Label: information for the patient

Orkambi 75 mg/94 mg powder for oral suspension

Orkambi 100 mg/125 mg powder for oral suspension

Orkambi 150 mg/188 mg powder for oral suspension

lumacaftor/ivacaftor

Read this label carefully before giving this medicine to your child, because it contains important information for you.

• Keep this label, as you may need to read it again.
• If you have any questions, consult your child's doctor or pharmacist.
• This medicine has been prescribed only for your child, and should not be given to other people even if they have the same symptoms as your child, as it may harm them.
• If your child experiences any side effects, consult your child's doctor or pharmacist, even if they are not listed in this label. See section 4.

Orkambi contains two active ingredients: lumacaftor and ivacaftor. It is a medication used for the long-term treatment of cystic fibrosis (CF) in patients 1 year 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.

No use Orkambi

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

Warnings and Precautions

Consult your child's doctor or pharmacist before starting Orkambi.

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

Consult your child's doctor before starting Orkambi if they have been told that your child has liver or kidney disease, as the doctor may need to adjust the dose of Orkambi.

Abnormal results have been frequently observed in liver function tests in some people taking Orkambi. Consult your child's doctor immediately if your child has 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 child's doctor should perform blood tests to check how your child's liver is functioning before and while taking Orkambi, especially during the first year.

Respiratory events such asdifficulty breathing or chest tightness or narrowing of the airwayshave been observed in patients starting treatment with Orkambi, especially in patients with deteriorated pulmonary function. If your child's pulmonary function is deteriorated, their doctor may closely monitor them when starting treatment with Orkambi.

Anincrease in blood pressurehas been observed in some patients treated with Orkambi. Your child's doctor may monitor their 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) has been observed without any effect on vision. Your child's doctor may perform some eye examinations before and during treatment with Orkambi.

Orkambi is not recommended for patients who have undergoneorgan transplantation.

Children under 1 year

The safety and efficacy of Orkambi in children under 1 year are unknown. Therefore, Orkambi should not be used in children under 1 year.

Other medications and Orkambi

Inform your child's doctor or pharmacist if your child is taking, has taken recently, or may need to take any other medication.

Especially, inform your doctor if your child is 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:

cyclosporin, 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

• H2 antagonists (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 contraceptive method 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

Cases of false positives in tetrahydrocannabinol (THC, an active component in cannabis) urine tests have been reported in patients taking Orkambi. Your child's doctor may request another test to verify the results.

Driving and operating machinery

Headaches have been reported in patients who received ivacaftor, a component of Orkambi, which may affect the ability to drive and operate machinery.

If a child experiences headaches while taking Orkambi, it is recommended that the child not ride a bicycle or engage in anything that requires absolute attention until the symptoms disappear.

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 child's doctor. In case of doubt, consult the doctor again.

Your child's doctor will determine the correct dose for your child. Your child should continue using all other medications, unless the doctor indicates that your child should stop taking one.

Recommended dose

The recommended dose for patients 1 year of age or older is indicated in the following table. Orkambi should be taken in the morning and at night (every 12 hours) with fatty foods.

There are different concentrations of Orkambi according to the age and weight of the child. Check that you have been prescribed the correct dose (below).

If your child has moderate or severe liver function problemsthe doctor may need to reduce the dose of Orkambi, as your child's liver will not eliminate Orkambi from the body as quickly as in children with normal liver function.

• Moderate liver problems: the dose can be reduced to one sachet per day in the morning and one sachet every 2 days at night.
• Severe liver problems: the dose can be reduced to one sachet per day or less frequently in the morning. No dose should be administered at night.

Administration form

Orkambi is taken orally.

Each sachet is for single use only.

You can start administering Orkambi to your child on any day of the week.

Administration of Orkambi granules to your child:

• Hold the sachet with the line for cutting upwards.
• Shake the sachet gently so that the contents settle.

• Open the sachet by breaking or cutting along the line for cutting.
• Mix the entire contents of one sachet with one tablespoon (5 ml) of a suitable soft or liquid food for the child's age. Foods or liquids should be at room temperature or cooler. Some examples of suitable soft or liquid foods for the child's age include fruit or vegetable puree, yogurt, apple sauce, water, milk, breast milk, formula milk, or juice.
• Once mixed, give the medicine to your child immediately. If this is not possible, give it to your child within the hour of mixing. Make sure your child takes the entire mixture immediately.
• Just before or just after administration, give your child a food or snack that contains fat (see below for examples).

It is essentialto take Orkambi with fatty foodsto achieve the required levels of the medicine in the body. Meals and snacks recommended in the FQ guidelines or meals recommended in standard nutritional guidelines contain adequate amounts of fat. Examples of meals or snacks that contain fat are those prepared with butter or oils or those that contain eggs. Examples of other foods that contain fat are:

• Dairy products, breast milk, formula milk, whole milk, whole dairy products
• Meat, blue fish
• Avocado, hummus (chickpea puree), soy-based products (tofu)
• Energy bars or nutritional beverages

If your child takes more Orkambi than they should

Consult your child's doctor or pharmacist for advice. If possible, show them the medicine and this leaflet. Your child may experience side effects, including those listed in section 4 below.

If you forget to administer Orkambi to your child

Administer the missed dose with fatty foods if less than 6 hours have passed since the time your child was supposed to take the granules. Otherwise, wait until your child's next scheduled dose. Do not give your child a double dose to make up for a missed dose.

If you interrupt Orkambi treatment in your child

Administer Orkambi to your child for the duration recommended by your child's doctor.

Do not stop treatment unless your child's doctor advises you to. You should continue administering the medicine as indicated by the doctor even if your child is feeling well.

If you have any other questions about the use of this medicine, ask your child's 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 child's doctor immediatelyif your child experiences:

• Abdominal pain or discomfort in the upper right side
• 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 passages*
• Runny or dripping nose
• Upper respiratory tract infection
• Sore throat
• Enlargement of the throat*
• Rash on the skin
• Gas
• Vomiting
• Increased levels of an enzyme in the blood (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*
• Inner ear disorder (feeling of dizziness or spinning)*
• Breast lump*

Rare(may affect up to 1 in 100 people)

• Irregular menstruation, including absence of menstruation or infrequent menstruation, or more frequent or heavier menstrual bleeding
• Increased blood pressure
• Ear blockage*
• Mastitis*
• 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 side effects

If your child experiences any type of side effect, consult your child's doctor or pharmacist, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through thenational reporting system included in theAppendix V. By reporting side effects, you can contribute to providing more information about 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/leaflet 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 child's pharmacist how to dispose of the packaging and medication your child no longer needs. This will help protect the environment.

Composition of Orkambi

The active ingredients are lumacaftor and ivacaftor.

Orkambi 75mg/94mg powder in a sachet:

Each sachet contains 75mg of lumacaftor and 94mg of ivacaftor.

Orkambi 100 mg/125 mg powder in a sachet:

Each sachet contains 100 mg of lumacaftor and 125 mg of ivacaftor.

Orkambi 150 mg/188 mg powder in a sachet:

Each sachet contains 150 mg of lumacaftor and 188 mg of ivacaftor.

The other components are: cellulose, microcrystalline; croscarmellose sodium; acetate succinate of hypromellose; povidone (K30); and sodium lauryl sulfate (see section2 “Orkambi contains sodium”).

Appearance of the product and contents of the pack

Orkambi powder is a white to off-white powder.

The powder is supplied in sachets.

Pack sizeof56 sachets (contains 4 individual cartons with 14 sachets 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

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

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

Last update of this leaflet:

Other sources of information

The detailed information on this medicine is available on the European Medicines Agency website:http://www.ema.europa.eu.There are also links to other websites on rare diseases and orphan medicines.