Orkambi

Package leaflet: Information for the patient

Orkambi 100 mg/125 mg film-coated tablets, 200 mg/125 mg film-coated tablets

lumacaftor/ivacaftor
Please read all of this leaflet carefully before you start taking this medicine because 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 others, even if they have the same symptoms as you, because it may be harmful.
• If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. See section 4.

Contents of this leaflet

1. What Orkambi is and what it is used for
2. What you need to know before taking 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 the long-term treatment of cystic fibrosis (CF) in patients aged 6 years and older who have a specific genetic alteration (called the F508del mutation) in the gene for a protein known as the cystic fibrosis transmembrane conductance regulator (CFTR); this protein plays an important role in regulating the flow of mucus in the lungs. People with this mutation produce an abnormal CFTR protein. Individuals have two copies of the CFTR gene; Orkambi is used in patients in whom both copies are affected by the F508del mutation (homozygous).
Lumacaftor and ivacaftor work together to improve the function of the abnormal CFTR protein. Lumacaftor increases the amount of CFTR available, while ivacaftor helps the abnormal protein function more effectively.
Orkambi may help breathing by improving lung function. You may also find it easier to gain weight.

2. What you should know before taking 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 must not be used in patients who do not have two copies of the F508del mutation
in the CFTR gene.
Tell your doctor before taking Orkambi if you have been diagnosed with a liver or kidney disease,
as your Orkambi dose may need to be adjusted.
Abnormal blood test results related to liver enzymes have commonly been observed in some people
treated with Orkambi. Inform your doctor immediately if you experience any of the following
symptoms, which could be signs of liver problems:

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

Your doctor should prescribe blood tests to monitor liver function before starting and during treatment
with Orkambi, especially during the first year.
Depression (including suicidal thoughts, changes in behaviour, anxiety, and sleep disorders) has been
reported in patients taking Orkambi, usually within the first three months of treatment. Contact your
doctor immediately if you (or someone taking this medicine) develop any of the following symptoms,
which may be signs of depression: sad or changed mood, anxiety, feelings of emotional distress, or
thoughts of self-harm or suicide and/or difficulty sleeping (see section 4).
Respiratory events such as shortness of breath, chest tightness, or narrowing of the airways have been
observed in patients at the start of treatment with Orkambi, particularly in those with compromised
lung function. If you have impaired lung function, your doctor may monitor you more closely at the
beginning of treatment with Orkambi.
An increase in blood pressure has 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), a lens abnormality (cataract) has been observed, without any effect on vision. Your doctor
may perform eye examinations before and during treatment with Orkambi.
Orkambi is not recommended for patients who have undergone organ transplantation.
Children under 6 years of age
Orkambi tablets must not be used in children under 6 years of age. Other formulations of this medicine
(granules in sachets) are more suitable for children under 6 years of age; please consult 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, inform your doctor if you are taking any of the following medicines:

• Antibiotics (used to treat bacterial infections), for example: telithromycin, clarithromycin, rifampicin, rifabutin, rifapentine, erythromycin
• Anticonvulsants (used to treat seizures [epileptic fits]), for example: phenobarbital, carbamazepine, phenytoin
• Benzodiazepines (used to treat anxiety or inability to sleep [insomnia], agitation, etc.), for example: midazolam, triazolam
• Antifungal medicines (used to treat fungal infections), for example: fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole
• Immunosuppressants (used after organ transplantation), for example: ciclosporin, everolimus, sirolimus, tacrolimus
• Herbal medicines, for example: St. John’s wort (Hypericum perforatum)
• Antiallergic medicines (used to treat allergies and/or asthma), for example: montelukast, fexofenadine
• Antidepressants (used to treat depression), for example: citalopram, escitalopram, sertraline, bupropion
• Anti-inflammatory medicines (used to treat inflammation), for example: ibuprofen
• H2-receptor antagonists (used to reduce stomach acid), for example: ranitidine
• Cardiac glycosides (used to treat 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 vessels), for example: warfarin, dabigatran
• Contraceptive medicines (used to prevent pregnancy): oral, injectable, and implantable contraceptives, and contraceptive skin patches, which may contain ethinylestradiol, norethisterone, and other progestins. When taken together with Orkambi, these medicines should not be relied upon as an effective method of contraception
• Corticosteroid medicines (used to treat inflammation): methylprednisolone, prednisone
• Proton pump inhibitors (used to treat acid reflux disease and ulcers): omeprazole, esomeprazole, lansoprazole
• Oral hypoglycaemics (used in the management of type 2 diabetes): repaglinide

False positive results in urine screening tests for tetrahydrocannabinol (THC, an active component of
cannabis) have been reported in patients treated with Orkambi. Your doctor may request additional
testing to confirm the results.
Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding,
ask your doctor for advice before taking this medicine. It is preferable to avoid using Orkambi during
pregnancy, if possible, and your doctor will help you decide what is best for you and your baby.
Ivacaftor and lumacaftor pass into breast milk. If you are planning to breastfeed, consult your doctor
before taking Orkambi. Your doctor will decide whether to recommend discontinuing breastfeeding or
discontinuing treatment with lumacaftor/ivacaftor, taking into account the benefits of breastfeeding for
the child and the benefits of treatment for you.
Driving and using machines
Dizziness has been reported in patients treated with ivacaftor , a component of Orkambi, which
could affect the ability to drive or operate machinery. If you experience dizziness, do not drive or use
machinery until these symptoms resolve.
If a child experiences dizziness during treatment with Orkambi , the child should be advised not to
ride a bicycle or engage in other activities requiring full attention until symptoms resolve.
Orkambi contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially ‘sodium-free’.

3. How to take Orkambi

Take this medicine exactly as your doctor has told you. If you are unsure, consult your doctor.
Recommended dose
The recommended dose for patients aged 6 years and older is two tablets in the morning and two tablets in the evening (12 hours apart), for a total of four tablets per day, taken with food containing fat.
There are different tablet strengths of Orkambi available for different age groups. Please check (below) whether you have been given the correct tablet.

You can start taking Orkambi on any day of the week.
If you have moderate or severe problems with liver function, your doctor might reduce the dose of
Orkambi, because the liver does not eliminate Orkambi as quickly as in people whose liver functions normally.

• 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. Your doctor may decide to further adjust the dosing frequency based on clinical response and tolerability.

Method of administration
Orkambi is for oral use. Swallow the tablets whole. Do not chew, break, or dissolve the tablets.
Taking Orkambi with fatty foods is important to achieve adequate levels of the medicine in the body. A meal or snack containing fat should be consumed just before or just after taking Orkambi. Meals and snacks recommended in cystic fibrosis dietary guidelines or those recommended in standard nutritional guidelines contain an adequate amount of fat. Examples of meals or snacks containing fat include those prepared with butter or oils, or those containing eggs. Examples of other fatty foods include:

• Cheese, whole milk, dairy products made from whole milk
• Meat, fatty fish
• Avocado, hummus, soy-based products (tofu)
• Protein bars or protein drinks

If you take more Orkambi than you should
Consult your doctor or pharmacist. If possible, bring the medicine and this package leaflet with you. Adverse effects may occur, including those listed in section 4 below.
If you forget to take Orkambi
Take the missed dose with fatty foods if less than 6 hours have passed since the scheduled time. Otherwise, wait until your next regularly scheduled dose. Do not take a double dose to make up for the missed tablet.
If you stop taking Orkambi
You must continue taking the medicine as instructed by your doctor, even if you feel well.
If you have any questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

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

Serious side effects

Possible signs of liver problems
Liver damage and worsening of liver function in people with or without pre-existing liver disease. For Orkambi, serious side effects include elevated blood levels of liver enzymes, liver injury, and worsening of severe pre-existing liver disease. Worsening liver function may be fatal or require liver transplantation (see section 2). These serious side effects are uncommon in frequency (may occur in up to 1 in 100 people).

Contact your doctor immediately if you experience any of the following symptoms:

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

Depression
Signs include depressed or changed mood, anxiety, feelings of emotional discomfort (see section 2).
Contact your doctor immediately if you have any of these symptoms.

Other side effects

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

• Cough with phlegm
• Nasal congestion
• Shortness of breath
• Headache
• Abdominal pain (stomach ache)
• Diarrhea
• Increased phlegm production
• Nausea
• Common cold*
• Dizziness*
• Changes in the types of bacteria present in mucus*

Common (may affect up to 1 in 10 people)

• Chest tightness
• Narrowing of the airways
• Nasal sinus congestion*
• Stuffy or runny nose
• Upper respiratory tract infection
• Sore throat
• Redness of the throat*
• Rash
• Gas (flatulence)
• Vomiting
• Increase in a blood enzyme (serum creatine phosphokinase)
• High levels of liver enzymes, detected by blood tests
• Irregular or painful menstruation (menstrual cycle)
• Ear pain, ear discomfort*
• Ringing in the ears*
• Redness inside the ear*
• Inner ear disorder (sensation of vertigo or dizziness)*
• Breast mass*

Uncommon (may affect up to 1 in 100 people)

• Abnormal menstruation, including absence of menstruation, infrequent periods, or more frequent or heavier menstrual bleeding
• Increased blood pressure
• Ear congestion
• Breast inflammation
• Enlargement of male breast
• Nipple changes or pain

Side effects observed with ivacaftor alone.

Additional side effects in children
Side effects observed in children are similar to those reported in adults and adolescents. However, increased liver enzymes in the blood have been observed more frequently in young children than in adults.

Reporting of side effects
If you experience any side effect, 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 listed in Annex V. By 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 pack/blister 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 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 components are:
  • Tablet core: microcrystalline cellulose; sodium croscarmellose; hypromellose acetate succinate; povidone (K30); sodium lauryl sulfate; magnesium stearate (see section 2 “Orkambi contains sodium”).
  • Tablet coating: polyvinyl alcohol; titanium dioxide (E171); macrogol 3350; talc; carmine (E120); brilliant blue FCF (E133); indigo carmine (E132).
  • Printing ink: shellac; black iron oxide (E172); propylene glycol; ammonium hydroxide.

Description of the appearance of Orkambi and pack contents
Orkambi 100 mg/125 mg film-coated tablets
Orkambi 100 mg/125 mg film-coated tablets (tablets) are pink, oval-shaped tablets (size 14 × 7.6 × 4.9 mm) with “1V125” printed 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 (size 14 × 8.4 × 6.8 mm) with “2V125” printed in black ink on one side.
Orkambi 200 mg/125 mg is available in multiple packs 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 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/. Additionally, links to other websites on rare diseases and related therapeutic treatments are provided.

Patient Information Leaflet

Orkambi 75 mg/94 mg granules in sachet, 100 mg/125 mg granules in sachet, 150 mg/188 mg granules in sachet

lumacaftor/ivacaftor
Please read this leaflet carefully before the child takes this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask the child's doctor or pharmacist.
• This medicine has been prescribed for the child only. Do not give it to other people, even if their symptoms are the same as the child's, because it could be harmful.
• If the child experiences any adverse reaction, including those not listed in this leaflet, contact the child's doctor or pharmacist. See section 4.

Contents of this leaflet

1. What Orkambi is and what it is used for
2. What you need to know before the 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 the long-term treatment of cystic fibrosis (CF) in patients aged 1 year and older who have a specific genetic mutation (called the F508del mutation) in the gene for a protein known as cystic fibrosis transmembrane conductance regulator (CFTR); this protein plays an important role in regulating the flow of mucus in the lungs. People with this mutation produce an abnormal CFTR protein. Cells carry two copies of the CFTR gene; Orkambi is used in patients in whom both copies carry the F508del mutation (homozygous).
Lumacaftor and ivacaftor work together to improve the function of the abnormal CFTR protein. Lumacaftor increases the amount of CFTR available, while ivacaftor helps the abnormal protein function more effectively.

2. What you should 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 giving Orkambi to your child.
Orkambi must not be used in patients who do not have two copies of the F508del mutation
in the CFTR gene.
Tell your child’s doctor before giving Orkambi to your child if your child has been diagnosed with
a liver or kidney disease, as the dose of Orkambi may need to be adjusted.
Abnormal blood test results related to liver enzymes have commonly been observed in some people
treated with Orkambi. Inform your child’s doctor immediately if your child experiences any of the
following symptoms, which could be signs of liver problems:

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

Your child’s doctor should order certain blood tests to monitor liver function before starting and during
treatment with Orkambi, especially during the first year.
Depression (including suicidal thoughts, changes in behaviour, anxiety, and sleep disorders) has been
reported in patients taking Orkambi, usually within the first three months of treatment. Contact your
child’s doctor immediately if you (or someone taking this medicine) experience any of the following
symptoms, which may be signs of depression: sad or changed mood, anxiety, feelings of emotional
distress, thoughts of self-harm or suicide, and/or difficulty sleeping (see section 4).
Respiratory events such as shortness of breath, chest tightness, or narrowing of the airways have
been observed in patients at the start of treatment with Orkambi, particularly in those with impaired
lung function. If your child has impaired lung function, your child’s doctor may monitor them more
closely at the beginning of treatment with Orkambi.
An increase in blood pressure has been observed in some patients treated with Orkambi.
During treatment with Orkambi, your child’s doctor may monitor your child’s blood pressure.
In some children and adolescents treated with Orkambi and ivacaftor alone (one of the components of
Orkambi), a lens abnormality (cataract) has been observed, without any effect on vision. Your
child’s doctor may perform eye examinations before and during treatment with Orkambi.
Orkambi is not recommended in patients who have undergone organ transplantation.
Children under 1 year of age
It is not known whether Orkambi is safe and effective in children under 1 year of age. Therefore,
Orkambi must not be used in children under 1 year of age.
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.
In particular, inform your child’s doctor if your child is taking any of the following medicines:

• Antibiotics (used to treat bacterial infections), for example: telithromycin, clarithromycin, rifampicin, rifabutin, rifapentine, erythromycin
• Anticonvulsants (used to treat seizures [epileptic seizures]), for example: phenobarbital, carbamazepine, phenytoin
• Benzodiazepines (used to treat anxiety or difficulty falling asleep [insomnia], agitation, etc.), for example: midazolam, triazolam
• Antifungal medicines (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)
• Antiallergic medicines (used to treat allergies and/or asthma), for example: montelukast, fexofenadine
• Antidepressants (used to treat depression), for example: citalopram, escitalopram, sertraline, bupropion
• Anti-inflammatory medicines (used to treat inflammation), for example: ibuprofen
• H2-antagonists (used to reduce stomach acid), for example: ranitidine
• Cardiac glycosides (used to treat 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), for example: warfarin, dabigatran
• Contraceptive medicines (used to prevent pregnancy): oral, injectable, and implantable contraceptives, and contraceptive skin patches, which may contain ethinylestradiol, norethisterone, and other progestins. When taken together with Orkambi, these medicines should not be relied upon as an effective method of contraception
• Corticosteroid medicines (used to treat inflammation): methylprednisolone, prednisone
• Proton pump inhibitors (used to treat acid reflux disease and ulcers): omeprazole, esomeprazole, lansoprazole
• Oral hypoglycaemics (used in the management of type 2 diabetes): repaglinide

In patients treated with Orkambi, false positive results in urine screening tests for tetrahydrocannabinol (THC, an active component of cannabis) have been reported. Your child’s doctor may request additional testing to confirm the results.
Driving and using machines
Dizziness has been reported in patients treated with ivacaftor , a component of Orkambi, which
could affect the ability to drive or operate machinery.
If a child experiences dizziness during treatment with Orkambi , the child should be advised not to ride a bicycle and to avoid other activities requiring full attention until symptoms resolve.
Orkambi contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially ‘sodium-free’.

3. How to take Orkambi

Give this medicine to the child exactly as instructed by the child's doctor.
If you have any doubts, consult the doctor.
The child's doctor will determine the correct dose to administer. The child must continue taking
all other usual medications, unless the child's doctor advises otherwise.
Recommended dose
The recommended dose for patients aged 1 year and older is shown in the following table. Orkambi
should be taken in the morning and in the evening (12 hours apart), with food containing fat.
Different Orkambi dosage strengths are available, based on the child's age and weight. Please check (below)
whether the child has been given the correct dose.

If the child has moderate or severe liver function problems, the doctor may reduce
the dose of Orkambi, because the liver does not eliminate Orkambi as quickly as in
children whose liver functions normally.

• Moderate liver problems: the dose may be reduced to one sachet in the morning and one sachet on alternate evenings.
• Severe liver problems: the dose may be reduced to one sachet per day or less frequently in the morning. No dose should be administered in the evening.

Instructions for administration
Orkambi is for oral use.
Each sachet is for single use only.
You may start administering Orkambi to the child on any day of the week.
How to give Orkambi granules to the child

• Take the granule sachet, holding it with the dotted line at the top.
• Gently shake the sachet to settle its contents at the bottom.
• Tear or cut the sachet along the dotted line.
• Mix the entire contents of the sachet with a teaspoon (5 ml) of soft or liquid food suitable for the child's age. The food or liquid should be at room temperature or cooler. Examples of suitable soft or liquid foods include fruit or vegetable puree, flavoured yoghurt, applesauce, water, milk, breast milk, infant formula, or juice.
• After mixing, give the mixture to the child immediately. If this is not possible, administer it within one hour of mixing. Ensure that the mixture is consumed immediately and completely.
• Immediately before or immediately after administration, give the child a meal or snack containing fat (some examples are provided below).

Taking Orkambi with fat-containing food is important to achieve adequate levels of
the medicine in the body. Meals and snacks recommended in cystic fibrosis guidelines or
meals recommended in standard nutritional guidelines contain sufficient fat.
Examples of fat-containing meals or snacks include those prepared with butter or oils, or those containing
eggs. Other examples of fat-containing foods include:

• Cheese, breast milk, infant formula, whole milk, dairy products made from whole milk
• Meat, fatty fish
• Avocado, hummus, soy-based products (tofu)
• Protein bars or protein drinks

If the child takes more Orkambi than they should
Contact the child’s doctor or pharmacist for advice. If possible, keep the child’s medicine and this leaflet with you.
Adverse effects may occur, including those listed in section 4 below.
If you forget to give Orkambi to the child
If less than 6 hours have passed since the scheduled time, give the missed dose with fat-containing food. Otherwise, wait until the next scheduled dose. Do not give a double dose to make up for a forgotten dose.
If you stop the child’s treatment with Orkambi
Give Orkambi to the child for the entire period recommended by the child’s doctor. Do not stop treatment unless instructed by the doctor. Continue administering the medicine as directed by the doctor, even if the child feels well.
If you have any doubts about using this medicine, consult the 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 (one of the active substances in Orkambi) used alone are listed below and may occur during treatment with Orkambi.

Serious side effects
Possible signs of liver problems
Liver damage and worsening of liver function in people with or without pre-existing liver disease.
For Orkambi, serious side effects include elevated levels of liver enzymes in the blood, liver injury, and worsening of severe pre-existing liver disease. Worsening liver function may be fatal or require liver transplantation (see section 2). These serious side effects are uncommon in frequency (may occur in up to 1 in 100 people).
Contact the child’s doctor immediately if any of the following symptoms occur:

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

Depression
Signs include depressed or changed mood, anxiety, feelings of emotional discomfort (see section 2).
Contact your doctor immediately if you experience any of these symptoms.

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)
• Diarrhea
• Increased sputum production
• Nausea
• Common cold*
• Dizziness*
• Changes in the types of bacteria present in mucus*

Common (may affect up to 1 in 10 people)

• Chest tightness
• Narrowing of the airways
• Nasal sinus congestion*
• Stuffy or runny nose
• Upper respiratory tract infection
• Sore throat
• Redness of the throat*
• Rash
• Flatulence
• Vomiting
• Increased levels of an enzyme in the blood (serum creatine phosphokinase)
• High levels of liver enzymes, detected by blood tests
• Irregular or painful menstruation (period)
• Ear pain, ear discomfort*
• Ringing in the ears*
• Redness inside the ear*
• Inner ear disorder (feeling of vertigo or dizziness)*
• Breast mass*

Uncommon (may affect up to 1 in 100 people)

• Abnormal menstruation, including absence of periods, infrequent periods, or more frequent or heavier menstrual flow
• Increased blood pressure
• Ear congestion
• Breast inflammation
• Enlargement of the breast in males
• Nipple changes or pain

Side effects observed with ivacaftor alone.

Additional side effects in children
Side effects observed in children are similar to those reported in adults and adolescents. However, increased liver enzymes in the blood have been observed more frequently in young children compared to adults.

Reporting of side effects
If the child experiences any side effect, including those not listed in this leaflet, talk to the child’s doctor or pharmacist. You may also report side effects directly through the national reporting system listed in Annex V. Reporting side effects 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 stated on the pack/pouch 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 any medicine via wastewater or household waste. Ask the child's pharmacist
how to dispose of medicines no longer required. This will help protect
the environment.

6. Package contents and other information

What Orkambi contains

• The active substances are lumacaftor and ivacaftor.

Orkambi 75 mg/94 mg granules in sachet:
Each sachet contains 75 mg of lumacaftor and 94 mg of 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 components are: microcrystalline cellulose; sodium croscarmellose; hypromellose acetate succinate; povidone (K30); sodium lauryl sulfate (see section 2 “Orkambi contains sodium”).

Description of the appearance of Orkambi and the contents of the pack
Orkambi granules are white to off-white in colour.
The granules are supplied in sachets.
Pack of 56 sachets (contains 4 individual trays with 14 sachets each).
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 related therapeutic treatments are provided.
ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS 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 lumacaftor/ivacaftor, the scientific conclusions of the PRAC are as follows:
In view of the cumulative data available regarding cases of hepatic failure, and in the context of updates made to the product information for elexacaftor/tezacaftor/ivacaftor, given the serious nature of these events, the PRAC concluded that the product information for medicinal products containing lumacaftor/ivacaftor should therefore be amended.
Considering the available data from post-marketing reports regarding anxiety and insomnia, including in some cases a positive drug de-challenge, and in the context of updates made to the product information for elexacaftor/tezacaftor/ivacaftor, the PRAC Rapporteur considers that a causal relationship between lumacaftor/ivacaftor and anxiety and insomnia constitutes at least a reasonable possibility. The PRAC concluded that the product information for medicinal products containing lumacaftor/ivacaftor should therefore be amended.
Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the general conclusions and the rationale of the recommendation.
Reasons for the variation of the terms of the marketing authorisation(s)
Based on the scientific conclusions on lumacaftor/ivacaftor, the CHMP considers that the benefit-risk balance of the medicinal product(s) containing lumacaftor/ivacaftor remains favourable, subject to the proposed changes to the product information.
The CHMP recommends the variation of the terms of the marketing authorisation(s).