Prospect: information for the patient

Orkambi 100 mg/125 mg film-coated tablets

Orkambi 200 mg/125 mg film-coated tablets

lumacaftor/ivacaftor

Read this prospect carefully before starting to take this medicine, because it contains important information for you.

• Keep this prospect, as you may need to read it again.
• If you have any doubts, consult your doctor or pharmacist.
• This medicine has been prescribed only to you, and you must not give it to other people even if they have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this prospect. See section 4.

1. What you need to know before starting to take Orkambi
2. How to take Orkambi

1. Adverse effects
2. Storage of Orkambi
3. Contents of the pack and additional information

Orkambi contains two active ingredients: lumacaftor and ivacaftor. It is a medication used for the long-term treatment of cystic fibrosis (CF) in patients 6 years of age or older who have a specific change (called mutationF508del) that affects the gene of a protein called cystic fibrosis transmembrane conductance regulator (CFTR, in English), which plays an important role in regulating mucus flow in the lungs. People with the mutation will produce an abnormal CFTR protein. Cells contain two copies of the CFTR geneCFTR. Orkambi is used in patients in whom the F508del mutation affects both copies (homozygous).

Lumacaftor and ivacaftor work together to improve the function of the abnormal CFTR protein. Lumacaftor increases the amount of CFTR available, and ivacaftor helps the abnormal protein to act more normally.

Orkambi may help you breathe by improving your lung function. You may also notice that it is easier for you to gain weight.

Do not take Orkambi

• if you are allergic to the active ingredients or any of the other components of this medication (listed in section 6).

Warnings and precautions

Consult your doctor or pharmacist before starting to take Orkambi.

Orkambi should not be used in patientswho do not have two copies of the F508del mutationin the CFTR gene.

Consult your doctor before taking Orkambi if you have been told that you have liver or kidney disease, as your doctor may need to adjust your Orkambi dose.

Frequent abnormal results have been observed in liver function tests in some people taking Orkambi. Consult your doctor immediately if you have any of the following symptoms, which may indicate liver problems:

• Abdominal pain or discomfort in the upper right side of the abdomen
• Yellowing of the skin or the white part of the eyes
• Loss of appetite
• Nausea or vomiting
• Dark urine
• Confusion

Your doctor should perform blood tests to check your liver function before and while you are taking Orkambi, especially during the first year.

Respiratory events such asdifficulty breathing or chest tightnessor narrowing of the airwayshave been observed in patients starting treatment with Orkambi, especially in patients with deteriorated lung function. If your lung function is deteriorated, your doctor may closely monitor you when starting treatment with Orkambi.

Anincrease in blood pressurehas been observed in some patients treated with Orkambi. Your doctor may monitor your blood pressure during treatment with Orkambi.

In some children and adolescents treated with Orkambi and ivacaftor alone (one of the components of Orkambi), ananomaly in the crystalline lens of the eye(cataract) without any effect on vision has been observed. Your doctor may perform eye examinations before and during treatment with Orkambi.

Orkambi is not recommended in patients who have undergoneorgan transplantation.

Children under 6 years

Orkambi tablets should not be used in children under 6 years of age. There are other forms of the medication (granules in a sachet) that are more suitable for children under 6 years of age; ask your doctor or pharmacist.

Other medications and Orkambi

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medication.

Especially, inform your doctor if you are taking any of the following medications:

• Antibiotics (used to treat bacterial infections), for example:

telithromycin, clarithromycin, rifampicin, rifabutin, rifapentine, erythromycin

• Anticonvulsants (used to treat seizures [epileptic crises]), for example:

phenobarbital, carbamazepine, phenytoin

• Benzodiazepines (used to treat anxiety, insomnia, agitation, etc.), for example:

midazolam, triazolam

• Antifungals (used to treat fungal infections), for example:

fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole

• Immunosuppressants (used after organ transplantation), for example: cyclosporine, everolimus, sirolimus, tacrolimus

• Herbal medicines, for example:

St. John's Wort (Hypericum perforatum)

• Antihistamines (used to treat allergies and/or asthma), for example:

montelukast, fexofenadine

• Antidepressants (used to treat depression), for example:

citalopram, escitalopram, sertraline, bupropion

• Anti-inflammatory medications (used to treat inflammation), for example:

ibuprofen

• Antagonists H2(used to reduce stomach acid), for example: ranitidine

• Cardiac glycosides (used to treat mild or moderate congestive heart failure and abnormal heart rhythm called atrial fibrillation), for example:

digoxin

• Anticoagulants (used to prevent blood clots or make them larger in the blood and blood vessels), for example:

warfarin, dabigatran

• Contraceptives (used to prevent pregnancy):

oral, injectable, and implantable contraceptives, as well as contraceptive patches; may include ethinylestradiol, norethindrone, and other progestogens. Do not consider a reliable method of contraception when administered with Orkambi.

• Corticosteroids (used to treat inflammation):

prednisolone, prednisone

• Inhibitors of the proton pump (used to treat gastroesophageal reflux disease and ulcers):

omeprazole, esomeprazole, lansoprazole

• Oral hypoglycemic agents (used to treat type 2 diabetes):

repaglinide

Falsely positive results in THC (tetrahydrocannabinol, a component of cannabis) urine tests have been reported in patients receiving Orkambi. Your doctor may request another test to verify the results.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or if you think you may be pregnant, consult your doctor before using this medication. It may be better, if possible, to avoid using Orkambi during pregnancy, and your doctor will help you make a decision about what is best for you and your child.

The excretion of lumacaftor or ivacaftor in breast milk is unknown. If you plan to breastfeed, consult your doctor before taking Orkambi. Your doctor will decide whether to recommend stopping breastfeeding or interrupting lumacaftor/ivacaftor treatment after considering the benefits of breastfeeding for the child and the benefits of treatment for you.

Driving and operating machinery

Dizziness has been reported in patients who received ivacaftor, a component of Orkambi, which may affect your ability to drive and operate machinery. If you experience dizziness, do not drive or operate machinery until the symptoms have disappeared.

If a child experiences dizziness while taking Orkambi, it is recommended that the child not ride a bicycle ordo anything that requires absolute attention until the symptoms have disappeared.

Orkambi contains sodium

This medication contains less than 23 mg of sodium (1 mmol) per dose; that is, it is essentially "sodium-free".

Follow exactly the administration instructions of this medication as indicated by your doctor.

In case of doubt, consult your doctor again.

Recommended dose

The recommended dose for patients 6 years of age or older is two tablets in the morning and two tablets at night (every 12 hours). This means a total of four tablets per day, which should be taken with foods containing fats.

There are different concentrations of Orkambi tablets for different age groups.

Check that you have been prescribed the correct tablet (see below).

You can start taking Orkambi on any day of the week.

If you have moderate or severe liver problems, your doctor may need to reduce your Orkambi dose, as your liver will not eliminate Orkambi from your body as quickly as in people with normal liver function.

• Moderate liver problems: the dose can be reduced to two tablets in the morning and one tablet at night.
• Severe liver problems: the dose can be reduced to one tablet in the morning and one tablet at night.Your doctor may decide to reduce the administration frequency based on clinical response and tolerability.

Administration form

Orkambi is taken orally. Swallow the tablets whole. Do not chew, break, or dissolve the tablets.

It is essentialto take Orkambi with foods containing fatsto achieve the appropriate levels of the medication in the body. Take a meal or snack containing fats just before or just after taking Orkambi. Meals and snacks recommended in the FQ guidelines or standard nutritional guidelines contain adequate amounts of fats. Examples of meals or snacks containing fats are those prepared with butter or oils or those containing eggs. Examples of other foods containing fats are:

• Dairy products, whole milk, whole milk products

• Meat, blue fish

• Avocado, hummus (chickpea puree), soy-based products (tofu)

• Bars or nutritional beverages

If you take more Orkambi than you should

Consult your doctor or pharmacist for advice. If possible, show them the medication and this leaflet. You may experience adverse effects, including those listed in section 4 below.

If you forgot to take Orkambi

Take the missed dose with foods containing fats if less than 6 hours have passed since the time you were supposed to take the tablet. Otherwise, wait until it is time to take the next dose as usual. Do not take a double dose to make up for a missed dose.

If you interrupt treatment with Orkambi

You should continue taking the medication as indicated by your doctor even if you feel well.

If you have any other questions about the use of this medication, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everyone will experience them. The side effects reported with Orkambi and ivacaftor administered alone (one of the active substances in Orkambi) are listed below and may occur with the use of Orkambi.

Theserious side effectsof Orkambi include increased levels of liver enzymes in the blood, liver damage, and worsening of pre-existing severe liver disease. Liver dysfunction can be fatal. These serious side effects are rare (may affect up to 1 in 100 people).

Inform your doctor immediatelyif you experience any of the following symptoms:

• Abdominal pain or discomfort in the upper right quadrant
• Yellowing of the skin or the white part of the eyes
• Loss of appetite
• Nausea or vomiting
• Confusion
• Dark-colored urine

Other side effects

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

• Cough with mucus
• Runny nose
• Difficulty breathing
• Headache
• Abdominal pain (stomach pain)
• Diarrhea
• Increased amount of mucus
• Nausea
• Common cold*
• Dizziness*
• Changes in the type of bacteria in mucus*

Common(may affect up to 1 in 10 people):

• Chest tightness
• Narrowing of the airways
• Conjunctivitis of the nasal sinuses*
• Runny or dripping nose
• Upper respiratory tract infection
• Sore throat
• Enlargement of the throat*
• Rash on the skin
• Flatulence
• Vomiting
• Increased levels of a blood enzyme (creatine phosphokinase in blood)
• High levels of liver enzymes (detected in blood tests)
• Irregular or painful menstruation
• Ear pain, discomfort in the ear*
• Tinnitus in the ears*
• Enlargement of the inner ear*
• Vestibular disorder (feeling of dizziness or spinning)*
• Swelling in the breast*

Rare(may affect up to 1 in 100 people):

• Irregular menstruation that includes absence of menstruation or infrequent menstruation, or more frequent or more abundant menstrual bleeding
• Increased blood pressure
• Ear blockage*
• Inflammation of the breast*
• Enlargement of the breasts in men*
• Changes or pain in the nipples*

*Side effects observed with ivacaftor alone.

Additional side effects in children

The side effects observed in children are similar to those observed in adults and adolescents. However, increased levels of liver enzymes in the blood are more frequent in young children than in adults.

Reporting of side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through the national notification system included in theAppendix V.By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the box/blister after CAD/EXP. The expiration date is the last day of the month indicated.

This medication does not require special storage conditions.

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the containers and medications you no longer need. This will help protect the environment.

Composition of Orkambi

The active ingredients are lumacaftor and ivacaftor.

Orkambi 100 mg/125 mg film-coated tablets:

Each film-coated tablet contains 100 mg of lumacaftor and 125 mg of ivacaftor.

Orkambi 200 mg/125 mg film-coated tablets:

Each film-coated tablet contains 200 mg of lumacaftor and 125 mg of ivacaftor.

Orkambi 100 mg/125 mg film-coated tablets and Orkambi 200 mg/125 mg film-coated tablets:

The other components are:

• Core tablet: cellulose, microcrystalline; sodium croscarmellose; acetate succinate of hypromellose; povidone (K30); sodium lauryl sulfate; and magnesium stearate(see section2 “Orkambi contains sodium”).
• Tablet coating: polyvinyl alcohol; titanium dioxide (E171); macrogol 3350; talc; carmine (E120); brilliant blue FCF lake (E133); and indigo carmine lake (E132).
• Printing ink: shellac; iron oxide black (E172); propylene glycol; and ammonium hydroxide.

Appearance of the product and contents of the pack

Orkambi 100mg/125mg film-coated tablets

Orkambi 100 mg/125 mg film-coated tablets are oblong-shaped, pink tablets (dimensions 14 x 7.6 x 4.9 mm), with the imprint “1V125” in black ink on one face.

Orkambi 100mg/125mg is presented in packs of 112film-coated tablets (4packs of 28film-coated tablets).

Orkambi 200 mg/125 mg film-coated tablets

Orkambi 200 mg/125 mg film-coated tablets are oblong-shaped, pink tablets (dimensions 14 x 8.4 x 6.8 mm), with the imprint “2V125” in black ink on one face.

Orkambi 200 mg/125 mg is presented in multiple packs of 112 film-coated tablets (4 packs of 28 film-coated tablets).

Only some pack sizes may be marketed.

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

Responsible for manufacturing:

Almac Pharma Services (Ireland) Limited

Finnabair Industrial Estate

Dundalk

Co. Louth

A91 P9KD

Ireland

Almac Pharma Services Limited

Seagoe Industrial Estate

Craigavon

BT63 5UA

UK

For further information about this medicinal product, please contact the local representative of the marketing authorization holder:

Last update of this leaflet:

Other sources of information

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