Kaftrio

Package leaflet: Information for the patient

Kaftrio 37.5 mg/25 mg/50 mg film-coated tablets, 75 mg/50 mg/100 mg film-coated tablets

ivacaftor/tezacaftor/elexacaftor
Please read this leaflet carefully before taking this medicine because it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to other people, even if they have the same symptoms as you, because it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet

1. What Kaftrio is and what it is used for
2. What you need to know before taking Kaftrio
3. How to take Kaftrio
4. Possible side effects
5. How to store Kaftrio
6. Contents of the pack and other information

1. What Kaftrio is and what it is used for

Kaftrio contains three active substances: ivacaftor, tezacaftor and elexacaftor. In some patients with
cystic fibrosis (CF), the medicine helps lung cells to function better. CF is an inherited disease in which
the lungs and digestive system can become blocked by thick, sticky mucus.
Kaftrio, taken with ivacaftor, is intended for patients aged 6 years and older with CF,
who have at least one mutation in the CFTR gene (cystic fibrosis transmembrane conductance regulator),
which responds to Kaftrio. It is intended as a long-term treatment.
Kaftrio acts on a protein called CFTR. This protein is defective in some people with CF if they have a mutation in the CFTR gene.
Kaftrio is usually taken together with another medicine, ivacaftor. Ivacaftor improves the function of the protein, while tezacaftor and elexacaftor increase the amount of protein on the cell surface.
Kaftrio (taken with ivacaftor) helps breathing by improving lung function. You may also notice that you do not get sick as often or that it is easier to gain weight.

2. What you need to know before taking Kaftrio

Do not take Kaftrio

• if you are allergic to ivacaftor, tezacaftor, elexacaftor, or to any of the other ingredients of this medicine (listed in section 6). Consult your doctor and do not take the tablets if this applies to you.

Warnings and precautions

• Tell your doctor if you have liver problems or have had them in the past. Your doctor may need to adjust your dose (see section 4).
• Before and during treatment with Kaftrio, your doctor will prescribe certain blood tests to monitor liver function, especially if previous blood tests have shown high levels of liver enzymes. In patients treated with Kaftrio, liver enzymes in the blood may increase.

Contact your doctor immediately if you experience any symptoms of liver problems. These are
listed in section 4.

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

Consult your doctor if you notice behavioural changes in a child within the first two months
after starting treatment.

• Consult your doctor if you have kidney problems or 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 a response to this medicine is not expected.
• Consult your doctor before starting treatment with Kaftrio if you have received an organ transplant.
• Consult your doctor if you are using a hormonal contraceptive, e.g., if you are a woman taking oral contraceptives. During treatment with Kaftrio, you may have an increased risk of developing a skin rash.
• Your doctor may perform certain eye examinations before and during treatment with Kaftrio. In some children and adolescents receiving this treatment, lens opacities (cataracts) have occurred, without affecting vision.

Children under 6 years of age
Do not give this medicine to children under 6 years of age, as it is not known whether Kaftrio tablets are safe and effective in this age group.
Other medicines and Kaftrio
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. Some medicines may affect how Kaftrio works or increase the likelihood of side effects. In particular, inform your doctor if you are taking any of the following medicines. Your doctor may need to adjust the dose of one of your medicines.

• Antifungal medicines (used to treat fungal infections). These include fluconazole, itraconazole, ketoconazole, posaconazole, and voriconazole.
• Antibiotic medicines (used to treat bacterial infections). These include clarithromycin, erythromycin, rifampicin, rifabutin, and telithromycin.
• Antiepileptic medicines (used to treat epileptic seizures). These include carbamazepine, phenobarbital, and phenytoin.
• Herbal medicines. These include St. John’s wort ( Hypericum perforatum ).
• Immunosuppressants (used after organ transplantation). These include ciclosporin, everolimus, sirolimus, and tacrolimus.
• Cardiac glycosides (used to treat certain heart conditions). These include digoxin.
• Anticoagulant medicines (used to prevent blood clots). These include warfarin.
• Medicines for diabetes. These include glimepiride, glipizide, glyburide, nateglinide, and repaglinide.
• Medicines to lower cholesterol levels in the blood. These include pitavastatin and rosuvastatin.
• Medicines to lower blood pressure. These include verapamil.

Kaftrio with food and drink
During treatment, avoid foods or drinks containing grapefruit, as they may increase the side effects of Kaftrio by increasing the amount of Kaftrio in the body.
Pregnancy and breastfeeding

• If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, ask your doctor for advice before taking this medicine.
• Pregnancy: it may be advisable to avoid using this medicine during pregnancy. Your doctor will help you decide the best option for you and your baby.
• Breastfeeding: ivacaftor, tezacaftor, and elexacaftor have been detected in breastfed infants. Your doctor will consider the benefits of breastfeeding for the newborn and the benefits of treatment for you when helping you decide whether to stop breastfeeding or stop treatment.

Driving and using machines
Kaftrio may cause dizziness. If you experience dizziness, do not drive, ride a bicycle, or use machines unless you do not experience these symptoms.
Kaftrio contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially ‘sodium-free’.

3. How to take Kaftrio

Take this medicine exactly as instructed by your doctor or pharmacist. If
you have any doubts, consult your doctor or pharmacist.
Your doctor will determine the correct dose for you.
Kaftrio is usually taken with ivacaftor.
Recommended dose for patients aged 6 years and older

Take the tablets in the morning and in the evening, approximately 12 hours apart.
The tablets are for oral use.
Take both Kaftrio tablets and ivacaftor tablets with food containing fat. Meals or snacks containing fat include those prepared with butter or oils, or those containing eggs. Other foods containing fat are:

• cheeses, whole milk, dairy products made from whole milk, yoghurt, chocolate
• meat, oily fish
• avocado, hummus, soy-based products (tofu)
• nuts, protein bars or protein drinks containing fat

While taking Kaftrio, avoid foods and drinks containing grapefruit. See Kaftrio with food and drink in section 2 for more details.
Swallow the tablets whole. Do not chew, crush, or split the tablets before swallowing.
You must continue to use all your other medications unless your doctor tells you to stop them.
If you have moderate or severe liver problems, your doctor may reduce the dose of the tablets or decide to stop treatment with Kaftrio. See also Warnings and precautions in section 2.
If you take more Kaftrio than you should
Consult your doctor or pharmacist. If possible, bring the medicine and this leaflet with you. You may experience side effects, including those listed in section 4 below.
If you forget to take Kaftrio
If you forget a dose, calculate how much time has passed since the time you missed the dose.

• If less than 6 hours have passed since you missed the morning or evening dose, take the missed tablet(s) as soon as possible. Then return to your usual dosing schedule.
• If more than 6 hours have passed:
• if you missed a morning dose 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 missed an evening dose of ivacaftor, do not take the missed dose. Wait until the next day and take the morning dose of Kaftrio tablets as usual. Do not take a double dose to make up for missed tablets.

If you stop taking Kaftrio
Your doctor will advise you how long treatment with Kaftrio needs to continue. It is important to take this medicine regularly. Do not make any changes unless instructed by your doctor.
If you have any questions about 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 everyone gets them.

Serious side effects:

Possible signs of liver problems
Liver damage and worsening of liver function in patients with or without pre-existing liver disease. Worsening liver function can be severe and may require liver transplantation (see section 2).
In patients treated with Kaftrio, increased liver enzymes in the blood are very common. The following symptoms may be signs of liver problems:

• pain or discomfort in the upper right abdominal area
• yellowing of the skin or the whites of the eyes
• loss of appetite
• nausea or vomiting
• dark urine

Depression. Signs include sadness, mood changes, anxiety, and feelings of emotional discomfort (see section 2).
Contact your doctor immediately if you experience any of these symptoms.

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

• Rash (more common in children and women than in men)
  Contact your doctor immediately if you develop a rash.

Other side effects:

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

• Headache
• Dizziness
• Upper respiratory tract infection (common cold)
• Oropharyngeal pain (sore throat)
• Nasal congestion
• Stomach or abdominal pain
• Diarrhoea
• Increased liver enzymes (signs of liver stress)
• Changes in the types of bacteria present in mucus
• Increased creatine phosphokinase (sign of muscle breakdown), observed in blood tests

Common (may affect up to 1 in 10 people)

• Influenza
• Abnormal breathing (shortness of breath or difficulty breathing)
• Low blood sugar levels (hypoglycaemia)
• Runny nose
• Sinus problems (sinus congestion)
• Redness or pain in the throat
• Ear problems: ear pain or discomfort, ringing in the ears, inflamed eardrum
• Sensation of dizziness (inner ear disorder)
• Intestinal gas (flatulence)
• Acne
• Itching of the skin
• Breast mass
• Feeling of nausea

Uncommon (may affect up to 1 in 100 people)

• Breast and nipple problems: inflammation, pain
• Breast enlargement in males
• Increased blood pressure
• Wheezing
• Blocked ears (aural congestion)

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

• Allergic reactions (hypersensitivity)
• Liver damage (liver injury)
• Increased bilirubin levels (blood test for liver function)
• Behavioural changes

Additional side effects in adolescents
Side effects in adolescents are similar to those observed in adults.

Additional side effects in children
Most cases of behavioural changes have been reported in young children aged 2 to 5 years.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system referred to in Annex V. Reporting side effects can help provide more information on the safety of this medicine.

5. How to store Kaftrio

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer carton and blister after Exp./EXP. The expiry date refers to the last day of that month.
This medicine requires no special storage conditions.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Package contents and other information

What Kaftrio contains

• The active substances 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 components are:
  • tablet core: hypromellose (E464), hypromellose acetate succinate, sodium lauryl sulfate (E487), croscarmellose sodium (E468), microcrystalline cellulose (E460(i)) and magnesium stearate (E470b)
  • film coating: hypromellose (E464), hydroxypropylcellulose (E463), titanium dioxide (E171), talc (E553b), yellow iron oxide (E172) and red iron oxide (E172).

See the end of section 2 for important information on the contents of Kaftrio.
Description of the appearance of Kaftrio and the contents of the pack
Kaftrio 37.5 mg/25 mg/50 mg film-coated tablets are light orange, capsule-shaped tablets with “T50” engraved on one side and smooth on the other.
Kaftrio 75 mg/50 mg/100 mg film-coated tablets are orange, capsule-shaped tablets with “T100” engraved on one side and smooth on the other.
Kaftrio is available in packs of 56 tablets (4 blisters with supporting card, each containing 14 tablets).
Marketing Authorisation 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
For further information on this medicinal product, please contact the local representative of the Marketing Authorisation Holder:
België/Belgique/Belgien, България, Česká republika, Danmark, Deutschland, Eesti, España, France, Hrvatska, Ireland, Ísland, Κύπρος, Latvija, Lietuva, Luxembourg/Luxemburg, Magyarország, Malta, Nederland, Norge, Österreich, Polska, Portugal, România, Slovenija, Slovenská republika, Suomi/Finland, Sverige
Vertex Pharmaceuticals (Ireland) Limited
Tél/Tel/Teл/Tlf/Sími/Τηλ/Puh: +353 (0)1 761 7299

Ελλάδα, Italia
Vertex Φαρμακευτική Μονοπρόσωπη Ανώνυμη Εταιρία (Italy) S.r.l.
Vertex Pharmaceuticals
Τηλ: +30 (211) 2120535
Tel: +39 0697794000

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu. In addition, links to other websites on rare diseases and their treatments are provided.

Patient information leaflet

Kaftrio 60 mg/40 mg/80 mg granules in sachet, 75 mg/50 mg/100 mg granules in sachet

ivacaftor/tezacaftor/elexacaftor
Please read this leaflet carefully before the child takes this medicine because
it contains important information for the child.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask the child's doctor or pharmacist.
• This medicine has been prescribed for the child only. Do not give it to others, even if their symptoms are the same as the child's, because it could be harmful.
• If any adverse reaction occurs, including those not listed in this leaflet, consult the child's doctor or pharmacist. See section 4.

Contents of this leaflet

1. What Kaftrio is and what it is used for
2. What you need to know before the child takes Kaftrio
3. How to take Kaftrio
4. Possible side effects
5. How to store Kaftrio
6. Contents of the pack and other information

1. What Kaftrio is and what it is used for

Kaftrio contains three active substances: ivacaftor, tezacaftor, and elexacaftor. In some patients with
cystic fibrosis (CF), the medicine helps lung cells to function better. CF is an inherited disease in which
the lungs and digestive system can become blocked due to thick and sticky mucus.
Kaftrio, taken with ivacaftor, is intended for patients aged 2 to less than 6 years with CF who have at
least one mutation in the CFTR gene (cystic fibrosis transmembrane conductance regulator), which
responds to Kaftrio. It is intended as a long-term treatment.
Kaftrio acts on a protein called CFTR. This protein is defective in some people with CF if they have a
mutation in the CFTR gene.
Kaftrio is usually taken with another medicine, ivacaftor. Ivacaftor improves the function of the protein, while tezacaftor and elexacaftor increase the amount of protein on the cell surface.
Kaftrio (taken with ivacaftor) helps the child breathe better by improving lung function. You may also notice that the child does not get sick as often or that it is easier for the child to gain weight.

2. What you should know before your child takes Kaftrio

Do not give Kaftrio to your child

• if your child is allergic to ivacaftor, tezacaftor, elexacaftor, or to any of the other ingredients of this medicine (listed in section 6). Consult your child’s doctor and do not give this medicine to your child if this applies.

Warnings and precautions

• Tell your child’s doctor if your child has liver problems or has had them in the past. Your child’s doctor may need to adjust the dose (see section 4).
• Before and during treatment with Kaftrio, your child’s doctor will prescribe blood tests to monitor your child’s liver function, especially if previous blood tests showed high levels of liver enzymes. In patients treated with Kaftrio, liver enzymes in the blood may increase.

Tell your child’s doctor immediately if your child experiences any symptoms of liver problems.
These are listed in section 4.

• Depression (including suicidal thoughts, behavioural changes, anxiety, and sleep disorders) has been reported in patients taking Kaftrio, usually beginning within the first three months of treatment. Contact your doctor immediately if your child shows any of the following symptoms, which may be signs of depression: sadness or mood changes, anxiety, feelings of emotional distress, thoughts of self-harm or suicide, and/or difficulty sleeping (see section 4).

Consult your doctor if you notice any behavioural changes in your child within the first two months of starting treatment.

• Consult your child’s doctor if your child has kidney problems or has had them in the past.
• If your child has two Class I mutations (mutations known not to produce the CFTR protein), do not administer Kaftrio to your child, as it is not expected to respond to this medicine.
• Consult your child’s doctor before starting treatment with Kaftrio if your child has received an organ transplant.
• Your child’s doctor may recommend eye examinations before and during treatment with Kaftrio. In some children and adolescents receiving this treatment, lens opacities (cataracts) have been observed, without any effect on vision.

Children under 2 years of age
Do not give Kaftrio granules to children under 2 years of age, as it is not known whether Kaftrio granules are safe and effective in this age group.

Other medicines and Kaftrio
Tell your child’s doctor or pharmacist if your child is taking, has recently taken, or might take any other medicines. Some medicines may affect how Kaftrio works or increase the likelihood of side effects. In particular, inform your child’s doctor if your child is taking any of the following medicines. Your child’s doctor may need to adjust the dose of one or more of the medicines your child is taking.

• Antifungal medicines (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.
• Antiepileptic medicines (used to treat epileptic seizures). These include carbamazepine, phenobarbital, and phenytoin.
• Herbal medicines. These include St. John’s wort (Hypericum perforatum).
• Immunosuppressants (used after organ transplantation). These include ciclosporin, everolimus, sirolimus, and tacrolimus.
• Cardiac glycosides (used to treat certain heart conditions). These include digoxin.
• Anticoagulant medicines (used to prevent blood clots). These include warfarin.
• Medicines for diabetes. These include glimepiride, glipizide, glyburide, nateglinide, and repaglinide.
• Medicines to lower cholesterol levels in the blood. These include pitavastatin and rosuvastatin.
• Medicines to lower blood pressure. These include verapamil.

Kaftrio with food and drinks
During treatment, avoid giving your child food or drinks containing grapefruit, as they may increase the side effects of Kaftrio by increasing the amount of Kaftrio in the body.

Driving and using machines
Kaftrio may cause dizziness. If your child feels dizzy, your child should not ride a bicycle or do anything else that requires full attention.

Kaftrio granules contain lactose and sodium
If your child’s doctor has diagnosed an intolerance to certain sugars, contact the doctor before your child takes this medicine.
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is essentially ‘sodium-free’.

3. How to take Kaftrio

Give this medicine to the child exactly as instructed by the child's doctor or pharmacist.
If you have any doubts, consult the child's doctor or pharmacist.
The doctor will determine the correct dose for the child. The child should continue taking all other
medicines unless the child's doctor advises otherwise.
Kaftrio is usually taken with ivacaftor.
Recommended dose for patients aged 2 to less than 6 years

Give the child the morning and evening doses approximately 12 hours apart.
The granules are for oral use.
How to prepare Kaftrio granules:

• Take the sachet of granules, holding the dotted line at the top.
• Gently shake the sachet to settle the Kaftrio granules at the bottom.
• Tear or cut the sachet along the dotted line.
• Carefully pour all the Kaftrio granules from the sachet into a teaspoon (5 mL) of soft food or liquid in a small container (for example, an empty bowl). Check the sachet to make sure no granules remain inside.
  o The food or liquid must be at room temperature or cooler.
  o Examples of suitable soft foods or liquids include fruit purée, flavoured yoghurt or pudding, milk, or juice.
• Mix the Kaftrio granules with the food or liquid. Once mixed, administer Kaftrio within 1 hour. Make sure the child takes all of the medicine.

Administer both Kaftrio and ivacaftor doses with food containing fat. Meals or snacks containing fat include those prepared with butter or oils, or those containing eggs. Other foods containing fat include:

• cheese, whole milk, dairy products made from whole milk, yoghurt, chocolate
• meat, oily fish
• avocado, hummus, soy-based products (tofu)
• nuts, protein bars or protein-containing beverages with fat

While taking Kaftrio, avoid giving the child foods and drinks containing grapefruit. See Kaftrio with food and drink in section 2 for more details.
If the child has moderate or severe liver problems, the child's doctor may reduce the dose of the medicine or decide to stop treatment with Kaftrio. See also Warnings and precautions in section 2.
If the child is given more Kaftrio than they should have
Consult the child's doctor or pharmacist. If possible, bring the medicine and this leaflet with you. The child may experience side effects, including those listed in section 4 below.
If you forget to give Kaftrio to the child
If you forget to give the child a dose, consider how much time has passed since the missed dose.

• If less than 6 hours have passed since the child missed the morning or evening dose, give the missed dose as soon as possible. Then return to the usual dosing schedule.
• If more than 6 hours have passed:
  • if the child missed a morning dose of Kaftrio, give it as soon as you remember. Do not give the evening dose of ivacaftor. Give the next morning dose at the usual time;
  • if the child missed an evening dose of ivacaftor, do not give the missed dose. Wait until the next day and give the morning dose of Kaftrio as usual. Do not give a double dose to make up for missed doses.

If the child stops treatment with Kaftrio
Give Kaftrio to the child for the entire duration recommended by the child's doctor. Do not stop treatment unless instructed by the child's doctor.
If you have any questions about using this medicine, consult the child's doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Serious side effects:
Possible signs of liver problems
Liver damage and worsening of liver function in patients with or without pre-existing liver disease. Worsening of liver function can be severe and may require liver transplantation (see section 2).
In patients treated with Kaftrio, an increase in liver enzymes in the blood is very common. The following symptoms may be signs of liver problems:

• pain or discomfort in the upper right part of the abdomen
• yellowing of the skin or the whites of the eyes
• reduced appetite
• nausea or vomiting
• dark urine

Depression. Signs include sadness, mood changes, anxiety, and feelings of emotional discomfort (see section 2).
Contact the child's doctor immediately if the child experiences any of these symptoms.
Very common side effects (may affect more than 1 in 10 people)

• Rash (more common in children and women than in men)
  Contact the child's doctor immediately if you notice a rash.

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

• Headache
• Dizziness
• Upper respiratory tract infection (common cold)
• Oropharyngeal pain (sore throat)
• Nasal congestion
• Stomach or abdominal pain
• Diarrhoea
• Increased liver enzymes (signs of liver stress)
• Changes in the types of bacteria present in mucus
• Increased creatine phosphokinase (a sign of muscle breakdown) observed in blood tests

Common (may affect up to 1 in 10 people)

• Influenza
• Abnormal breathing (shortness of breath or difficulty breathing)
• Low blood sugar levels (hypoglycaemia)
• Runny nose
• Sinus problems (sinus congestion)
• Redness or soreness of the throat
• Ear problems: ear pain or discomfort, ringing in the ears, inflamed eardrum
• Feeling of dizziness (inner ear disorder)
• Intestinal gas (flatulence)
• Acne
• Itching of the skin
• Breast mass
• Feeling of nausea

Uncommon (may affect up to 1 in 100 people)

• Breast and nipple problems: inflammation, pain
• Breast enlargement in males
• Increased blood pressure
• Wheezing
• Blocked ears (aural congestion)

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

• Allergic reactions (hypersensitivity)
• Liver damage (liver injury)
• Increased bilirubin levels (liver function blood test)
• Behavioural changes

Additional side effects in adolescents
Side effects in adolescents are similar to those observed in adults.
Additional side effects in children
Most cases of behavioural changes have been reported in young children aged between 2 and 5 years.
Reporting of side effects
If the child experiences any side effect, including those not listed in this leaflet, talk to the child's doctor or pharmacist. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Kaftrio

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer carton and sachet after Exp./EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Kaftrio contains

• The active substances are ivacaftor, tezacaftor and elexacaftor.

Kaftrio 60 mg/40 mg/80 mg granules
Each sachet contains 60 mg of ivacaftor, 40 mg of tezacaftor and 80 mg of elexacaftor.
Kaftrio 75 mg/50 mg/100 mg granules
Each sachet contains 75 mg of ivacaftor, 50 mg of tezacaftor and 100 mg of elexacaftor.

• The other components are: anhydrous colloidal silica (E551), sodium croscarmellose (E468), hypromellose (E464), hypromellose acetate succinate, lactose monohydrate, magnesium stearate (E470b), mannitol (E421), sodium lauryl sulfate (E487) and sucralose (E955).

See the end of section 2 for important information on the contents of Kaftrio.
Description of the appearance of Kaftrio and contents of the pack
Kaftrio 60 mg/40 mg/80 mg granules is a white to off-white granule in a sealed sachet.
Kaftrio 75 mg/50 mg/100 mg granules is a white to off-white granule in a sealed sachet.
Kaftrio is available in packs of 28 sachets (4 weekly trays, each containing 7 sachets).
Marketing Authorisation 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
For further information on this medicinal product, please contact the local representative of the Marketing Authorisation Holder:
België/Belgique/Belgien, България, Česká España
republika, Danmark, Deutschland, Eesti, Vertex Pharmaceuticals Spain, S.L.
France, Hrvatska, Ireland, Ísland, Κύπρος, Tel: + 34 91 7892800
Latvija, Lietuva, Luxembourg/Luxemburg,
Magyarország, Malta, Nederland, Norge,
Österreich, Polska, Portugal, România,
Slovenija, Slovenská republika,
Suomi/Finland, Sverige
Vertex Pharmaceuticals (Ireland) Limited
Tél/Tel/Teл/Tlf/Sími/Τηλ/Puh:
+353 (0) 1 761 7299
Ελλάδα Italia
Vertex Φαρμακευτική Μονοπρόσωπη Ανώνυμη Vertex Pharmaceuticals
Εταιρία (Italy) S.r.l.
Τηλ: +30 (211) 2120535 Tel: +39 0697794000
Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency, https://www.ema.europa.eu. In addition, links to other websites on rare diseases and their therapeutic treatments are provided.
ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE VARIATION OF THE TERMS OF THE MARKETING AUTHORISATION(S)
Scientific conclusions
Taking into account the assessment by the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Report(s) (PSUR) for ivacaftor/tezacaftor/elexacaftor, the scientific conclusions of the PRAC are as follows:
In view of the available data on increased transaminases and hepatic injury from spontaneous reports, including in two cases a close temporal relationship, and considering a plausible mechanism of action, the PRAC considers that a causal relationship between ivacaftor/tezacaftor/elexacaftor and drug-induced liver injury is at least a reasonable possibility. The PRAC concluded that the product information for medicines containing ivacaftor/tezacaftor/elexacaftor should be amended accordingly.
In view of the available data on insomnia, anxiety and behavioural changes from literature and spontaneous reports, including in some cases a close temporal relationship and a positive re-challenge, and considering a plausible mechanism of action, the PRAC considers that a causal relationship between ivacaftor/tezacaftor/elexacaftor and insomnia, anxiety and behavioural changes is at least a reasonable possibility. The PRAC concluded that the product information for medicines containing ivacaftor/tezacaftor/elexacaftor should be amended accordingly.
Having reviewed the PRAC's recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the general conclusions and rationale of the recommendation.
Reasons for the variation of the terms of the marketing authorisation(s)
Based on the scientific conclusions on ivacaftor/tezacaftor/elexacaftor, the CHMP considers that the benefit-risk balance of the medicinal product(s) containing ivacaftor/tezacaftor/elexacaftor remains favourable, subject to the proposed changes to the product information.
The CHMP recommends the variation of the terms of the marketing authorisation(s).