B. PACKAGE LEAFLET

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Orkambi is and what it is used for

• 2. What you need to know before you take Orkambi

• 3. How to take Orkambi

• 4. Possible side effects

• 5. How to store Orkambi

• 6. Contents of the pack and other information

1. What Orkambi is and what it is used for

Orkambi contains two active substances, lumacaftor and ivacaftor. It is a medicine used for long-term treatment of cystic fibrosis (CF) in patients aged 6 years and older who have a specific change (called F508del mutation) affecting the gene for a protein called cystic fibrosis transmembrane conductance regulator (CFTR), which plays an important role in regulating the flow of mucus in the lungs. People with the mutation will produce an abnormal CFTR protein. Cells contain two copies of the CFTR gene; Orkambi is used in patients in whom both copies are affected by the F508del mutation (homozygotes).

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 work more normally.

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

2. What you need to know before you take Orkambi

Do not take Orkambi

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

Warnings and precautions

Talk to your doctor or pharmacist before taking Orkambi.

Orkambi should not be used in patients other than those who have two copies of the F508del mutation in their CFTR gene.

Talk to your doctor before taking Orkambi if you have been told you have liver or kidney disease as your doctor may need to adjust the dose of Orkambi.

• Abnormal blood tests of the liver have been commonly seen in some people receiving Orkambi. Tell your doctor straight away if you have any of these symptoms, which may be a sign of liver problems: Pain or discomfort in the upper right stomach (abdominal) area
• Yellowing of your skin or the white part of your eyes
• Loss of appetite
• Nausea or vomiting
• Dark urine
• Confusion

Your doctor should do some blood tests to check your liver before and while you are taking Orkambi, particularly during the first year.

Respiratory events such as shortness of breath or chest tightness or narrowing of the airways were seen in patients when starting Orkambi, especially in patients who have poor lung function. If you have poor lung function your doctor may monitor you more closely when you start Orkambi.

An increase in blood pressure has been seen in some patients treated with Orkambi. Your doctor may monitor your blood pressure during treatment with Orkambi.

Abnormality of the lens of the eye (cataract) without any effect on vision has been noted in some children and adolescents treated with Orkambi and ivacaftor alone (one of the components of Orkambi).Your doctor may perform some eye examinations prior to and during treatment with Orkambi.

Orkambi is not recommended in patients who have undergone an organ transplant.

Children under 6 years old

Orkambi tablets should not be used in children under the age of 6 years. Other forms of this medicine (granules in a sachet) are more suitable for children under 6 years of age, ask your doctor or pharmacist.

Other medicines and Orkambi

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Especially tell your doctor if you take any of the following medicines:

• Antibiotic medicines (used for the treatment of bacterial infections) for example: telithromycin, clarithromycin, rifampicin, rifabutin, rifapentine, erythromycin
• Anticonvulsant medicines (used for the treatment of fits [epileptic seizures]) for example: phenobarbital, carbamazepine, phenytoin
• Benzodiazepines (used for the treatment of anxiety or sleeplessness [insomnia], agitation, etc.) for example: midazolam, triazolam
• Antifungal medicines (used for the treatment of fungal infections) for example: fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole

Immunosuppressants (used after an organ transplantation) for example:

ciclosporin, everolimus, sirolimus, tacrolimus

Herbal medicines, for example:

St. John’s wort (Hypericum perforatum )

Anti-allergic medicines (used for the treatment of allergies and/or asthma) for example: montelukast, fexofenadine

Antidepressant medicines (used for the treatment of depression) for example: citalopram, escitalopram, sertraline, bupropion

Anti-inflammatory medicines (used for the treatment of inflammation) for example: ibuprofen

H2 Antagonist medicines (used to reduce stomach acid) for example: ranitidine

• Cardiac glycosides (used for the treatment of mild to moderate congestive heart failure and an abnormal heart rhythm called atrial fibrillation) for example: digoxin
• Anticoagulants (used to prevent blood clots from forming or growing larger in blood and blood vessels) for example: warfarin, dabigatran
• Contraceptive medicines (used for the prevention of pregnancy):

oral, injectable, and implantable contraceptives as well as contraceptive skin patches; that may include ethinyl estradiol, norethindrone, and other progestogens. These should not be relied upon as an effective method of birth control when given with Orkambi

• Corticosteroid medicines (used to treat inflammation): methylprednisolone, prednisone
• Proton pump inhibitor medicines (used to treat acid reflux disease and ulcers): omeprazole, esomeprazole, lansoprazole
• Oral hypoglycaemics (used for the management of type 2 diabetes):

repaglinide

There have been reports of false positive urine screening tests for tetrahydrocan­nabinol (THC – an active component in cannabis) in patients receiving Orkambi. Your doctor may request another test to verify results.

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. It may be better to avoid using Orkambi during pregnancy, if possible, and your doctor will help you decide what is best for you and your child.

It is unknown if lumacaftor or ivacaftor are found in human milk. If you plan to breast-feed, ask your doctor for advice before taking Orkambi. Your doctor will decide whether to recommend that you stop breast-feeding or for you to stop lumacaftor/iva­caftor therapy. Your doctor will take into account the benefit of breast-feeding for the child and the benefit of therapy for you.

Driving and using machines

Dizziness has been reported in patients receiving ivacaftor , a component of Orkambi, which could influence the ability to drive or use machines. If you experience dizziness, you should not drive or use machines until these symptoms disappear.

If a child experiences dizziness while taking Orkambi , it is advised that the child does not ride a bike or do anything else that needs their full attention, until their symptoms disappear.

Orkambi contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

3. How to take Orkambi

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

Recommended dose

The recommended dose for patients aged 6 years and over is two tablets in the morning, and two tablets in the evening (12 hours apart). That is a total of four tablets per day, to be taken with food containing fat.

There are different strengths of Orkambi tablet for different age groups. Check you have been given the right tablet (below).

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

If you have moderate or severe problems with liver function , your doctor may need to reduce the dose of Orkambi as your liver will not clear Orkambi as fast as in people who have normal liver function.

• Moderate liver problems: the dose may be reduced to two tablets in the morning and one tablet in the evening.
• Severe liver problems: the dose may be reduced to one tablet in the morning and one tablet in the evening.

Method of administration

Orkambi is for oral use. Swallow the tablets whole. Do not chew, break, or dissolve the tablets.

• Taking Orkambi with fat-containing food is important to get the right levels of medicine in your body. A fat-containing meal or snack should be consumed just before or just after taking Orkambi. Meals and snacks recommended in CF 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 containing eggs. Examples of other fat-containing foods are: Cheese, whole milk, whole-milk dairy products
• Meats, oily fish
• Avocados, hummus, soy-based products (tofu)
• Nutritional bars or drinks

If you take more Orkambi than you should

Contact your doctor or pharmacist for advice. If possible, have your medicine and this leaflet with you.

You may experience side effects, including those mentioned in section 4 below.

If you forget to take Orkambi

Take the missed dose with fat-containing food if less than 6 hours have passed since the time you missed the dose. Otherwise, wait until your next scheduled dose as you normally would. Do not take a double dose to make up for the forgotten tablets.

If you stop taking Orkambi

You should keep taking the medicine as your doctor directs even if you feel well.

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. The side effects reported with Orkambi and ivacaftor alone (one of the active substances of Orkambi) are listed below and may occur with the use of Orkambi.

Serious side effects for Orkambi include raised levels of liver enzymes in the blood, liver injury, and worsening of pre-existing severe liver disease. The worsening of liver function can be fatal. These serious side effects are uncommon (may affect up to 1 in 100 people).

Tell your doctor straight away if you have any of the following symptoms:

• Pain or discomfort in the upper right stomach (abdominal) area
• Yellowing of your skin or the white part of your eyes
• Loss of appetite
• Nausea or vomiting
• Confusion
• Dark urine

Other side effects

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

• Cough with sputum
• Nasal congestion
• Shortness of breath
• Headache
• Abdominal pain (stomach ache)
• Diarrhoea
• Increase in sputum
• 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
• Sinus congestion*
• Stuffy or runny nose
• Upper respiratory tract infection
• Sore throat
• Redness in the throat*
• Rash
• Passing gas
• Vomiting
• Increase of an enzyme in your blood (blood creatine phosphokinase)
• High levels of liver enzymes, shown by blood test
• Irregular periods (menses) or pain with menses
• Ear pain, ear discomfort*
• Ringing in the ears*
• Redness inside the ear*
• Inner ear disorder (feeling dizzy or spinning)
• Breast mass

Uncommon (may affect up to 1 in 100 people)

• Abnormal periods, including the absence or infrequent menses, or more frequent or heavier menstrual bleeding
• Increase in blood pressure
• Ear congestion*
• Breast inflammation*
• Enlargement of the breast in males*
• Nipple changes or pain

• Side effects seen for ivacaftor alone.

Side effects in children

Side effects seen in children are similar to those seen in adults and adolescents. However, increased liver enzymes in the blood have been seen more frequently in younger children than 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 inBy reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Orkambi

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

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Orkambi contains

The active substances 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 ingredients are:

• Tablet core: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; povidone (K30); sodium laurilsulfate; and magnesium stearate (see section 2 “Orkambi contains sodium”).
• Tablet coating: polyvinyl alcohol; titanium dioxide (E171); macrogol 3350; talc; carmine (E120); brilliant blue FCF aluminium lake (E133); and indigo carmine aluminium lake (E132).
• Printing ink: shellac; iron oxide black (E172); propylene glycol; and ammonium hydroxide.

What Orkambi looks like and contents of the pack

If your child gets any side effects, talk to your child’s doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Orkambi is and what it is used for

• 2. What you need to know before your child takes Orkambi

• 3. How to take Orkambi

• 4. Possible side effects

• 5. How to store Orkambi

• 6. Contents of the pack and other information

1. What Orkambi is and what it is used for

Orkambi contains two active substances, lumacaftor and ivacaftor. It is a medicine used for long-term treatment of cystic fibrosis (CF) in patients aged 2 years and older who have a specific change (called F508del mutation) affecting the gene for a protein called cystic fibrosis transmembrane conductance regulator (CFTR), which plays an important role in regulating the flow of mucus in the lungs. People with the mutation will produce an abnormal CFTR protein. Cells contain two copies of the CFTR gene; Orkambi is used in patients in whom both copies are affected by the F508del mutation (homozygotes).

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 work more normally.

2. What you need to know before your child takes Orkambi

Do not use Orkambi

• if your child is allergic to lumacaftor, ivacaftor, or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Talk to your child’s doctor or pharmacist before taking Orkambi.

Orkambi should not be used in patients other than those who have two copies of the F508del mutation in their CFTR gene.

Talk to your child’s doctor before taking Orkambi if you have been told your child has liver or kidney disease as the doctor may need to adjust the dose of Orkambi.

Abnormal blood tests of the liver have been commonly seen in some people receiving Orkambi. Tell your child’s doctor straight away if your child has any of these symptoms, which may be a sign of liver problems:

• Pain or discomfort in the upper right stomach (abdominal) area
• 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 do some blood tests to check your child’s liver before and while she/he is taking Orkambi, particularly during the first year.

Respiratory events such as shortness of breath or chest tightness or narrowing of the airways were seen in patients when starting Orkambi, especially in patients who have poor lung function. If your child has poor lung function your child’s doctor may monitor your child more closely when she/he starts Orkambi.

An increase in blood pressure has been seen in some patients treated with Orkambi. Your child’s doctor may monitor your child’s blood pressure during treatment with Orkambi.

Abnormality of the lens of the eye (cataract) without any effect on vision has been noted in some children and adolescents treated with Orkambi and ivacaftor alone (one of the components of Orkambi). Your child’s doctor may perform some eye examinations prior to and during treatment with Orkambi.

Orkambi is not recommended in patients who have undergone an organ transplant.

Children under 2 years old

It is not known if Orkambi is safe and effective in children under 2 years of age. Therefore, Orkambi should not be used in children under the age of 2 years.

Other medicines and Orkambi

Tell your child’s doctor or pharmacist if your child is taking, has recently taken or might take any other medicines.

Especially tell the doctor if your child takes any of the following medicines:

• Antibiotic medicines (used for the treatment of bacterial infections) for example: telithromycin, clarithromycin, rifampicin, rifabutin, rifapentine, erythromycin
• Anticonvulsant medicines (used for the treatment of fits [epileptic seizures]) for example: phenobarbital, carbamazepine, phenytoin
• Benzodiazepines (used for the treatment of anxiety or sleeplessness [insomnia], agitation, etc.) for example: midazolam, triazolam
• Antifungal medicines (used for the treatment of fungal infections) for example: fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole
• Immunosuppressants (used after an organ transplantation) for example:

ciclosporin, everolimus, sirolimus, tacrolimus

• Herbal medicines, for example:

St. John’s wort (Hypericum perforatum )

• Anti-allergic medicines (used for the treatment of allergies and/or asthma) for example:

montelukast, fexofenadine

• Antidepressant medicines (used for the treatment of depression) for example: citalopram, escitalopram, sertraline, bupropion
• Anti-inflammatory medicines (used for the treatment of inflammation) for example:

ibuprofen

• H2 Antagonist medicines (used to reduce stomach acid) for example: ranitidine
• Cardiac glycosides (used for the treatment of mild to moderate congestive heart failure and an abnormal heart rhythm called atrial fibrillation) for example: digoxin
• Anticoagulants (used to prevent blood clots from forming or growing larger in blood and blood vessels) for example: warfarin, dabigatran
• Contraceptive medicines (used for the prevention of pregnancy):

oral, injectable, and implantable contraceptives as well as contraceptive skin patches; that may include ethinyl estradiol, norethindrone, and other progestogens. These should not be relied upon as an effective method of birth control when given with Orkambi

• Corticosteroid medicines (used to treat inflammation): methylprednisolone, prednisone
• Proton pump inhibitor medicines (used to treat acid reflux disease and ulcers): omeprazole, esomeprazole, lansoprazole
• Oral hypoglycaemics (used for the management of type 2 diabetes): repaglinide

There have been reports of false positive urine screening tests for tetrahydrocan­nabinol (THC – an active component in cannabis) in patients receiving Orkambi. Your child’s doctor may request another test to verify results.

Driving and using machines

Dizziness has been reported in patients receiving ivacaftor , a component of Orkambi, which could influence the ability to drive or use machines.

If a child experiences dizziness while taking Orkambi , it is advised that the child does not ride a bike or do anything else that needs their full attention, until their symptoms disappear.

Orkambi contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

How to take Orkambi

Always give your child this medicine exactly as your child’s doctor has told you. Check with the doctor if you are not sure.

Your child’s doctor will determine the correct dose for your child. Your child must keep using all other medicines, unless your child’s doctor tells you to stop using any.

Recommended dose

The recommended dose for patients aged 2 years and over is indicated in the table below. Orkambi has to be taken in the morning and in the evening (12 hours apart) with food containing fat.

There are different strengths of Orkambi according to a child’s age and weight. Check your child has been given the right dose (below).

If your child has moderate or severe problems with liver function , your child’s doctor may need to reduce the dose of Orkambi as your child’s liver will not clear Orkambi as fast as in children who have normal liver function.

• Moderate liver problems: the dose may be reduced on alternate days: two sachets on one day (morning and evening), one sachet the next (morning only).
• Severe liver problems: the dose may be reduced to one sachet per day, or less often.

Method of administration

Orkambi is for oral use.

Each sachet is for single use only.

You may start giving your child Orkambi on any day of the week.

Giving Orkambi granules to your child:

• Hold sachet of granules with cut line on top.
• Shake sachet gently to settle contents.
• Tear or cut sachet open along the line.
• Mix the entire contents of a sachet with one teaspoon (5 mL) of age-appropriate soft food or liquid. Food or liquid should be at room temperature or below. Some examples of age-appropriate soft foods and liquids include pureed fruits, flavoured yogurt, and milk or juice.
• Once mixed, give the product to your child immediately. If this is not possible, give it within the hour after mixing. Make sure that the mixture is consumed immediately and completely.
• Food containing fat should be given to your child just before or just after dosing (some

examples are provided below).

Taking Orkambi with fat-containing food is important to get the right levels of medicine in the body. Meals and snacks recommended in CF 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 containing eggs. Examples of other fat-containing foods are:

• Cheese, whole milk, whole-milk dairy products
• Meats, oily fish
• Avocados, hummus, soy-based products (tofu)

Nutritional bars or drinks

If your child takes more Orkambi than he/she should

Contact your child’s doctor or pharmacist for advice. If possible, have your child’s medicine and this leaflet with you. Your child may experience side effects, including those mentioned in section 4 below.

If you forget to give your child Orkambi

Give the missed dose with fat-containing food if less than 6 hours have passed since the time your child missed the dose. Otherwise, wait until your child’s next scheduled dose as you normally would. Do not give your child a double dose to make up for the forgotten dose.

If you stop giving your child Orkambi

Give Orkambi to your child for as long as your child’s doctor recommends. Do not stop unless your child’s doctor advises you to. You should keep giving the medicine as the doctor directs even if the child feels well.

If you have any further questions on the use of this medicine, ask your child’s doctor or pharmacist.

4. Possible side effects

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

Serious side effects for Orkambi include raised levels of liver enzymes in the blood, liver injury and worsening of pre-existing severe liver disease. The worsening of liver function can be fatal. These serious side effects are uncommon (may affect up to 1 in 100 people).

Tell your child’s doctor straight away if he/she gets any of these:

• Pain or discomfort in the upper right stomach (abdominal) area
• Yellowing of the skin or the white part of the eyes
• Loss of appetite
• Nausea or vomiting
• Confusion
• Dark urine

Other side effects

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

• Cough with sputum
• Nasal congestion
• Shortness of breath
• Headache
• Abdominal pain (stomach ache)
• Diarrhoea
• Increase in sputum
• 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
• Sinus congestion*
• Stuffy or runny nose
• Upper respiratory tract infection
• Sore throat
• Redness in the throat*
• Rash
• Passing gas
• Vomiting
• Increase of an enzyme in the blood (blood creatine phosphokinase)
• High levels of liver enzymes, shown by blood test
• Irregular periods (menses) or pain with menses
• Ear pain, ear discomfort*
• Ringing in the ears*
• Redness inside the ear*
• Inner ear disorder (feeling dizzy or spinning)
• Breast mass

Uncommon (may affect up to 1 in 100 people)

• Abnormal periods, including the absence or infrequent menses, or more frequent or heavier menstrual bleeding
• Increase in blood pressure
• Ear congestion*
• Breast inflammation*
• Enlargement of the breast in males*
• Nipple changes or pain

Side effects seen for ivacaftor alone.

Side effects in children

Side effects seen in children are similar to those seen in adults and adolescents. However, increased liver enzymes in the blood have been seen more frequently in younger children than in adults.

Reporting of side effects

If your child gets any side effects, talk to your child’s 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 inBy reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Orkambi

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

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your child’s pharmacist how to throw away medicines your child no longer uses. These measures will help protect the environment.

6. Contents of the pack and other information

What Orkambi contains

The active substances are lumacaftor and ivacaftor.

Orkambi 100 mg/125 mg granules in sachet:

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

Orkambi 150 mg/188 mg granules in sachet:

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

The other ingredients are: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; povidone (K30); and sodium laurilsulfate (see section 2 “Orkambi contains sodium”).

What Orkambi looks like and contents of the pack

Orkambi 100 mg/125 mg film-coated tablets

Orkambi 100 mg/125 mg film-coated tablets (tablets) are pink, oval-shaped tablets (dimensions 14 x

• 7.6 × 4.9 mm) printed with “1V125” in black ink on one side.

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

Orkambi 200 mg/125 mg film-coated tablets

Orkambi 200 mg/125 mg film-coated tablets (tablets) are pink, oval-shaped tablets (dimensions 14 x

• 8.4 × 6.8 mm) printed with “2V125” in black ink on one side.

Orkambi 200 mg/125 mg is available in multipacks containing 112 film-coated tablets (4 packs of 28 film-coated tablets).

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Vertex Pharmaceuticals (Ireland) Limited

Unit 49, Block F2, Northwood Court, Santry,

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

BT63 5UA

United Kingdom

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Belgie/Belgiqu­e/Belgien, Et.nrapun, Česká republika, Danmark, Deutschland, Eesti, France, Hrvatska, Ireland, island, Kúnpog, Latvija, Lietuva, Luxembourg/Lu­xemburg, Magyarország, Malta, Nederland, Norge, Österreich, Polska, Portugal, Romania, Slovenija, Slovenská republika, Suomi/Finland, Sverige, United Kingdom (Northern Ireland)

Vertex Pharmaceuticals (Ireland) Limited Tél/Tel/Ten/T­lf/Sími/TnVPuh:

+353 (0) 1 761 7299

EXÁáóa

Vertex OappaKsuTiK^ Movonpôoœnn Avóvupn

ETaipía

Tql: +30 (211) 2120535

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:

There are also links to other websites about rare diseases and treatments.

Package leaflet: Information for the patient

Orkambi 100 mg/125 mg granules in sachet

Orkambi 150 mg/188 mg granules in sachet lumacaftor/iva­caftor

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects your child may get. See the end of section 4 for how to report side effects.

Read all of this leaflet carefully before your child starts taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your child’s doctor or pharmacist.
• This medicine has been prescribed for your child only. Do not pass it on to others. It may harm

them even if their signs of illness are the same as your child’s.

If your child gets any side effects, talk to your child’s doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Orkambi is and what it is used for

• 2. What you need to know before your child takes Orkambi

• 3. How to take Orkambi

• 4. Possible side effects

• 5. How to store Orkambi

• 6. Contents of the pack and other information

1. What Orkambi is and what it is used for

Orkambi contains two active substances, lumacaftor and ivacaftor. It is a medicine used for long-term treatment of cystic fibrosis (CF) in patients aged 2 years and older who have a specific change (called F508del mutation) affecting the gene for a protein called cystic fibrosis transmembrane conductance regulator (CFTR), which plays an important role in regulating the flow of mucus in the lungs. People with the mutation will produce an abnormal CFTR protein. Cells contain two copies of the CFTR gene; Orkambi is used in patients in whom both copies are affected by the F508del mutation (homozygotes).

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 work more normally.

2. What you need to know before your child takes Orkambi

Do not use Orkambi

• if your child is allergic to lumacaftor, ivacaftor, or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Talk to your child’s doctor or pharmacist before taking Orkambi.

Orkambi should not be used in patients other than those who have two copies of the F508del mutation in their CFTR gene.

Talk to your child’s doctor before taking Orkambi if you have been told your child has liver or kidney disease as the doctor may need to adjust the dose of Orkambi.

Abnormal blood tests of the liver have been commonly seen in some people receiving Orkambi. Tell your child’s doctor straight away if your child has any of these symptoms, which may be a sign of liver problems:

• Pain or discomfort in the upper right stomach (abdominal) area
• 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 do some blood tests to check your child’s liver before and while she/he is taking Orkambi, particularly during the first year.

Respiratory events such as shortness of breath or chest tightness or narrowing of the airways were seen in patients when starting Orkambi, especially in patients who have poor lung function. If your child has poor lung function your child’s doctor may monitor your child more closely when she/he starts Orkambi.

An increase in blood pressure has been seen in some patients treated with Orkambi. Your child’s doctor may monitor your child’s blood pressure during treatment with Orkambi.

Abnormality of the lens of the eye (cataract) without any effect on vision has been noted in some children and adolescents treated with Orkambi and ivacaftor alone (one of the components of Orkambi). Your child’s doctor may perform some eye examinations prior to and during treatment with Orkambi.

Orkambi is not recommended in patients who have undergone an organ transplant.

Children under 2 years old

It is not known if Orkambi is safe and effective in children under 2 years of age. Therefore, Orkambi should not be used in children under the age of 2 years.

Other medicines and Orkambi

Tell your child’s doctor or pharmacist if your child is taking, has recently taken or might take any other medicines.

Especially tell the doctor if your child takes any of the following medicines:

• Antibiotic medicines (used for the treatment of bacterial infections) for example: telithromycin, clarithromycin, rifampicin, rifabutin, rifapentine, erythromycin
• Anticonvulsant medicines (used for the treatment of fits [epileptic seizures]) for example: phenobarbital, carbamazepine, phenytoin
• Benzodiazepines (used for the treatment of anxiety or sleeplessness [insomnia], agitation, etc.) for example: midazolam, triazolam
• Antifungal medicines (used for the treatment of fungal infections) for example: fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole
• Immunosuppressants (used after an organ transplantation) for example:

ciclosporin, everolimus, sirolimus, tacrolimus

• Herbal medicines, for example:

St. John’s wort (Hypericum perforatum )

• Anti-allergic medicines (used for the treatment of allergies and/or asthma) for example:

montelukast, fexofenadine

• Antidepressant medicines (used for the treatment of depression) for example: citalopram, escitalopram, sertraline, bupropion
• Anti-inflammatory medicines (used for the treatment of inflammation) for example:

ibuprofen

• H2 Antagonist medicines (used to reduce stomach acid) for example: ranitidine
• Cardiac glycosides (used for the treatment of mild to moderate congestive heart failure and an abnormal heart rhythm called atrial fibrillation) for example: digoxin
• Anticoagulants (used to prevent blood clots from forming or growing larger in blood and blood vessels) for example: warfarin, dabigatran
• Contraceptive medicines (used for the prevention of pregnancy):

oral, injectable, and implantable contraceptives as well as contraceptive skin patches; that may include ethinyl estradiol, norethindrone, and other progestogens. These should not be relied upon as an effective method of birth control when given with Orkambi

• Corticosteroid medicines (used to treat inflammation): methylprednisolone, prednisone
• Proton pump inhibitor medicines (used to treat acid reflux disease and ulcers): omeprazole, esomeprazole, lansoprazole
• Oral hypoglycaemics (used for the management of type 2 diabetes): repaglinide

There have been reports of false positive urine screening tests for tetrahydrocan­nabinol (THC – an active component in cannabis) in patients receiving Orkambi. Your child’s doctor may request another test to verify results.

Driving and using machines

Dizziness has been reported in patients receiving ivacaftor , a component of Orkambi, which could influence the ability to drive or use machines.

If a child experiences dizziness while taking Orkambi , it is advised that the child does not ride a bike or do anything else that needs their full attention, until their symptoms disappear.

Orkambi contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Always give your child this medicine exactly as your child’s doctor has told you. Check with the doctor if you are not sure.

Your child’s doctor will determine the correct dose for your child. Your child must keep using all other medicines, unless your child’s doctor tells you to stop using any.

Recommended dose

The recommended dose for patients aged 2 years and over is indicated in the table below. Orkambi has to be taken in the morning and in the evening (12 hours apart) with food containing fat.

There are different strengths of Orkambi according to a child’s age and weight. Check your child has been given the right dose (below).

If your child has moderate or severe problems with liver function , your child’s doctor may need to reduce the dose of Orkambi as your child’s liver will not clear Orkambi as fast as in children who have normal liver function.

• Moderate liver problems: the dose may be reduced on alternate days: two sachets on one day (morning and evening), one sachet the next (morning only).
• Severe liver problems: the dose may be reduced to one sachet per day, or less often.

Method of administration

Orkambi is for oral use.

Each sachet is for single use only.

You may start giving your child Orkambi on any day of the week.

Giving Orkambi granules to your child:

• Hold sachet of granules with cut line on top.
• Shake sachet gently to settle contents.
• Tear or cut sachet open along the line.
• Mix the entire contents of a sachet with one teaspoon (5 mL) of age-appropriate soft food or liquid. Food or liquid should be at room temperature or below. Some examples of age-appropriate soft foods and liquids include pureed fruits, flavoured yogurt, and milk or juice.
• Once mixed, give the product to your child immediately. If this is not possible, give it within the hour after mixing. Make sure that the mixture is consumed immediately and completely.
• Food containing fat should be given to your child just before or just after dosing (some

examples are provided below).

Taking Orkambi with fat-containing food is important to get the right levels of medicine in the body. Meals and snacks recommended in CF 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 containing eggs. Examples of other fat-containing foods are:

• Cheese, whole milk, whole-milk dairy products
• Meats, oily fish
• Avocados, hummus, soy-based products (tofu)

Nutritional bars or drinks

If your child takes more Orkambi than he/she should

Contact your child’s doctor or pharmacist for advice. If possible, have your child’s medicine and this leaflet with you. Your child may experience side effects, including those mentioned in section 4 below.

If you forget to give your child Orkambi

Give the missed dose with fat-containing food if less than 6 hours have passed since the time your child missed the dose. Otherwise, wait until your child’s next scheduled dose as you normally would. Do not give your child a double dose to make up for the forgotten dose.

If you stop giving your child Orkambi

Give Orkambi to your child for as long as your child’s doctor recommends. Do not stop unless your child’s doctor advises you to. You should keep giving the medicine as the doctor directs even if the child feels well.

If you have any further questions on the use of this medicine, ask your child’s doctor or pharmacist.

4. Possible side effects

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

Serious side effects for Orkambi include raised levels of liver enzymes in the blood, liver injury and worsening of pre-existing severe liver disease. The worsening of liver function can be fatal. These serious side effects are uncommon (may affect up to 1 in 100 people).

Tell your child’s doctor straight away if he/she gets any of these:

• Pain or discomfort in the upper right stomach (abdominal) area
• Yellowing of the skin or the white part of the eyes
• Loss of appetite
• Nausea or vomiting
• Confusion
• Dark urine

Other side effects

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

• Cough with sputum
• Nasal congestion
• Shortness of breath
• Headache
• Abdominal pain (stomach ache)
• Diarrhoea
• Increase in sputum
• 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
• Sinus congestion*
• Stuffy or runny nose
• Upper respiratory tract infection
• Sore throat
• Redness in the throat*
• Rash
• Passing gas
• Vomiting
• Increase of an enzyme in the blood (blood creatine phosphokinase)
• High levels of liver enzymes, shown by blood test
• Irregular periods (menses) or pain with menses
• Ear pain, ear discomfort*
• Ringing in the ears*
• Redness inside the ear*
• Inner ear disorder (feeling dizzy or spinning)
• Breast mass

Uncommon (may affect up to 1 in 100 people)

• Abnormal periods, including the absence or infrequent menses, or more frequent or heavier menstrual bleeding
• Increase in blood pressure
• Ear congestion*
• Breast inflammation*
• Enlargement of the breast in males*
• Nipple changes or pain

Side effects seen for ivacaftor alone.

Side effects in children

Side effects seen in children are similar to those seen in adults and adolescents. However, increased liver enzymes in the blood have been seen more frequently in younger children than in adults.

Reporting of side effects

If your child gets any side effects, talk to your child’s 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 inBy reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Orkambi

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

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your child’s pharmacist how to throw away medicines your child no longer uses. These measures will help protect the environment.

6. Contents of the pack and other information

What Orkambi contains

The active substances are lumacaftor and ivacaftor.

Orkambi 100 mg/125 mg granules in sachet:

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

Orkambi 150 mg/188 mg granules in sachet:

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

The other ingredients are: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; povidone (K30); and sodium laurilsulfate (see section 2 “Orkambi contains sodium”).

What Orkambi looks like and contents of the pack

Orkambi 100 mg/125 mg granules in sachet are white to off-white granules.

Orkambi 150 mg/188 mg granules in sachet are white to off-white granules.

The granules are supplied in sachets.

• Pack size of 56 sachets (contains 4 individual wallets with 14 sachets per wallet)

Marketing Authorisation Holder

Vertex Pharmaceuticals (Ireland) Limited

Unit 49, Block F2, Northwood Court, Santry,

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

BT63 5UA

United Kingdom

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Belgie/Belgiqu­e/Belgien, EB^rapua, Česká republika, Danmark, Deutschland, Eesti, France, Hrvatska, Ireland, island, Kúnpog, Latvija, Lietuva, Luxembourg/Lu­xemburg, Magyarország, Malta, Nederland, Norge, Österreich, Polska, Portugal, Romania, Slovenija, Slovenská republika, Suomi/Finland, Sverige, United Kingdom (Northern Ireland)

Vertex Pharmaceuticals (Ireland) Limited Tél/Tel/Ten/T­lf/Sími/TnVPuh:

+353 (0) 1 761 7299

EXXûôa Italia

Vertex GappaKsuTiKrç Movonpôoœnn Avœvuⁿ Vertex Pharmaceuticals

ETaipia (Italy) S.r.l.

Tql: +30 (211) 2120535 Tel: +39 0697794000

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: There are also links to other websites about rare diseases and treatments.

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