SYMKEVI 50 mg/75 mg FILM-COATED TABLETS

2. What you need to know before you take Symkevi

Do not take Symkevi:

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

Consult your doctor,without taking 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.

• Your doctor will do some blood tests to check how your liver is working before and during treatment with Symkevi, especially if your blood tests have shown raised liver enzymes in the past. An increase in liver enzymes in the blood has been seen in CF patients taking Symkevi.

• Liver damage and worsening of liver function have been seen in patients with severe liver disease who received other CFTR modulators. The worsening of liver function can be severe and may require a transplant.

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

• Depression (including thoughts of suicide and suicidal behaviour) has been reported in patients taking Symkevi, usually in the first 3 months of treatment. Tell your doctor immediately if you (or someone taking this medicine) experience any of the following symptoms, which may be signs of depression: feeling sad or changed mood, anxiety, feeling emotionally upset or thoughts of self-harm or suicide.

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

• Tell your doctor if you have kidney problemsor have had them in the past.

• Tell your doctorbefore starting treatment if you have had an organ transplant.

Children under 6 years

Symkevi must not be used in children under 6 years. It is not known if Symkevi is safe and effective in children under 6 years.

Other medicines and Symkevi

Tell your doctor or pharmacistif you are taking, have recently taken or might take any other medicines. Some medicines may affect how Symkevi 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 ketoconazole, itraconazole, posaconazole, voriconazole and fluconazole.
• Antibiotics(used to treat bacterial infections). These include telithromycin, clarithromycin, erythromycin, rifampicin and rifabutin.
• Anticonvulsants(used to treat epilepsy and seizures). These include phenobarbital, carbamazepine and phenytoin.
• Herbal products.These include St. John's Wort (Hypericum perforatum).
• Immunosuppressants(used after an organ transplant). These include ciclosporin, tacrolimus, sirolimus and everolimus.
• 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 and glipizide.

Taking Symkevi with food and drink

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

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

• 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: tezacaftor and ivacaftor may pass into breast milk. Your doctor will consider the benefit of breast-feeding for the child and the benefit of treatment for you in order to help you decide whether to stop breast-feeding or stop the treatment.

Driving and using machines

Symkevi may cause dizziness. If you feel dizzy, do not drive, ride a bicycle or use machines unless you are sure that you are not affected.

Symkevi contains sodium

This medicine contains less than 23 mg of sodium (1 mmol) per dose unit, which is essentially “sodium-free”.

3. How to take Symkevi

Always take this medicine exactly as your doctor has told you.

If you are not sure, ask your doctor or pharmacist.

There are different doses of Symkevi for different age groups. Check that you have been prescribed the correct dose (see below).

Symkevi is usually taken with ivacaftor.

Take the tablets approximately 12 hours apart.

Take the Symkevi and ivacaftor tablets with fat-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, nut bars or nutritional drinks that contain fat

The tablets are taken by mouth.

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,moderate or severe, your doctor may need to reduce your dose of the tablets as your liver will not process this medicine as quickly as usual.

If you take more Symkevi than 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 take Symkevi

• If you miss a morning dose of Symkevi or an evening dose of ivacaftor, and you remember within 6 hoursof the time you were supposed to take the dose, take the missed tablet as soon as possible.
• If more than 6 hourshave passed, do not take the missed tablet. Wait and take the next tablet at the usual time.
• Do nottake 2 tablets to make up for a missed dose.

If you stop taking Symkevi

Your doctor will tell you how long you need to take Symkevi. 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

Possible signs of liver problems

An increase in liver enzymes in the blood is very common in patients with CF. This may be a sign 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 of depression include feeling sad or changed mood, anxiety or feeling emotionally upset.

Tell your doctor immediatelyif you experience any of these symptoms.

Side effects seen with Symkevi:

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

• Headache
• Common cold

Common(may affect up to 1 in 10 people)

• Feeling sick
• Stuffy nose (nasal congestion)
• Dizziness

Side effects seen with ivacaftor:

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

• Infection of the upper respiratory tract (common cold), including sore throat and nasal congestion
• Headache
• Dizziness
• Stomach pain (abdominal pain)
• Diarrhoea
• Increased liver enzymes in the blood
• Rash
• Changes in the type of bacteria in the mucus

Common(may affect up to 1 in 10 people)

• Runny nose
• Ear pain, discomfort in the ear
• Ringing in the ears
• Redness inside the ears
• Inner ear disorder (feeling dizzy or that everything is spinning)
• Nasal congestion
• Redness of the throat
• Lump in the breast

Uncommon(may affect up to 1 in 100 people)

• Blocked ears
• Breast inflammation
• Enlargement of the breasts in men
• Changes or pain in the nipples

Additional side effects in children and adolescents

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

Reporting of side effects

If you get 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. Storing Symkevi

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 after EXP. The expiry date refers to the last day of that month.

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 protect the environment.

6. Contents of the pack and other information

The active substances are tezacaftor and ivacaftor.

Symkevi 50 mg of tezacaftor/75 mg of ivacaftor film-coated tablets

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

The other ingredients are:

• Tablet core: hypromellose acetate succinate, sodium lauryl sulfate (E487), hypromellose 2910 (E464), microcrystalline cellulose (E460(i)), sodium croscarmellose (E468) and magnesium stearate (E470b) (see section 2 “Symkevi contains sodium”).
• Tablet coating: hypromellose 2910 (E464), hydroxypropyl cellulose (E463), titanium dioxide (E171) and talc (E553b).

Symkevi 100 mg of tezacaftor/150 mg of ivacaftor film-coated tablets

Each film-coated tablet contains 100 mg of tezacaftor and 150 mg of ivacaftor.

The other ingredients are:

• Tablet core: hypromellose acetate succinate, sodium lauryl sulfate (E487), hypromellose 2910 (E464), microcrystalline cellulose (E460(i)), sodium croscarmellose (E468) and magnesium stearate (E470b) (see section 2 “Symkevi contains sodium”).
• Tablet coating: hypromellose 2910 (E464), hydroxypropyl cellulose (E463), titanium dioxide (E171), talc (E553b) and yellow iron oxide (E172).

Appearance and packaging

Symkevi 50 mg/75 mg film-coated tablets are oblong tablets (12.70 mm x 6.78 mm) white in colour with “V50” printed on one side and plain on the other.

Symkevi 100 mg/150 mg film-coated tablets are oblong tablets (15.9 mm x 8.5 mm) yellow in colour with “V100” printed on one side and plain on the other.

Symkevi is available in the following pack sizes:

Pack size of 28 tablets (4 blister cards of 7 tablets each).

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

County Armagh

BT63 5UA

United Kingdom

Date of last revision of this leaflet:

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu. There are also links to other web sites about rare diseases and orphan medicines.