KAFTRIO 75 mg/50 mg/100 mg FILM-COATED TABLETS

2. What you need to know before you take Kaftrio

Do not takeKaftrio

• to ivacaftor, tezacaftor, elexacaftor or any of the other ingredients of this medicine (listed in section 6).

Consult your doctorand do not take the tablets if this applies to you.

Warnings and precautions

• Consult your doctorif you have liver problemsor have had them in the past. Your doctor may need to adjust your dose (see section 4).

• Your doctor will do some blood tests to check how your liver is workingbefore and during treatment with Kaftrio, especially if your blood tests have shown elevated liver enzymes in the past. Liver enzymes in the blood may increase in patients taking Kaftrio.

Tell your doctor immediatelyif you have any symptoms that may indicate liver problems. These are listed in section 4.

• Depression (including suicidal thoughts, changes in behaviour, anxiety and sleep disturbances) has been reported in patients taking Kaftrio, usually starting in the first three months of treatment. Consult your doctor immediately if you (or someone taking this medicine) experience any of the following symptoms that may be signs of depression: sadness or mood changes, anxiety, feeling of emotional distress or thoughts of self-harm or suicide, and/or difficulty sleeping (see section 4).

Consult your doctor if you notice changes in your child's behaviourinthe first 2 months of treatment.

• Consult your doctorif you have kidney problemsor have had them in the past.

• If you have two Class I mutations(mutations known not to produce the CFTR protein),you should not take Kaftrio, as it is not expected to respond to this medicine.

• Consult your doctorbefore starting treatment with Kaftrio if you have had an organ transplant.

• Consult your doctorif you are using hormonal contraceptives, for example, women using the contraceptive pill. It may mean that you are more likely to get a skin rash while taking Kaftrio.

• Your doctor may doeye examinationsbefore and during treatment with Kaftrio. In some children and adolescents who have taken this treatment, cataracts (clouding of the lens) have occurred without affecting vision.

Childrenunder 6years

Do not give this medicine to children under 6 years as it is not known if Kaftrio tablets are safe and effective in this age group.

Other medicines andKaftrio

Tell your doctor or pharmacistif you are taking, have recently taken or might take any other medicines. Some medicines may affect how Kaftrio works or may increase the chance of side effects. In particular, tell your doctor if you are taking any of the medicines listed below. Your doctor may need to change the dose of one of your medicines if you are taking some of these.

• Antifungals(used to treat fungal infections). These include fluconazole, itraconazole, ketoconazole, posaconazole and voriconazole.
• Antibiotics(used to treat bacterial infections). These include clarithromycin, erythromycin, rifampicin, rifabutin and telithromycin.
• Medicines for epilepsy(used to treat seizures or fits). These include carbamazepine, phenobarbital and phenytoin.
• Herbal products. These include St John's Wort (Hypericum perforatum).
• Immunosuppressants(used after an organ transplant). These include ciclosporin, everolimus, sirolimus and tacrolimus.
• Cardiac glycosides(used to treat certain heart conditions). These include digoxin.
• Anticoagulants(used to prevent blood clots). These include warfarin.
• Medicines for diabetes. These include glimepiride, glipizide, gliburide, nateglinide and repaglinide.
• Medicines to lower blood cholesterol. These include pitavastatin and rosuvastatin.
• Medicines to lower blood pressure. These include verapamil.

Taking Kaftrio withfood and drinks

Avoid foods or drinks that contain grapefruit during treatment as they may increase the side effects of Kaftrio by increasing the amount of Kaftrio in the body.

Pregnancy and breast-feeding

• Consult your doctorbefore using this medicine if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby.
• Pregnancy: it may be better to avoid using this medicine during pregnancy. Your doctor will help you decide what is best for you and your baby.
• Breast-feeding: ivacaftor, tezacaftor and elexacaftor are excreted in breast milk. Your doctor will consider the benefit of breast-feeding for your child and the benefit of treatment for you in order to help you decide whether to stop breast-feeding or stop treatment.

Driving and using machines

Kaftrio may cause dizziness. If you feel dizzy, do not drive, cycle or use machines unless you are sure that you are not affected.

Kaftrio contains sodium

This medicinecontainsless than 23 mg of sodium (1 mmol) per dose unit; this is essentially “sodium-free”.

3. How to take Kaftrio

Always take this medicine exactly as your doctor or pharmacist has told you. If you are not sure, check with your doctor or pharmacist.

Your doctor will decide the correct dose for you.

Kaftrio is usually taken with ivacaftor.

Recommended dose for patients 6years of age and older

Take the morning and evening tablets with an interval of about 12 hours.

The tablets are taken by mouth.

Take the Kaftrio and ivacaftor tablets withfat-containing foods. Fat-containing meals or snacks are those prepared with butter or oils or those that contain eggs. Examples of other fat-containing foods are:

• Cheese, whole milk, whole milk dairy products, yoghurt, chocolate
• Meat, oily fish
• Avocado, hummus (chickpea paste), soy products (tofu)
• Nuts, bars or nutritional drinks that contain fat

Avoid foods and drinks that contain grapefruit while taking Kaftrio. See Taking Kaftrio with food and drinksin section 2 for more information.

Swallow the tablets whole.Do not chew, crush or break the tablets before swallowing.

You should keep taking all your other medicines unless your doctor tells you to stop.

If you have liver problems,either moderate or severe, your doctor may reduce your dose of the tablets or decide to stop your treatment with Kaftrio. See Warnings and precautionsin section 2.

If you take moreKaftriothan you should

Consult your doctor or pharmacist.If possible, take the medicine and this leaflet with you. You may experience side effects, including those mentioned in section 4 below.

If you forget to takeKaftrio

If you miss a dose, calculate how much time has passed since you were supposed to take the dose.

• Ifit has been less than 6hourssince the time you were supposed to take the dose, either the morning or the evening dose, take the missed tablet(s) as soon as possible. Then continue with your normal schedule.

• Ifit has been more than 6hours:
• If you misseda morningdose of Kaftrio, take it as soon as you remember. Do not take the evening dose of ivacaftor. Take the next morning dose at the usual time.
• If you missedan evening dose of ivacaftor, do not take the missed dose. Wait until the next day and take the morning dose of Kaftrio at the usual time.

Do nottake a double dose to make up for a forgotten tablet.

If you stop takingKaftrio

Your doctor will tell you how long you need to take Kaftrio. It is important that you take this medicine regularly. Do not make any changes unless your doctor tells you to.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects

Signs of liver problems

Liver damage and worsening of liver functionin people with or without liver disease. Worsening of liver function may be severe and may require a transplant (see section 2).

Increased liver enzymes in the blood are common in patients with Kaftrio. The following may be signs of liver problems:

• Pain or discomfort in the upper right side of the stomach (abdominal area).
• Yellowing of the skin or the white part of the eyes.
• Lack of appetite.
• Feeling sick or being sick.
• Dark urine.

Depression.Signs include feeling sad or having mood changes, anxiety, feeling emotionally upset.

Tell your doctor immediatelyif you experience any of these symptoms.

Very common side effects(may affect more than 1 in 10 people)

• Skin rash (more common in children and women than in men).

Tell your doctor immediatelyif you experience a rash.

Other side effects:

Very common(may affect more than 1 in 10 people)

• Headache.
• Dizziness.
• Upper respiratory tract infection (common cold).
• Sore throat.
• Nasal congestion.
• Stomach or abdominal pain.
• Diarrhoea.
• Increased liver enzymes (sign of liver stress).
• Changes in the type of bacteria in the mucus.
• Increased creatine phosphokinase (sign of muscle breakdown), seen in blood tests.

Common(may affect up to 1 in 10 people)

• Flu.
• Abnormal breathing (shortness of breath or difficulty breathing).
• Low blood sugar (hypoglycaemia).
• Runny nose.
• Sinus problems (sinus congestion).
• Sore or painful throat.
• Ear problems: ear pain or discomfort, ringing in the ears, inflamed eardrum.
• Feeling of dizziness or spinning (inner ear disorder).
• Wind (flatulence).
• Spots (acne).
• Itchy skin.
• Breast lump.
• Feeling sick.

Uncommon(may affect up to 1 in 100 people)

• Breast or nipple problems: inflammation, pain.
• Increased breast size in men.
• Increased blood pressure.
• Wheezing.
• Ear blockage (ear congestion).

Frequency not known(cannot be estimated from the available data)

• Allergic reactions (hypersensitivity)
• Liver damage (liver injury).
• Increased bilirubin (liver blood test).
• Changes in behaviour

Additional side effects in adolescents

The side effects seen in adolescents are similar to those seen in adults.

Additional side effects in children

Most cases of changes in behaviour have been reported in young children aged 2 to 5 years.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Kaftrio

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and on the blister after EXP. The expiry date is the last day of the month stated.

This medicine does not require any special storage conditions.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. Package Contents and Additional Information

Composition ofKaftrio

• The active ingredients are ivacaftor, tezacaftor, and elexacaftor.

Kaftrio 37.5 mg/25 mg/50 mg film-coated tablets

Each film-coated tablet contains 37.5 mg of ivacaftor, 25 mg of tezacaftor, and 50 mg of elexacaftor.

Kaftrio 75 mg/50 mg/100 mg film-coated tablets

Each film-coated tablet contains 75 mg of ivacaftor, 50 mg of tezacaftor, and 100 mg of elexacaftor.

• The other ingredients are:

• Tablet core: hypromellose (E464), hypromellose acetate succinate, sodium lauryl sulfate (E487), sodium croscarmellose (E468), microcrystalline cellulose (E460(i)), and magnesium stearate (E470b).
• Tablet coating: hypromellose (E464), hydroxypropyl cellulose (E463), titanium dioxide (E171), talc (E553b), yellow iron oxide (E172), and red iron oxide (E172).

See the end of section 2 for important information about the contents of Kaftrio.

Appearance and Package Contents

Kaftrio 37.5 mg/25 mg/50 mg film-coated tablets are capsule-shaped, light orange tablets with the imprint “T50” on one side and smooth on the other.

Kaftrio 75 mg/50 mg/100 mg film-coated tablets are capsule-shaped, orange tablets with the imprint “T100” on one side and smooth on the other.

Kaftrio is available in pack sizes of 56 tablets (4 blister cards of 14 tablets each).

Marketing Authorization Holder

Vertex Pharmaceuticals (Ireland) Limited

Unit 49, Block 5, Northwood Court, Northwood Crescent, ,

Dublin 9, D09 T665,

Ireland

Tel.: +353 (0)1 761 7299

Manufacturer

Almac Pharma Services (Ireland) Limited

Finnabair Industrial Estate

Dundalk

Co. Louth

A91 P9KD

Ireland

Almac Pharma Services Limited

Seagoe Industrial Estate

Craigavon

Northern Ireland

BT63 5UA

United Kingdom

You can request more information about this medicinal product by contacting the local representative of the marketing authorization holder:

Date of the last revision of this leaflet:

Other Sources of Information

Detailed information on this medicinal product is available on the European Medicines Agency website: https://www.ema.europa.eu. There are also links to other websites on rare diseases and orphan medicines.