ORKAMBI 200 mg/125 mg FILM-COATED TABLETS

2. What you need to know before you take Orkambi

Do not take Orkambi

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

Warnings and precautions

Talk to your doctor or pharmacist before you start taking Orkambi.

Orkambi must not be used in patients who do not have two copies of the F508delmutationin the CFTRgene.

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

Abnormal results in liver blood tests have been commonly seen in some people taking Orkambi. Tell your doctor immediately if you have any of the following symptoms, which could indicate liver problems:

• Pain or discomfort in the upper right side of the stomach (abdomen)
• Yellowing of the skin or the white part of the eyes
• Loss of appetite
• Feeling sick (nausea) or being sick (vomiting)
• Dark urine
• Confusion

Your doctor should do blood tests to check how your liver is working before and while you are taking Orkambi, especially during the first year.

Respiratory events such as difficulty breathing or tightness in the chestor narrowing of the airwayshave been seen in patients starting treatment with Orkambi, especially in patients with poor lung function. If your lung function is poor, your doctor may closely monitor you when you start treatment with Orkambi.

An increase in blood pressurehas been seen in some patients taking Orkambi. Your doctor may check your blood pressure during treatment with Orkambi.

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

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

Children under 6 years

Orkambi tablets should not be used in children under 6 years of age. There are other forms of the medicine (granules in a sachet) that 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.

In particular, tell your doctor if you are taking any of the following medicines:

• Antibiotics (used to treat infections caused by bacteria), such as:

telithromycin, clarithromycin, rifampicin, rifabutin, rifapentine, erythromycin

• Anticonvulsants (used to treat seizures [epileptic fits]), such as:

phenobarbital, carbamazepine, phenytoin

• Benzodiazepines (used to treat anxiety, insomnia, agitation, etc.), such as:

midazolam, triazolam

• Antifungals (used to treat infections caused by fungi), such as:

fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole

• Immunosuppressants (used after an organ transplant), such as: cyclosporin, everolimus, sirolimus, tacrolimus

• Herbal medicines, such as:

St John's Wort (Hypericum perforatum)

• Antihistamines (used to treat allergies and/or asthma), such as:

montelukast, fexofenadine

• Antidepressants (used to treat depression), such as:

citalopram, escitalopram, sertraline, bupropion

• Anti-inflammatory medicines (used to treat inflammation), such as:

ibuprofen

• H2 antagonists (used to reduce acid in the stomach), such as: ranitidine

• Cardiac glycosides (used to treat mild or moderate heart failure and irregular heartbeat called atrial fibrillation), such as:

digoxin

• Anticoagulants (used to prevent blood clots from forming or getting bigger in the blood and blood vessels), such as:

warfarin, dabigatran

• Contraceptives (used to prevent pregnancy):

oral, injectable and implantable contraceptives as well as contraceptive patches; these may include ethinylestradiol, norethindrone and other progestogens. These should not be considered a reliable method of contraception when taken with Orkambi.

• Corticosteroids (used to treat inflammation):

methylprednisolone, prednisone

• Proton pump inhibitors (used to treat acid reflux disease and stomach ulcers):

omeprazole, esomeprazole, lansoprazole

• Oral hypoglycaemics (used to treat type 2 diabetes):

repaglinide

There have been reports of false positive results in tests to detect tetrahydrocannabinol (THC, an active component in cannabis) in urine in patients taking Orkambi. Your doctor may request another test to confirm the 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, if possible, to avoid the use of Orkambi during pregnancy and your doctor will help you to make a decision on what is best for you and your baby.

It is not known whether lumacaftor or ivacaftor are excreted in human milk. If you are breast-feeding, ask your doctor for advice before taking Orkambi. Your doctor will decide whether you should stop breast-feeding or stop lumacaftor/ivacaftor treatment, taking into account the benefit of breast-feeding for the child and the benefit of treatment for you.

Driving and using machines

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

If a child experiences dizziness while taking Orkambi, it is recommended that the child does not ride a bicycle or do anything that requires full attention until the symptoms have resolved.

Orkambi contains sodium

This medicine contains less than 23 mg of sodium (1 mmol) per dose; this is 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 older is 2 tablets in the morning and 2 tablets in the evening (every 12 hours). This is a total of 4 tablets per day, which should be taken with fat-containing foods.

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

Check that you have been prescribed the correct strength of 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 dose of Orkambi, as your liver will not remove Orkambi from your body as quickly as in people with normal liver function.

• Moderate liver problems: the dose may be reduced to 2 tablets in the morning and 1 tablet in the evening.
• Severe liver problems: the dose may be reduced to 1 tablet in the morning and 1 tablet in the evening. Your doctor may decide to reduce the frequency of administration based on clinical response and tolerability.

Method of administration

Orkambi is taken by mouth. Swallow the tablets whole. Do not chew, break or crush the tablets.

It is important to take Orkambi with fat-containing foodsto get the right levels of the medicine in your body. You should have a meal or snack that contains fat just before or just after taking Orkambi. Meals and snacks recommended in the cystic fibrosis guidelines or standard nutritional guidelines contain suitable amounts of fat. Examples of fat-containing foods are those prepared with butter or oils or those that contain eggs. Other examples of foods that contain fat are:

• Cheese, whole milk, whole milk dairy products

• Meat, oily fish

• Avocado, hummus (chickpea paste), soy products (tofu)

• Nutritional bars or drinks

If you take more Orkambi than you should

Talk to your doctor or pharmacist for advice. If possible, show them the medicine and this leaflet. You may experience side effects, including those listed in section 4 below.

If you forget to take Orkambi

Take the missed dose with fat-containing foods if it is less than 6 hours since the time you should have taken the tablet. Otherwise, wait until it is time for your next dose. Do not take a double dose to make up for a forgotten dose.

If you stop taking Orkambi

You should keep taking the medicine as your doctor has told you, 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 given alone (one of the active substances in Orkambi) are listed below and may occur with Orkambi.

Serious side effectsof Orkambi include increased liver enzyme levels in the blood, liver damage and worsening of pre-existing severe liver disease. Worsening of liver function can be fatal. These serious side effects are uncommon (may affect up to 1 in 100 people).

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

• Pain or discomfort in the upper right side of the stomach (abdomen)
• Yellowing of the skin or the white part of the eyes
• Loss of appetite
• Feeling sick (nausea) or being sick (vomiting)
• Confusion
• Dark urine

Other side effects

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

• Cough with phlegm
• Nasal congestion
• Difficulty breathing
• Headache
• Abdominal pain (stomach ache)
• Diarrhoea
• Increased amount of phlegm
• Feeling sick (nausea)
• Common cold*
• Dizziness*
• Changes in the type of bacteria in the mucus*

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

• Chest tightness
• Narrowing of the airways
• Sinus congestion*
• Nasal congestion or runny nose
• Upper respiratory tract infection
• Sore throat
• Redness of the throat*
• Rash
• Wind
• Being sick (vomiting)
• Increased level of an enzyme in the blood (creatine phosphokinase in blood)
• High levels of liver enzymes (detected in blood tests)
• Irregular or painful periods
• Ear pain, discomfort in the ear*
• Ringing in the ears*
• Redness inside the ears*
• Inner ear disorder (feeling of dizziness or spinning)*
• Lump in the breast*

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

• Abnormal periods, including absence of periods or infrequent periods, or more frequent or heavier periods
• Increased blood pressure
• Ear blockage*
• Breast inflammation*
• Breast enlargement in men*
• Changes or pain in the nipples*

*Side effects seen with ivacaftor alone.

Additional side effects in children

The side effects seen in children are similar to those seen in adults and adolescents. However, increased liver enzymes in the blood are more common in young 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 in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of 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 the month shown.

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. Package Contents and Additional Information

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 ingredients are:

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

Appearance and Package Contents

Orkambi 100 mg/125 mg film-coated tablets

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

Orkambi 100 mg/125 mg is presented in packs of 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 are oblong, pink tablets (dimensions 14 x 8.4 x 6.8 mm), with the imprint “2V125” in black ink on one side.

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

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

Date of Last Revision of this Leaflet:

Other Sources of Information

Detailed information on this medicinal product 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.