Symkevi

Patient Information Leaflet

Symkevi 50 mg/75 mg film-coated tablets, 100 mg/150 mg film-coated tablets

tezacaftor/ivacaftor
Please read all of this leaflet carefully before you start taking this medicine as 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 pass it on to other people, even if their symptoms are the same as yours, as it may be harmful to them.
• If you experience any side effects, including those not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Contents of this leaflet

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

1. What Symkevi is and what it is used for

Symkevi contains two active substances, tezacaftor and ivacaftor. The medicine helps lung cells
function better in certain patients with cystic fibrosis (CF). CF is an inherited disease in
which the lungs and digestive system can become blocked due to thick, sticky mucus.
Symkevi acts on a protein called CFTR (cystic fibrosis transmembrane conductance regulator),
which is defective in some people with CF (those who have a mutation in the
CFTR gene). Ivacaftor improves the protein's function, while tezacaftor increases the
amount of protein on the cell surface. Symkevi is usually taken with ivacaftor, another
medicine.
Symkevi taken with ivacaftor is intended for long-term treatment of patients aged 6 years and
older with CF who have specific genetic mutations that result in reduced amount and/or function of the CFTR protein.
Symkevi taken with ivacaftor helps breathing by improving lung function. You may also notice that you do not get sick as often and/or that gaining weight becomes easier.

2. What you need to know before taking 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 the dose (see section 4).

• Your doctor will prescribe certain blood tests to monitor liver function before and during treatment with Symkevi, especially if previous blood tests showed high levels of liver enzymes. Increased liver enzymes in the blood have been observed in cystic fibrosis (CF) patients treated with Symkevi.
• Liver damage and worsening of liver function have been observed in patients treated with other CFTR modulator regimens, with or without pre-existing liver disease. Worsening liver function can be severe and may require liver transplantation.

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

• Depression (including suicidal thoughts, changes in behavior, anxiety, and sleep disorders) has been reported in patients taking Symkevi, usually appearing within three months of starting treatment. Contact your doctor immediately if you (or someone taking this medicine) experience any of the following symptoms, which may be signs of depression: low or altered mood, anxiety, feelings of emotional distress, or thoughts of self-harm or suicide, and/or sleep disturbances (see section 4).
• Your doctor may perform eye examinations before and during treatment with Symkevi. Lens opacities (cataracts), without any effect on vision, have occurred in some children and adolescents receiving this treatment.
• Consult your doctor if you have kidney problems or have had them in the past.
• Consult your doctor before starting treatment if you have received an organ transplant.

Children under 6 years of age
Symkevi must not be used in children under 6 years of age. It is not known whether Symkevi is safe and
effective in children under 6 years of age.
Other medicines and Symkevi
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other
medicines. Some medicines may affect how Symkevi 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 or more of your medicines.

• Antifungal medicines (used to treat fungal infections). These include ketoconazole, itraconazole, posaconazole, voriconazole, and fluconazole.
• Antibiotic medicines (used to treat bacterial infections). These include telithromycin, clarithromycin, erythromycin, rifampicin, and rifabutin.
• Anticonvulsant medicines (used to treat epilepsy and seizures). These include phenobarbital, carbamazepine, and phenytoin.
• Herbal medicines. These include St. John’s wort ( Hypericum perforatum ).
• Immunosuppressants (used after organ transplantation). These include ciclosporin, tacrolimus, sirolimus, and everolimus.
• 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 and glipizide.

Symkevi with food and drink
Avoid foods or drinks containing grapefruit during treatment, as they may increase the side effects of Symkevi by increasing the amount of Symkevi in the body.
Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, are planning a pregnancy, 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 what is best for you and your baby.
• Breastfeeding: tezacaftor and ivacaftor are excreted in breast milk. Your doctor will consider the benefits of breastfeeding for the child and the benefits of treatment for you to help you decide whether to discontinue breastfeeding or discontinue treatment.

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

3. How to take Symkevi

Take this medicine exactly as your doctor has told you. If you have any doubts, consult your doctor or pharmacist.
There are different doses of Symkevi for different age groups. Please check below to make sure you have been given the correct dose.
Symkevi is usually taken together with ivacaftor.

Take the tablets approximately 12 hours apart.
Take both Symkevi tablets and ivacaftor tablets with food containing fat. Meals or
snacks containing fat include those prepared with butter or oil, or those containing eggs. Other foods
containing fat are:

• 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 drinks containing fat

The tablets are for oral use.
Swallow the tablet whole. Do not chew, crush, or split the tablets before swallowing.
You must continue to use all your other medicines, unless your doctor tells you otherwise.
If you have moderate or severe liver problems, your doctor may need to reduce your tablet dose,
because your liver may not eliminate the medicine as quickly as usual.
If you take more Symkevi than you should
Consult your doctor or pharmacist. If possible, bring the medicine and this leaflet with you. You may
experience adverse effects, including those listed in section 4 below.
If you forget to take Symkevi

• If you forget to take the morning Symkevi tablet or the evening ivacaftor tablet and remember within 6 hours of the time you were supposed to take it, take the missed tablet immediately.
• If more than 6 hours have passed, do not take the missed tablet. Wait and take the next tablet at your usual time.
• Do not take two tablets to make up for a forgotten dose.

If you stop taking Symkevi
Your doctor will advise you on how long you need to continue treatment with Symkevi. It is important to take this medicine regularly. Do not make any changes unless instructed by your doctor.
If you have any doubts about how to use this medicine, consult 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
In patients with CF, 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 whites of the eyes
• loss of appetite
• nausea or vomiting
• dark urine

Depression
Signs include feeling sad or irritable, anxiety, and emotional discomfort.
Contact your doctor immediately if you experience any of these symptoms.
Side effects observed 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 unwell (nausea)
• Nasal congestion (sinus congestion)
• Dizziness

Side effects observed with ivacaftor:
Very common (may affect more than 1 in 10 people)

• Upper respiratory tract infection (common cold), including sore throat and nasal congestion
• Headache
• Dizziness
• Abdominal pain
• Diarrhea
• Increased liver enzymes in the blood
• Rash
• Changes in the type of bacteria present in mucus

Common (may affect up to 1 in 10 people)

• Runny nose
• Earache, ear discomfort
• Ringing in the ears
• Redness inside the ear
• Inner ear disorder (sensation of dizziness or spinning)
• Nasal sinus congestion
• Redness in the throat
• Breast lump

Uncommon (may affect up to 1 in 100 people)

• Ear congestion
• Inflammation of the breast
• Enlargement of the breast in males
• Changes or pain in the nipple

Additional side effects in children and adolescents
Side effects in children and adolescents are similar to those observed in adults.
Reporting of side effects
If you get any side effects, 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. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Symkevi

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging 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 Symkevi contains
The active substances are tezacaftor and ivacaftor.
Symkevi 50 mg/75 mg film-coated tablets
Each film-coated tablet contains 50 mg of tezacaftor and 75 mg of ivacaftor.
The other components 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 film coating: hypromellose 2910 (E464), hydroxypropylcellulose (E463), titanium dioxide (E171), talc (E553b).

Symkevi 100 mg/150 mg film-coated tablets
Each film-coated tablet contains 100 mg of tezacaftor and 150 mg of ivacaftor.
The other components 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 film coating: hypromellose 2910 (E464), hydroxypropylcellulose (E463), titanium dioxide (E171), talc (E553b) and yellow iron oxide (E172).

Description of the appearance of Symkevi and contents of the pack
Symkevi 50 mg/75 mg film-coated tablets are white, oval-shaped tablets (size 12.70 mm × 6.78 mm), with “V50” imprinted on one side and smooth on the other.
Symkevi 100 mg/150 mg film-coated tablets are yellow, oval-shaped tablets (size 15.9 mm × 8.5 mm), with “V100” imprinted on one side and smooth on the other.
Symkevi is available in the following pack sizes:
Pack of 28 tablets (4 blisters with supporting cardboard, each containing 7 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
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 GROUNDS FOR THE VARIATION OF THE TERMS OF THE MARKETING AUTHORISATION(S)
Scientific conclusions
Taking into account the evaluation by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Report(s) (PSUR) for tezacaftor/ivacaftor, the scientific conclusions of the PRAC are as follows:
In light of available data on cases of hepatic failure reported in patients with and without pre-existing liver disease for elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), and in the context of updates made to the product information for ELX/TEZ/IVA, given the serious nature of the events concerned, the PRAC considers that the product information for medicinal products containing tezacaftor/ivacaftor should be amended accordingly.
In light of available data on anxiety and insomnia from post-marketing reports, including in some cases a positive response upon discontinuation (positive de-challenge), the PRAC considers that a causal relationship between tezacaftor/ivacaftor and anxiety and insomnia is at least a reasonable possibility. The PRAC concluded that the product information for medicinal products containing tezacaftor/ivacaftor should be amended accordingly.
Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the overall conclusions and rationale of the recommendation.
Grounds for the variation of the terms of the marketing authorisation(s)
Based on the scientific conclusions for tezacaftor/ivacaftor, the CHMP considers that the benefit-risk balance of the medicinal product(s) containing tezacaftor/ivacaftor remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends the variation of the terms of the marketing authorisation(s).