be co-administered with a luteinising hormone-releasing hormone (LHRH) agonist, according to current clinical practice standards.

Dose modifications.

Management of severe or intolerable ADRs may require temporary dose interruption, dose reduction, or permanent discontinuation of Kisqali. If dose reduction is required, the recommended dose reduction guidelines are listed in Table 1.
Refer to the full Product Information of co-administered medicines (aromatase inhibitor, fulvestrant or LHRH agonist) for dose modification guidelines and other relevant safety information in the event of toxicity.
Tables 2 to 6 provide recommendations for dose interruption, reduction, or discontinuation of Kisqali in the management of specific ADRs. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/ risk assessment (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
In case of QTcF prolongation at any given time during treatment:
Perform analysis of serum electrolytes (K+, Ca2+, PO43-, Mg2+). If outside the normal range, interrupt ribociclib treatment, correct with supplements or appropriate therapy as soon as possible, and repeat electrolytes until documented as normal.
Review concomitant medication usage for the potential to inhibit CYP3A4 and/or to prolong the QT interval.
More frequent ECG monitoring is recommended, e.g. 7 and 14 days after resumption of Kisqali.
Dose modification for use of Kisqali with strong CYP3A inhibitors. Avoid concomitant use of Kisqali with strong CYP3A inhibitors and consider an alternative concomitant medication with less potential for CYP3A inhibition. If a strong CYP3A inhibitor must be co-administered, reduce the Kisqali dose to 200 mg once daily.
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 Kisqali dose should be changed (after 5 elimination half-lives of the strong CYP3A inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties).
Special populations.

Renal impairment.

Based on population pharmacokinetic analyses and data from cancer patients in clinical trials, no dose adjustment is necessary in patients with mild or moderate renal impairment. Based on a renal impairment study in healthy subjects and non-cancer subjects, the recommended starting dose is 200 mg Kisqali once daily for patients with severe renal impairment (see Section 5.2 Pharmacokinetic Properties). There is no experience in cancer patients with severe renal failure or who require haemodialysis with the use of Kisqali. Caution and close monitoring for toxicity should be used in patients with severe renal impairment.

Hepatic impairment.

A pharmacokinetic study in healthy subjects and non-cancer subjects with impaired hepatic function found that no dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). A dose adjustment is required in 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 Kisqali 400 mg once daily is recommended. Ribociclib has not been studied in breast cancer patients with moderate and severe hepatic impairment (see Section 5.2 Pharmacokinetic Properties).
Review the full Product Information for co-administered medicines (aromatase inhibitor, fulvestrant, or LHRH agonist) for dose modifications related to hepatic impairment.

Paediatric use.

The safety and efficacy of Kisqali in children and adolescents aged below 18 years have not been established.

Use in the elderly.

No dose adjustment is necessary (see Section 5.2 Pharmacokinetic Properties).

Administration.

Kisqali should be administered orally once daily at the same time every day, preferably in the morning, with or without food.
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.
Kisqali tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.

4.3 Contraindications

Kisqali is contraindicated in patients with corrected QT interval (QTcF) > 450 milliseconds (ms) prior to treatment, or who have long QT syndrome, or who are at significant risk of developing QTc prolongation (see Section 4.4 Special Warnings and Precautions for Use).
Kisqali is contraindicated in patients with hypersensitivity to ribociclib succinate or any of the excipients, which include soya lecithin (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

QT interval prolongation.

Kisqali causes QT interval prolongation in a concentration-dependent manner (see Section 5.1 Pharmacodynamic Properties, Cardiac electrophysiology).
Increased QT prolongation occurs with co-administration of Kisqali and tamoxifen. Use of Kisqali with tamoxifen is not recommended (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Cardiac electrophysiology).
The phase III clinical studies (MONALEESA-2, MONALEESA-7 and MONALEESA-3) excluded patients with certain conditions known to increase QT prolongation risk, such as heart failure, cardiomyopathy, or recent coronary disease. Across these studies, in patients with advanced or metastatic breast cancer who received the combination of Kisqali plus an aromatase inhibitor or fulvestrant, 14 out of 1054 patients (1%) had > 500 ms post-baseline QTcF value, and 59 out of 1054 patients (6%) had a > 60 ms increase from baseline in QTcF intervals. These ECG changes were reversible with dose interruption and the majority (63%) occurred within the first four weeks of treatment. There were no reported cases of Torsades de Pointes.
In MONALEESA-2, in the Kisqali plus letrozole treatment arm, there was one (0.3%) sudden death in a patient with Grade 3 hypokalaemia and Grade 2 QT prolongation that improved to Grade 1 on the same day, reported 10 days before the event. No cases of sudden death were reported in MONALEESA-7 or MONALEESA-3 (see Section 4.8 Adverse Effects (Undesirable Effects)).
ECG should be assessed before initiating treatment. Treatment with Kisqali should be initiated only in patients with QTcF values < 450 ms (see Section 4.3 Contraindications). ECG should be repeated at approximately day 14 of the first cycle, at the beginning of the second cycle and then as clinically indicated. More intensive ECGs should be considered based on a patient's individual risk factors, if there are any symptoms that may be related to QT prolongation (e.g. palpitations or syncope), or if there is any increase in the risk of QT prolongation (e.g. new medication, or condition that may increase the likely exposure to ribociclib).
Appropriate monitoring of serum electrolytes (including potassium, calcium, phosphorus and magnesium) should be performed before initiating treatment, at the beginning of each of the first 6 cycles, and then as clinically indicated. Treatment should be interrupted for any abnormalities to be corrected before commencing or continuing Kisqali therapy.
Kisqali should be avoided in patients who already have or who are at significant risk of developing QTc prolongation. This includes patients with:
QTcF > 450 ms prior to treatment (see Section 4.3 Contraindications);
a history of ventricular arrhythmias;
long QT syndrome;
significant risk of developing QTc prolongation including: uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina, and bradyarrhythmias; electrolyte abnormalities.
Kisqali should be avoided in patients taking medicinal products that are known to prolong the QTc interval (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) and/or strong CYP3A inhibitors as this may lead to clinically meaningful prolongation of the QTcF. If treatment with a strong CYP3A4 inhibitor cannot be avoided, the dose should be reduced to 200 mg once daily (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties).
Based on the observed QT prolongation during treatment, Kisqali may require dose interruption, reduction or discontinuation as described in Table 2 (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.2 Pharmacokinetic Properties).

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 immediately and permanently discontinued.

Interstitial lung disease (ILD)/pneumonitis.

Severe, life threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with Kisqali and other CDK4/6 inhibitors.
Across clinical trials (MONALEESA-2, MONALEESA-3, MONALEESA-7), 1.1% of Kisqali treated patients had ILD/pneumonitis of any grade, 0.3% had Grade 3 or 4, and 0.1% had a fatal outcome. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported.
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis which may include hypoxia, cough and dyspnoea. In patients who have new or worsening respiratory symptoms suspected to be due to ILD or pneumonitis, interrupt Kisqali immediately and evaluate the patient. Permanently discontinue Kisqali in patients with recurrent symptomatic or severe ILD/pneumonitis. (See Section 4.2 Dose and Method of Administration for dosing adjustment table).

Hepatobiliary toxicity.

Ribociclib commonly causes reversible elevations in transaminase levels, and uncommonly causes life-threatening hepatotoxicity.
In MONALEESA-2, MONALEESA-7 and MONALEESA-3, increases in transaminases were observed. Grade 3 or Grade 4 increases in ALT (10% vs 2%) and AST (7% vs 2%) were reported in the Kisqali and placebo arms, respectively.
Among the patients who had Grade 3 or Grade 4 ALT/AST elevation, the median time to onset was 85 days for patients treated with Kisqali plus an aromatase inhibitor or fulvestrant. The median time to resolution (to normalisation or ≤ Grade 2) was 22 days in patients treated with Kisqali plus an aromatase inhibitor or fulvestrant.
The majority of increases in ALT and AST were reported without concurrent elevation of bilirubin. In MONALEESA-2 and MONALEESA-3, concurrent elevations of ALT or AST greater than three times the upper limit of normal (ULN) and of total bilirubin greater than two times the ULN, with normal alkaline phosphatase levels, in the absence of cholestasis occurred in 6 patients (1%), and all patients recovered after discontinuation of Kisqali. There were no such cases in MONALEESA-7.
Liver function tests (LFTs) should be performed before initiating therapy with Kisqali. LFTs should be monitored every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, and then as clinically indicated.
Based on the severity of the transaminase elevations, Kisqali may require dose interruption, reduction, or discontinuation as described in Table 4 (see Section 4.2 Dose and Method of Administration). Recommendations for patients who have elevated AST/ALT > Grade 3 at baseline have not been established.

Neutropenia.

In MONALEESA-2, MONALEESA-7 and MONALEESA-3, neutropenia was the most frequently reported adverse reaction (74%) and a Grade 3 or Grade 4 decrease in neutrophil counts (based on laboratory findings) was reported in 59% of patients receiving Kisqali plus an aromatase inhibitor or fulvestrant. Among the patients who had Grades 2, 3 or 4 neutropenia, the median time to onset was 16 days. The median time to resolution of Grade ≥ 3 neutropenia (to normalisation or Grade < 3) was 12 days in patients treated with Kisqali plus an aromatase inhibitor or fulvestrant. Febrile neutropenia was reported in 1% of patients exposed to Kisqali plus an aromatase inhibitor or fulvestrant. Patients should be instructed to report any fever promptly (see Section 4.8 Adverse Effects (Undesirable Effects)).
A full blood count (FBC) should be performed before initiating therapy with Kisqali. FBC should be monitored every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, and then as clinically indicated.
Based on the severity of the neutropenia, Kisqali may require dose interruption, reduction or discontinuation as described in Table 3 (see Section 4.2 Dose and Method of Administration).

Blood creatinine increase.

Ribociclib may cause blood creatinine increase as an inhibitor of the renal transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1), which are involved in the active secretion of creatinine from the proximal tubules (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). In case of blood creatinine increase while on treatment, it is recommended that further assessment of the renal function be performed to exclude renal impairment.

Reproductive toxicity and fertility.

Women of reproductive potential should be advised to use an effective method of contraception while taking Kisqali and for at least 21 days after the last dose (see Section 4.6 Fertility, Pregnancy and Lactation).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drugs that may increase the QT interval.

Co-administration of Kisqali with medicinal products with a known potential to prolong the QT interval may have an additive effect with ribociclib and increase the risk of QT prolongation.
Avoid co-administration of Kisqali with medicinal products with a known potential to prolong the QT interval, including, but not limited to: amiodarone, disopyramide, procainamide, quinidine, sotalol, ciprofloxacin, levofloxacin, azithromycin, moxifloxacin, erythromycin, clarithromycin, fluconazole, pentamidine, citalopram, escitalopram, lithium, clomipramine, desipramine, imipramine, trimipramine, chlorpromazine, haloperidol, ziprasidone, cisapride, ondansetron, dolasetron, chloroquine, halofantrine, methadone, bepridil, and pimozide. If coadministration cannot be avoided, consider reducing the dose of ribociclib and monitor by ECG for QT prolongation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Drugs that may increase ribociclib plasma concentrations). Kisqali is not recommended for use in combination with tamoxifen (see Section 4.4 Special Warnings and Precautions for Use).

Interactions with co-administered anticancer medicines.

Ribociclib and letrozole.

Comparison of data from clinical trials in patients with breast cancer to historical controls, and a population PK analysis indicated no clinically important drug-drug interaction between ribociclib and letrozole following their co-administration.

Ribociclib and anastrozole.

Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug-drug interaction between ribociclib and anastrozole following their co-administration.

Ribociclib and fulvestrant.

Data from a clinical trial in patients with breast cancer indicated no clinically relevant effect of fulvestrant on ribociclib exposure following co-administration of the drugs.

Ribociclib and tamoxifen.

Kisqali is not indicated for concomitant use with tamoxifen. Data from a clinical trial in patients with breast cancer indicated that tamoxifen exposure (Cmax and AUC) approximately doubled following co-administration of ribociclib and tamoxifen.

In vitro interaction data.

Effect of ribociclib on cytochrome P450 enzymes.

In vitro, ribociclib is a reversible inhibitor of CYP1A2, CYP2E1 and CYP3A4/5 and a time dependent inhibitor of CYP3A4/5, at clinically relevant concentrations. In vitro evaluations indicated that ribociclib has no potential to inhibit the activities of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 at clinically relevant concentrations. Ribociclib has no potential for time dependent inhibition of CYP1A2, CYP2C9, and CYP2D6.
In vitro data indicate that ribociclib has no potential to induce UGT enzymes or the CYP enzymes CYP2B6, CYP2C9, CYP2C19 and CYP3A4 via CAR or PXR. Therefore, Kisqali is unlikely to affect substrates of these enzymes.

Effect of transporters on ribociclib.

Based on in vitro data, ribociclib is a substrate of P-gp but not a substrate of BCRP. However, P-gp mediated transport is unlikely to affect the extent of oral absorption of ribociclib at therapeutic doses because of moderate passive permeability. Ribociclib is not a substrate for hepatic uptake transporters OATP1B1/1B3 or OCT-1 in vitro.

Effect of ribociclib on transporters.

In vitro evaluations indicated that ribociclib has a potential to inhibit the activities of drug transporters Pgp, BCRP, OATP1B1/1B3, OCT1, OCT2, MATE1, MATE2K 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. Ribociclib did not inhibit OAT1, OAT3 or MRP2 at clinically relevant concentrations in vitro.

Drugs that may increase ribociclib plasma concentrations.

CYP3A4 inhibitors.

Ribociclib is primarily metabolised by CYP3A4 and is a time-dependent inhibitor of CYP3A4 in vitro (see Section 5.2 Pharmacokinetic Properties, Metabolism). Therefore, medicinal products which can influence CYP3A4 enzyme activity may alter the PK of ribociclib. No dose adjustments are required for mild and moderate CYP3A4 inhibitors, however, if treatment with a moderate CYP3A4 inhibitor is initiated, close monitoring for ribociclib-related AEs is recommended.
Concomitant use of strong CYP3A inhibitors including, but not limited to, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir (see below), nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole should be avoided (see Section 4.4 Special Warnings and Precautions for Use). Alternative concomitant medications with less potential to inhibit CYP3A should be considered and patients should be monitored for adverse drug reactions (ADRs) (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Metabolism).
If co-administration of ribociclib with a strong CYP3A inhibitor cannot be avoided, reduce Kisqali dose to 200 mg. However, there are no clinical data with this dose adjustment (see Section 4.2 Dose and Method of Administration). If the strong inhibitor is discontinued, resume the Kisqali dose (after at least 5 half-lives of the CYP3A inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Due to inter-patient variability, the recommended dose adjustments may not be optimal in all individual patients, therefore close monitoring for ribociclib related AEs is recommended. In case of ribociclib related toxicity, dose should be modified (see Section 4.2 Dose and Method of Administration), or treatment should be interrupted until toxicity is resolved. (See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Metabolism).

Ritonavir.

A drug interaction trial in healthy subjects was conducted with ritonavir (strong CYP3A inhibitor). Compared to ribociclib alone, ritonavir (100 mg bid for 14 days) increased ribociclib Cmax and AUCinf by 1.7-fold and 3.2-fold, respectively, following a single 400 mg ribociclib dose. Cmax and AUClast for LEQ803 (a prominent metabolite of LEE011, accounting for < 10% of parent exposure) decreased by 96% and 98%, respectively.

Erythromycin.

Simulations using physiologically-based pharmacokinetic modelling (PBPK) suggested that erythromycin, a moderate CYP3A4 inhibitor, may increase ribociclib Cmax and AUC by 1.3-fold and 1.9-fold, respectively.

Drugs that may decrease ribociclib plasma concentrations.

CYP3A4 inducers.

Avoid concomitant use of strong CYP3A inducers, including, but not limited to, phenytoin, rifampin, carbamazepine and St. John's wort (Hypericum perforatum). Consider an alternate concomitant medication with no or minimal potential to induce CYP3A (see Section 4.4 Special Warnings and Precautions for Use).

Rifampicin.

A drug interaction trial in healthy subjects was conducted with rifampicin, a strong CYP3A4 inducer. Compared to ribociclib alone, co-administration with rifampicin (600 mg daily for 14 days) decreased ribociclib Cmax and AUCinf by 81% and 89%, respectively, following a single 600 mg ribociclib dose. LEQ803 Cmax increased 1.7-fold and AUCinf decreased by 27%, respectively.

Efavirenz.

Simulations using PBPK suggested that efavirenz, a moderate CYP3A inducer, may decrease ribociclib Cmax and AUC by 37% and 60%, respectively.

Effect of ribociclib on other drugs.

CYP3A substrates.

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.
Caution is recommended in case of concomitant use with sensitive CYP3A substrates with a narrow therapeutic index (see Section 4.4 Special Warnings and Precautions for Use). The dose of a sensitive CYP3A substrate with a narrow therapeutic index, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus, may need to be reduced as ribociclib can increase their exposure.

Midazolam.

Simulations using PBPK suggested that at a 600 mg ribociclib dose, midazolam Cmax and AUC may increase 2.4-fold and 5.2-fold, respectively.
Co-administration of midazolam (CYP3A4 substrate) with multiple doses of ribociclib (400 mg) increased the midazolam exposure by 3.8-fold in healthy subjects, compared with administration of midazolam alone. Simulations using physiologically-based PK (PBPK) models suggested that ribociclib given at the clinically relevant dose of 600 mg is expected to increase the midazolam AUC by 5.2-fold.

Caffeine.

Simulations using PBPK suggested only weak inhibitory effects on CYP1A2 substrates at a 600 mg ribociclib dose.
Co-administration of caffeine (CYP1A2 substrate) with multiple doses of ribociclib (400 mg) decreased Cmax by 10% and increased the caffeine AUCinf by 20% in healthy subjects, compared with administration of caffeine alone. At the clinically relevant ribociclib dose of 600 mg, simulations using PBPK models predicted only weak inhibitory effects of ribociclib on CYP1A2 substrates (less than 2-fold increase in AUC).

Drug-food interactions.

Patients should be instructed to avoid fruits (including fruit juices) that are known to be strong inducers or inhibitors of cytochrome CYP3A enzymes and may therefore increase exposure to ribociclib. These include grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges.
Kisqali can be administered with or without food (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Gastric pH elevating medications.

Ribociclib exhibits high solubility at or below pH 4.5 and in bio-relevant media (at pH 5.0 and 6.5). Co-administration of ribociclib with medicinal products that elevate the gastric pH was not evaluated in a clinical trial; however, altered ribociclib absorption with proton pump inhibitors was not observed in population pharmacokinetic analysis, non-compartmental pharmacokinetic analyses nor in simulations using PBPK models.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no clinical data available regarding effects of Kisqali on human fertility. Based on animal studies, Kisqali may impair fertility in males of reproductive potential.
(Category D)
There are no adequate and well-controlled studies in pregnant women. Based on findings in animals, ribociclib can cause foetal harm (including fetal developmental abnormalities and fetal loss) when administered to a pregnant woman (see Section 5.3 Preclinical Safety Data). Kisqali is not recommended during pregnancy and in females of reproductive potential not using highly effective contraception.

Pregnancy testing.

The pregnancy status for females of reproductive potential should be verified prior to initiating treatment with Kisqali.

Contraception.

Females of reproductive potential who are receiving Kisqali should use effective contraception (methods that result in less than 1% pregnancy rates) during therapy and for at least 21 days after stopping treatment with Kisqali.
It is not known if Kisqali is present in human milk. There are no data on the effects of Kisqali on the breastfed child or the effects of Kisqali on milk production. Ribociclib and its metabolites readily passed into the milk of lactating rats (see Section 5.3 Preclinical Safety Data). Patients receiving Kisqali should not breastfeed for at least 21 days after the last dose.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of ribociclib on the ability to drive or operate machinery have been conducted. Patients experiencing fatigue, dizziness, or vertigo while taking ribociclib should exercise caution when driving or operating machinery (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

MONALEESA-2: Kisqali in combination with letrozole.

Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy.

The safety data reported below are based on a clinical study of 668 postmenopausal women receiving Kisqali plus letrozole or placebo plus letrozole. The median duration of exposure to Kisqali plus letrozole was 13 months with 58% of patients exposed for ≥ 12 months. Dose reductions due to adverse reactions (ARs) occurred in 45% of patients receiving Kisqali plus letrozole and in 3% of patients receiving placebo plus letrozole. Among patients receiving Kisqali plus letrozole, 7% were reported to have permanently discontinued both Kisqali and letrozole and 7% were reported to have permanently discontinued Kisqali alone due to ARs. Among patients receiving placebo plus letrozole, 2% were reported to have permanently discontinued both and 0.9% were reported to have permanently discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation of Kisqali in patients receiving Kisqali plus letrozole were ALT increased (4%), AST increased (3%), vomiting (2%). Antiemetics and antidiarrhoea medications were used to manage symptoms as clinically indicated.
On-treatment deaths, regardless of causality, were reported in three (0.9%) patients treated with Kisqali plus letrozole versus one (0.3%) patient treated with placebo plus letrozole. Causes of death on Kisqali plus letrozole included one case each of the following: progressive disease, death (cause unknown), and sudden death (in a patient who had Grade 3 hypokalaemia and Grade 2 QT prolongation that improved to Grade 1 on the same day, reported 10 days before the event).
The most common ARs (reported at a frequency ≥ 20% in the Kisqali arm and ≥ 2% higher than placebo) were neutropenia, nausea, fatigue, diarrhoea, leukopenia, alopecia, vomiting, constipation, headache, and back pain.
The most common Grade 3/4 ARs (reported at a frequency ≥ 5%) were neutropenia, leukopenia, abnormal liver function tests, and lymphopenia. Syncope occurred in 9 patients (3%) in the Kisqali plus letrozole arm versus 3 (1%) in the placebo plus letrozole arm.
Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-2 are listed in Table 7 and Table 8, respectively.
MONALEESA-7: Kisqali in combination with an aromatase inhibitor.

Pre- or perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine-based therapy.

MONALEESA-7 was conducted in 672 pre- or perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer receiving either Kisqali plus endocrine therapy (goserelin plus either a non-steroidal aromatase inhibitor (NSAI) or tamoxifen) or placebo plus endocrine therapy (goserelin plus either a NSAI or tamoxifen). The median duration of exposure on the Kisqali arm was 15.2 months with 66% of patients exposed for ≥ 12 months.
Kisqali is not recommended for use in combination with tamoxifen due to the risk of QTc prolongation (see Section 4.4 Special Warnings and Precautions for Use).
The safety data reported below are based on 495 NSAI-treated patients, which included 248 patients who received Kisqali plus goserelin plus NSAI (the Kisqali arm) and 247 patients who received placebo plus goserelin plus NSAI (the placebo arm). Dose reductions due to adverse reactions (ARs) occurred in 33% of patients in the Kisqali arm and in 4% of patients in the placebo arm. In the Kisqali arm, 3% were reported to have permanently discontinued both Kisqali and NSAI and 3% were reported to have permanently discontinued Kisqali alone due to ARs. In the placebo arm, 2% were reported to have permanently discontinued both and 0.8% were reported to have permanently discontinued placebo alone due to ARs. Adverse reactions leading to Kisqali or placebo treatment discontinuation in the Kisqali arm versus the placebo arm were ALT increased (2% vs 0.8%), AST increased (2% vs 0.8%) and drug-induced liver injury (1% vs 0.4%). One patient (0.4%) died while on treatment with Kisqali plus NSAI plus goserelin due to the underlying malignancy.
The most common ARs (reported at a frequency ≥ 20% in the Kisqali arm and ≥ 2% higher than placebo) were neutropenia, infections, leukopenia, arthralgia, nausea, and alopecia. The most common Grade 3/4 ARs (reported at a frequency ≥ 5%) were neutropenia, leukopenia, and abnormal liver function tests.
Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-7 are listed in Table 9 and Table 10, respectively.
MONALEESA-3: Kisqali in combination with fulvestrant.

Postmenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine-based therapy or after disease progression on endocrine therapy.

The safety data reported below are based on a clinical study of 724 postmenopausal women receiving Kisqali plus fulvestrant or placebo plus fulvestrant. The median duration of exposure to Kisqali plus fulvestrant was 15.8 months with 58% of patients exposed for ≥ 12 months. Dose reductions due to adverse reactions (ARs) occurred in 32% of patients receiving Kisqali plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Among patients receiving Kisqali plus fulvestrant, 8% were reported to have permanently discontinued both Kisqali and fulvestrant and 9% were reported to have discontinued Kisqali alone due to ARs. Among patients receiving placebo plus fulvestrant, 4% were reported to have permanently discontinued both and 2% were reported to have discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation of Kisqali in patients receiving Kisqali plus fulvestrant (as compared to the placebo arm) were ALT increased (5% vs 0%), AST increased (3% vs 0.6%), and vomiting (1% vs 0%).
On-treatment deaths, regardless of causality, were reported in seven patients (1.4%) due to the underlying malignancy and six patients (1.2%) due to other causes while on treatment with Kisqali plus fulvestrant. Causes of death included one pulmonary embolism, one acute respiratory distress syndrome, one cardiac failure, one pneumonia, one haemorrhagic shock, and one ventricular arrhythmia. Seven patients (2.9%) died due to the underlying malignancy and 1 patient (0.4%) died due to pulmonary embolism while on placebo plus fulvestrant.
The most common ARs (reported at a frequency ≥ 20% in the Kisqali arm and ≥ 2% higher than placebo) were neutropenia, infections, leukopenia, cough, nausea, diarrhoea, vomiting, constipation, pruritus, and rash. The most common Grade 3/4 ARs (reported at a frequency ≥ 5%) were neutropenia, leukopenia, infections, and abnormal liver function tests.
Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-3 are listed in Table 11 and Table 12, respectively.

Post-marketing data.

The following ADR is derived from post-marketing experience with Kisqali via spontaneous case reports and literature cases. As this reaction is reported voluntarily from a population of uncertain size, it is not possible to reliably estimate its frequency which is therefore categorized as not known. See Table 13.

Description of selected adverse drug reactions.

QT prolongation.

In the phase III clinical studies, 8% of ribociclib-treated patients and 3% of placebo-treated patients had at least one event of QT interval prolongation or syncope. Dose interruptions/adjustments were reported in 2% of the Kisqali-treated patients due to QT interval prolongation or syncope.
A central analysis of ECG data (average of triplicate) showed that at least one post-baseline QTcF of > 480 ms occurred in 5% ribociclib-treated patients and 1% of placebo-treated patients. Among the ribociclib-treated patients who had QTcF prolongation of > 480 ms, the median time to onset was 15 days regardless of what treatment ribociclib was combined with, and these changes were reversible with dose interruption and/or dose reduction (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
In MONALEESA-7, the observed mean QTcF increase from baseline was > 10 ms higher in the tamoxifen plus placebo subgroup compared with NSAI plus placebo subgroup, suggesting that tamoxifen contributed to the QTcF prolongation observed in the ribociclib plus tamoxifen group (see Section 5.1 Pharmacodynamic Properties, Cardiac electrophysiology). A QTcF increase of > 60 ms from baseline occurred in zero patients who received placebo plus NSAI, 7% of patients who received placebo plus tamoxifen, 7% of patients who received ribociclib plus NSAI, and 16% of patients who received ribociclib plus tamoxifen. Co-administration of Kisqali and tamoxifen is not recommended (see Section 4.4 Special Warnings and Precautions for Use).

Hepatobiliary toxicity.

Across the phase III clinical studies, hepatobiliary toxicity events occurred in a higher proportion of ribociclib-treated patients compared with placebo-treated patients (23% vs 17%), and more Grade 3/4 adverse events were reported in ribociclib-treated than placebo-treated patients (11% vs 5%). Dose interruptions and/or adjustments due to hepatobiliary toxicity events were reported in 10% of ribociclib-treated patients, primarily due to ALT increased (7%) and/or AST increased (6%). Discontinuation of treatment with Kisqali due to abnormal liver function tests and hepatotoxicity occurred at rates of 2% and 0.4%, respectively (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Neutropenia.

Neutropenia was most frequently reported by laboratory findings in the phase III studies. Based on its severity, neutropenia was managed by laboratory monitoring, dose interruption and/or dose modification. Permanent treatment discontinuation due to neutropenia was low in patients receiving Kisqali (0.8%), however, dose interruptions and/or modifications were required in around half of ribociclib-treated patients (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms and signs.

Limited experience in humans suggests that in the event of Kisqali overdosage, nausea, vomiting, neutropenia and thrombocytopenia could occur. QTc prolongation may also occur, as it is known to be concentration-dependent.

Treatment.

The treatment of overdose should consist of general symptomatic and supportive measures. For information on the management of overdose, contact the Poison Information Centre on telephone number 13 11 26 (local call in all areas).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors.
Anatomical Therapeutic Chemical (ATC) code: L01XE42.

Mechanism of action.

Ribociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6. These kinases are activated upon binding to D-cyclins and play a crucial role in signalling 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).
In vitro, ribociclib decreased pRb phosphorylation leading to arrest in the G1 phase of the cell cycle and reduced cell proliferation in breast cancer cell lines. In vivo, treatment with single agent ribociclib in a rat xenograft model with human tumour cells led to decreased tumour volumes, which correlated with inhibition of pRb phosphorylation.
In studies using patient-derived oestrogen receptor-positive breast cancer xenograft models, combination of ribociclib and antioestrogen (e.g. letrozole) resulted in increased tumour growth inhibition compared to each drug alone. Additionally, the combination of ribociclib and fulvestrant resulted in tumor growth inhibition in an estrogen receptor positive breast cancer xenograft model.

Pharmacodynamic effects.

Ribociclib inhibits the CDK4/cyclin-D1 and CDK6/cyclin-D3 enzyme complexes with concentration resulting in 50% inhibition (IC50) values of 0.01 micromolar (microM) (4.3 nanogram/mL) and 0.039 microM (16.9 nanogram/mL) in biochemical assays, respectively.
In cell based assays with pRb positive cancer cell lines, ribociclib inhibits CDK4/6-dependent pRb phosphorylation with an IC50 of 0.06 microM (26 nanogram/mL). Ribociclib halts G1 to S-phase cell cycle progression measured by flow cytometry with IC50 of 0.11 microM (47.8 nanogram/mL). Ribociclib also inhibits cellular proliferation measured by bromodeoxyuridine uptake with IC50 of 0.08-microM (34.8 nanogram/mL).
When tested in a panel of breast cancer cell lines with known ER status, ER-positive cell lines were more sensitive than ER-negative cell lines to the anti-proliferation effects of ribociclib. Ribociclib had no inhibitory activity in the tested pRb-negative cancer cell lines.

Cardiac electrophysiology.

Serial, triplicate electrocardiograms (ECGs) were collected following a single dose and at steady-state to evaluate the effect of ribociclib on the QTc interval in patients with advanced cancer. In vitro studies have shown that both ribociclib and its major metabolite, LEQ803, interact with hERG channels. A pharmacokinetic-pharmacodynamic analysis included a total of 997 patients treated with ribociclib at doses ranging from 50 mg to 1200 mg. The analysis suggested that ribociclib causes concentration-dependent increases in the QTc interval. The estimated mean change from baseline in QTcF for Kisqali 600 mg in combination with aromatase inhibitors or fulvestrant was 22.0 ms (90% CI: 20.6, 23) and 23.7 ms (90% CI: 22.3, 25.1), respectively, and was 34.7 ms (90% CI: 31.6, 37.8) in combination with tamoxifen at the geometric mean Cmax at steady-state (see Section 4.4 Special Warnings and Precautions for Use).

Clinical trials.

MONALEESA-2 (study CLEE011A2301). MONALEESA-2 was a randomised, double-blind, placebo-controlled, multicentre clinical study of Kisqali plus letrozole versus placebo plus letrozole conducted in postmenopausal women with HR positive, HER2-negative, advanced breast cancer who had received no prior therapy for advanced disease.
A total of 668 patients were randomised to receive either Kisqali plus letrozole (n=334) or placebo plus letrozole (n=334), stratified according to the presence of liver and/or lung metastases. Demographics and baseline disease characteristics were balanced and comparable between study arms. Letrozole 2.5 mg was given orally once daily for 28 days, with either Kisqali 600 mg or placebo orally once daily for 21 consecutive days followed by 7 days off treatment, until disease progression or unacceptable toxicity. Patients who had prior neoadjuvant or adjuvant therapy with anastrozole or letrozole must have completed it at least 12 months before study randomisation, and patients were not allowed to cross over from placebo to Kisqali during the study or after disease progression. The primary efficacy endpoint for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Patients enrolled in MONALEESA-2 had a median age of 62 years (range 23 to 91). The majority of patients were Caucasian (82%), Asian (8%) or Black (3%), and all patients had an ECOG performance status of 0 or 1. A total of 44% of patients had received chemotherapy and 52% had received antihormonal therapy in the neoadjuvant or adjuvant setting. At study entry, 34% of patients had de novo metastatic disease, 21% had bone only disease and 59% had visceral disease.
The efficacy findings are summarised in Table 14 and Figure 1. The results shown are from pre-planned primary interim efficacy analysis of PFS and from an updated analysis performed at the time of the second interim analysis of overall survival (OS). Results were consistent across patient subgroups of prior adjuvant or neoadjuvant chemotherapy or hormonal therapies, liver and/or lung involvement, and bone-only metastatic disease. The PFS assessment based on a blinded independent central radiological review was consistent with investigator assessment. At the time of the second interim OS analysis, 17% of patients had died, and OS data remained immature.
MONALEESA-7 (study CLEE011E2301). MONALEESA-7 was a randomised, double-blind, placebo-controlled, multicentre clinical study of Kisqali plus endocrine therapy (goserelin plus either a non-steroidal aromatase inhibitor (NSAI) or tamoxifen) versus placebo plus endocrine therapy (goserelin plus either a NSAI or tamoxifen) for the treatment of pre- and perimenopausal women with HR-positive, HER2-negative, advanced breast cancer who had received no prior endocrine therapy for advanced disease.
A total of 672 patients were randomised to receive either Kisqali plus goserelin plus NSAI/tamoxifen (n=335) or placebo plus goserelin plus NSAI/tamoxifen (n=337), stratified according to the presence of liver and/or lung metastases, prior chemotherapy for advanced disease and endocrine combination partners (NSAI and goserelin [n=493] versus tamoxifen and goserelin [n=179]). Kisqali is not recommended for use in combination with tamoxifen due to the risk of QTc prolongation (see Section 4.4 Special Warnings and Precautions for Use).
In the NSAI-treated patients, NSAI (letrozole 2.5 mg or anastrozole 1 mg) was given orally once daily on a continuous schedule, and goserelin (3.6 mg) was administered subcutaneously on day 1 of each 28 day cycle, with either Kisqali 600 mg or placebo orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. Patients were not allowed to cross over from placebo to Kisqali during the study or after disease progression, or to switch between endocrine combination partners. The primary efficacy endpoint for the study was investigator-assessed PFS using RECIST v1.1.
Patients enrolled in MONALEESA-7 had a median age of 44 years (range 25 to 58) and 28% were younger than 40. The majority of patients were Caucasian (58%), Asian (29%) or Black (3%), and nearly all patients (99%) had an ECOG performance status of 0 or 1. Of the 672 patients, 33% had received chemotherapy in the adjuvant setting, 18% had received chemotherapy in the neoadjuvant setting, 40% had received endocrine therapy in the adjuvant setting, and 0.7% had received endocrine therapy in the neoadjuvant setting. At study entry, 40% of patients had de novo metastatic disease, 24% had bone only disease, and 57% had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms, including in endocrine combination partner subgroups.
The efficacy results from a pre-specified subgroup analysis of 495 patients who had received Kisqali or placebo in combination with NSAI plus goserelin are summarised in Table 15 and Figure 2. In the NSAI subgroups, there was no significant difference demonstrated between the treatment arms for the Time to response (TTR) or Duration of response (DoR) - responders. Consistent results were observed in stratification subgroups of disease site and prior chemotherapy for advanced disease. At the time of the PFS analysis, 13% of patients had died, and overall survival data were immature.

Final overall survival (OS) analysis.

At the time of the second OS analysis (30-Nov-2018 cut-off), the study met its key secondary endpoint demonstrating a statistically significant improvement in OS (HR: 0.712; 95% CI: 0.535, 0.948; one-sided stratified log-rank test p-value: 0.00973), and is consistent across exploratory subgroups. Median OS was not reached in the Kisqali arm and was 40.9 months (95% CI: 37.8, NE) in the placebo arm.
The safety profile of both treatment arms remained consistent with the results from the primary analysis.
A more mature update of overall survival data (30-Nov-2018 cut off) is provided in Table 16 as well as in Figure 3.
Additionally, time to progression on next-line therapy or death (PFS2) in patients in the Kisqali arm was longer compared to patients in the placebo arm (HR: 0.692 (95% CI: 0.548, 0.875)) in the overall study population. The median PFS2 was 32.3 months (95% CI: 27.6, 38.3) in the placebo arm and was not reached (95% CI: 39.4, NE) in the Kisqali arm. Similar results were observed in the NSAI sub-group (HR: 0.660 (95% CI: 0.503, 0.868); median PFS2: 32.3 months (95% CI: 26.9, 38.3) in the placebo arm vs not reached (95% CI: 39.4, NE) in the ribociclib arm).
MONALEESA-3 (study CLEE011F2301). MONALEESA-3 was a randomised double-blind, placebo-controlled, multicentre clinical study of Kisqali plus fulvestrant versus placebo plus fulvestrant for the treatment of men and postmenopausal women with HR-positive, HER2-negative, advanced breast cancer who had received no or only one line of prior endocrine treatment for advanced disease.
A total of 726 patients were randomised to receive either Kisqali plus fulvestrant (n=484) or placebo plus fulvestrant (n=242), stratified according to the presence of liver and/or lung metastases and prior endocrine therapy. First-line patients with advanced breast cancer (A) include de novo advanced breast cancer with no prior endocrine therapy, and patients who relapsed after 12 months of (neo)adjuvant endocrine therapy completion.
Second-line patients' subgroup (B) includes those patients whose disease relapsed during adjuvant therapy or less than 12 months after endocrine adjuvant therapy completion, and those who progressed to first line endocrine therapy. Fulvestrant 500 mg was administered intramuscularly on days 1, 15, 29, and once monthly thereafter, with either Kisqali 600 mg or placebo given orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity.
Patients enrolled in MONALEESA-3 had a median age of 63 years (range 31 to 89), and 14% were at least 75 years old. The majority of patients were Caucasian (85%), Asian (9%) or Black (1%), and nearly all patients (99.7%) had an ECOG performance status of 0 or 1. First and second line patients were enrolled in this study (of which 19% had de novo metastatic disease). Of the 726 patients, 43% had received chemotherapy in the adjuvant setting, 13% had received chemotherapy in the neoadjuvant setting, 59% had received endocrine therapy in the adjuvant setting and 1% had received endocrine therapy in the neoadjuvant setting. At study entry, 21% of patients had bone only disease and 61% had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms.

Primary analysis.

The primary efficacy endpoint for the study was investigator-assessed PFS using RECIST v1.1, based on the investigator assessment in the full analysis set (all randomized patients) and confirmed by a random central audit of 40% imaging subset by a blinded independent review committee (BIRC). The median follow-up time at the time of primary PFS analysis was 20.4 months.
PFS analyses based on the BIRC were supportive of the primary efficacy results, the PFS hazard ratio was 0.492 (95% CI, 0.345 to 0.703).
The efficacy results from MONALEESA-3 are summarised in Table 17 and Figure 4. Consistent results were observed in stratification subgroups of disease site and prior endocrine treatment for advanced disease.
At the time of the PFS analysis, 17% of patients had died, and overall survival data were immature.
The clinical benefit rate in the Kisqali plus fulvestrant arm and in the placebo plus fulvestrant arm is summarized in Table 18.

Final OS analysis.

In the pre-specified second OS interim analysis, the study crossed pre-specified Lan-DeMets (O'Brien-Fleming) stopping boundary, demonstrating a statistically significant improvement in OS.
The OS results from this interim analysis with a 03-Jun-19 cut-off are provided in Table 19 and Figure 5.
Additionally, time to progression on next-line therapy or death (PFS2) in patients in the Kisqali arm was longer compared to patients in the placebo arm (HR: 0.670 (95% CI: 0.542, 0.830)) in the overall study population. The median PFS2 was 39.8 months (95% CI: 32.5, NE) for the Kisqali arm and 29.4 months (95% CI: 24.1, 33.1) in the placebo arm.

5.2 Pharmacokinetic Properties

The pharmacokinetics (PK) of ribociclib was investigated in patients with advanced cancer following oral daily doses ranging from 50 mg to 1200 mg. Healthy subjects received single oral doses ranging from 400 mg to 600 mg or repeated daily oral doses (for 8 days) at 400 mg. At the recommended dose of ribociclib 600 mg, the inter-patient variability in pharmacokinetics was approximately 60%.

Absorption.

Following oral administration of Kisqali to patients with advanced solid tumours or lymphomas, peak plasma levels (Cmax) of ribociclib were achieved between 1 and 4 hours (time to reach maximum concentration, Tmax). The geometric mean absolute bioavailability of ribociclib after a single oral dose of 600 mg was 65.8% in healthy subjects. Following repeated once daily dosing, steady-state was generally achieved after 8 days and ribociclib accumulated with a geometric mean accumulation ratio of 2.51 (range: 0.97 to 6.40).

Linearity/ non-linearity.

Ribociclib exhibited slightly over-proportional increases in exposure (Cmax and AUC) across the dose range of 50 mg to 1200 mg following both single dose and repeated doses. The observed over-proportional increases in exposure might be attributed to auto-inhibition of CYP3A4. This analysis is limited by the small sample sizes for most of the dose cohorts with the majority of data coming from the 600 mg dose cohort.

Food effect.

Compared to the fasted state, oral administration of a single 600 mg dose of Kisqali with a high-fat, high-calorie meal had no effect on the rate and extent of absorption of ribociclib. The geometric mean ratio (GMR) for Cmax was 1.00 (90% CI: 0.898, 1.11) and for AUCinf was 1.06 (90% CI: 1.01, 1.12).
See also fruits and juices to avoid (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Distribution.

Binding of ribociclib to human plasma proteins in vitro was approximately 70% and independent of concentration (10 nanogram/mL to 10,000 nanogram/mL). Ribociclib was equally distributed between red blood cells and plasma with a mean in vivo blood-to-plasma ratio of 1.04. The mean apparent volume of distribution at steady-state (Vss/F) was 1090 L based on population PK analysis.

Metabolism.

In vitro and in vivo studies indicated ribociclib undergoes extensive hepatic metabolism mainly via CYP3A4 in humans. Following oral administration of a single 600 mg dose of [14C] ribociclib to humans, the primary metabolic pathways for ribociclib involved oxidation {dealkylation, C and/or N-oxygenation, oxidation (-2H)} and combinations thereof. Phase II conjugates of ribociclib Phase I metabolites involved N-acetylation, sulfation, cysteine conjugation, glycosylation and glucuronidation. Ribociclib was the major circulating drug-derived entity in plasma (44%). The major circulating metabolites included metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide), each representing an estimated 9%, 9%, and 8% of total radioactivity, and 22%, 20%, and 18% of ribociclib exposure, respectively. Clinical activity (pharmacological and safety) of ribociclib was due primarily to the parent drug, with negligible contribution from the circulating metabolites.
Ribociclib was extensively metabolised with unchanged drug accounting for 17% and 12% in faeces and urine, respectively. Metabolite LEQ803 was a significant metabolite in excreta and represented approximately 14% and 4% of the administered dose in faeces and urine, respectively. Numerous other metabolites were detected in both feces and urine in minor abundance (≤ 3% of the administered dose).

Excretion.

The geometric mean plasma effective half-life (based on accumulation ratio) was 32.0 hours (63% CV) and the geometric mean apparent oral clearance (CL/F) was 25.5 L/hr (66% CV) at steady-state at 600 mg in patients with advanced cancer. The geometric mean apparent plasma terminal half-life (t1/2) of ribociclib ranged from 29.7 to 54.7 hours and the geometric mean CL/F of ribociclib ranged from 39.9 to 77.5 L/hr at 600 mg across studies in healthy subjects.
Ribociclib is eliminated mainly via faeces, with some elimination by the renal route. In six healthy male subjects, following a single oral dose of [14C] ribociclib, 92% of the total administered radioactive dose was recovered within 22 days; faeces was the major route of excretion (69%), with 23% of the dose recovered in urine. The estimated oral absorption of ribociclib was 59%.

Special patient populations.

Renal impairment.

The effect of renal function on the pharmacokinetics of ribociclib was also assessed in a renal impairment study in non-cancer subjects that included 14 subjects with normal renal function (absolute Glomerular Filtration Rate (aGFR) ≥ 90 mL/min), 8 subjects with mild renal impairment (aGFR 60 to < 90 mL/min), 6 subjects with moderate renal impairment (aGFR 30 to < 60 mL/min), 7 subjects with severe renal impairment (aGFR 15 to < 30 mL/min), and 3 subjects with end stage renal disease (ESRD) (aGFR < 15 mL/min) at a single oral ribociclib dose of 400 mg/day.
AUCinf increased to 1.62-fold, 1.94-fold and 2.67-fold, and Cmax increased to 1.80-fold, 1.79-fold and 2.30-fold in subjects with mild, moderate and severe renal impairment, relative to the exposure in subjects with normal renal function. A fold difference for subjects with ESRD was not calculated due to the small number of subjects (see Section 4.2 Dose and Method of Administration).
No dose adjustment is necessary in patients with mild or moderate renal impairment. The effect of renal function on the pharmacokinetics of ribociclib was also assessed in cancer patients.
Based on a population pharmacokinetic analysis that included 438 cancer patients with normal renal function (eGFR ≥ 90 mL/min/1.73 m2), 488 patients with mild renal impairment (eGFR 60 to < 90 mL/min/1.73 m2) and 113 patients with moderate renal impairment (eGFR 30 to < 60 mL/min/1.73 m2), mild and moderate renal impairment had no effect on the exposure of ribociclib.
In addition, in a sub-group analysis of PK data from studies in cancer patients following oral administration of ribociclib 600 mg as a single dose or repeat doses (MONALEESA-7, CLEE011X2101 and CLEE011X2107), AUC and Cmax of ribociclib following a single dose or at steady state in patients with mild or moderate renal impairment were comparable to patients with normal renal function, suggesting no clinically meaningful effect of mild or moderate renal impairment on ribociclib exposure (see Section 4.2 Dose and Method of Administration).

Hepatic impairment.

No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh A); a dose adjustment is required in patients with moderate (Child-Pugh B), or severe hepatic impairment (Child-Pugh C) and starting dose of 400 mg is recommended. Based on a PK trial in patients with hepatic impairment, mild hepatic impairment had no effect on the exposure of ribociclib. The mean exposure for ribociclib was increased less than 2-fold in patients with moderate hepatic impairment (geometric mean ratio [GMR]: 1.44 for Cmax; 1.28 for AUCinf) and severe hepatic impairment (GMR: 1.32 for Cmax; 1.29 for AUCinf). Based on a population PK analysis that included 160 patients with normal hepatic function and 47 patients with mild hepatic impairment, mild hepatic impairment had no effect on the exposure of ribociclib, further supporting the findings from the dedicated hepatic impairment study (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

Of 334 patients who received Kisqali in MONALEESA 2 (ribociclib plus letrozole arm), 150 patients (45%) were ≥ 65 years of age and 35 patients (10%) were ≥ 75 years of age. Of 484 patients who received Kisqali in MONALEESA 3 (ribociclib plus fulvestrant arm), 226 patients (47%) were ≥ 65 years of age and 65 patients (13%) were ≥ 75 years of age. No overall differences in safety or effectiveness of Kisqali were observed between these patients and younger patients (see Section 4.2 Dose and Method of Administration).

Paediatric use.

No studies have been conducted to investigate the pharmacokinetics of ribociclib in paediatric patients.

Effect of age, weight, gender and race.

Population PK analysis showed that there are no clinically relevant effects of age, body weight, gender, or race on the systemic exposure of ribociclib that would require a dose adjustment.

5.3 Preclinical Safety Data

Safety pharmacology.

QT prolongation.

In vivo cardiac safety studies in dogs demonstrated dose and concentration related QTc interval prolongation at an exposure that would be expected to be achieved in patients following the recommended dose of 600 mg. As well, there is potential to induce incidences of premature ventricular contractions (PVCs) at elevated exposures (approximately 4-fold the anticipated clinical Cmax).

Phototoxicity.

Ribociclib was shown to absorb light in the UV-B and UV-A range, however, phototoxicity was not suggested by in vitro testing. The risk that Kisqali causes photosensitisation in patients is considered very low.

Repeated-dose toxicity.

Repeated dose toxicity studies (treatment schedule of 3 weeks on/1 week off) in rats up to 26 weeks duration and dogs up to 39 weeks duration, revealed the hepatobiliary system (proliferative changes, cholestasis, sand-like gall bladder calculi, inspissated bile, periportal hepatocyte necrosis and arteriopathy in the hilar region) as the primary target organ of toxicity of ribociclib.
Additionally, effects on bone marrow (hypocellularity), pancytopenia, lymphoid system (lymphoid depletion), testes (atrophy), intestinal mucosa (atrophy), skin (atrophy), bone/ribs (decreased bone formation), lung (increased incidence of alveolar macrophages), and kidney (concurrent degeneration and regeneration of tubular epithelial cells) were described. In general, these changes in rats and dogs demonstrated either reversibility or a clear tendency towards reversibility. Exposure to ribociclib in animals in these toxicity studies was generally less than or equal to that observed in patients receiving multiple doses of 600 mg/day (based on AUC).

Reproductive toxicity and fertility.

Ribociclib showed foetotoxicity and teratogenicity at doses which did not show maternal toxicity in rats or rabbits. Following prenatal exposure, increased incidences of post-implantation loss and reduced foetal weights were observed in rats and ribociclib was teratogenic in rabbits at exposures lower than or 1.5 times the exposure in humans, respectively, at the highest recommended dose of 600 mg/day based on AUC.
In rats, reduced foetal weights accompanied by skeletal changes considered to be transitory and/or related to the lower foetal weights were noted. In rabbits, there were adverse effects on embryo-foetal development as evidenced by increased incidences of foetal abnormalities (malformations and external, visceral and skeletal variants) and foetal growth (lower foetal weights). These findings included reduced/small lung lobes and additional vessel on the aortic arch and diaphragmatic hernia, absent accessory lobe or (partly) fused lung lobes and reduced/small accessory lung lobe (30 and 60 mg/kg), extra/rudimentary thirteenth ribs and misshapen hyoid bone and reduced number of phalanges in the pollex. There was no evidence of embryo-foetal mortality.
In a fertility study in female rats, ribociclib did not affect reproductive function, fertility or early embryonic development at doses up to 300 mg/kg/day (approximately 0.6 times the clinical exposure in patients at the highest recommended dose of 600 mg/day based on AUC).
Ribociclib has not been evaluated in male fertility studies. However, atrophic changes in testes were reported in rat and dog toxicity studies at exposures that were less than or equal to human exposure at the highest recommended daily dose of 600 mg/day based on AUC. These effects can be linked to a direct anti-proliferative effects on the testicular germ cells resulting in atrophy of the seminiferous tubules.
Ribociclib and its metabolites passed readily into rat milk. In lactating rats administered a single dose of 50 mg/kg, exposure to ribociclib was 4-fold higher in milk compared to maternal plasma.

Genotoxicity.

Genotoxicity studies in bacteria, and in mammalian cells (human lymphocytes and mouse lymphoma cells) in vitro with and without metabolic activation, and in a micronucleus test in rats did not reveal any evidence for a mutagenic potential of ribociclib.

Carcinogenicity.

Ribociclib was assessed for carcinogenicity in a 2-year rat study.
Oral administration of ribociclib for 2 years resulted in an increased incidence of endometrial epithelial tumours and glandular and squamous hyperplasia in the uterus/cervix of female rats at doses ≥ 300 mg/kg/day (0.9 times the exposure in patients at the maximum recommended human dose of 600 mg/day [based on plasma AUC]) as well as an increased incidence in follicular tumours in the thyroid glands of male rats at a dose of 15 mg/kg/day (0.3 times the exposure in patients at 600 mg/day based on plasma AUC).
Additional non-neoplastic proliferative changes consisted of increased liver altered foci (basophilic and clear cell) and testicular interstitial (Leydig) cell hyperplasia in male rats at doses of ≥ 5 mg/kg/day (0.03 times the exposure in patients at 600 mg/day based on plasma AUC) and 50 mg/kg/day (equivalent to the exposure in patients based on plasma AUC), respectively.
The effects on the uterus/cervix and on the testicular interstitial (Leydig) cell may be related to prolonged hypoprolactinemia secondary to CDK4 inhibition of lactotrophic cell function in the pituitary gland, altering the hypothalamus-pituitary-gonadal axis.
Any potential increase of oestrogen/progesterone ratio in humans by this mechanism would be compensated by an inhibitory action of concomitant anti-estrogen therapy on estrogen synthesis as in humans Kisqali is indicated in combination with estrogen-lowering agents.
Considering important differences between rodents and humans with regard to synthesis and role of prolactin, this mode of action is not expected to have consequences for uterine tumours and Leydig cell hyperplasia in humans.
The mechanism for the thyroid findings in males is considered to be a rodent-specific microsomal enzyme induction in the liver with unclear clinical relevance to humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each tablet contains microcrystalline cellulose, hyprolose, crospovidone, colloidal silicon dioxide, magnesium stearate (vegetable source), polyvinyl alcohol, titanium dioxide (E171), iron oxide black CI77499, iron oxide red CI77491, purified talc, lecithin (soya), and xanthan gum. Kisqali does not contain sucrose, lactose, gluten, or synthetic colours.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store Kisqali tablets below 30°C.

6.5 Nature and Contents of Container

Kisqali tablets are supplied in Aclar/aluminium blisters platforms in packs containing either 63, 42, or 21 tablets.

6.6 Special Precautions for Disposal

Any unused product should not be disposed of in household waste or wastewater. Return it to a pharmacist for safe disposal.

6.7 Physicochemical Properties

Kisqali tablets contain ribociclib succinate which is a light yellow to yellowish brown, crystalline powder. It is soluble in a 1:1 mixture of water and acetonitrile, and the pH of a 1% w/v aqueous solution is about 5.2 at 25°C.
Chemical name: butanedioic acid - 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl) pyridin-2-yl] amino}-7H-pyrrolo[2,3-d] pyrimidine-6-carboxamide (1/1).
Molecular formula: C23H30N8O.C4H6O4.
Molecular weight: As succinate: 552.64, and free base: 434.55.

Chemical structure.


CAS number.

Chemical Abstracts Service (CAS) numbers: 1374639-75-4 (as succinate) and 1211441-98-3 (as free base).

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription medicine.

Summary Table of Changes