Consumer medicine information

Orkambi

Lumacaftor; Ivacaftor

BRAND INFORMATION

Brand name

Orkambi

Active ingredient

Lumacaftor; Ivacaftor

Schedule

SUMMARY CMI

ORKAMBI^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using ORKAMBI?

ORKAMBI contains the active ingredients lumacaftor and ivacaftor. ORKAMBI is used for the treatment of cystic fibrosis (CF) in patients aged 1 year or older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. For more information, see Section 1. Why am I using ORKAMBI? in the full CMI.

2. What should I know before I use ORKAMBI?

Do not use if you have ever had an allergic reaction to ORKAMBI or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ORKAMBI? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ORKAMBI and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use ORKAMBI?

Your doctor will tell you how much ORKAMBI you need to take each day. This may depend on your condition and whether or not you are taking any other medicines. ORKAMBI is for oral use.

More instructions can be found in Section 4. How do I use ORKAMBI? in the full CMI.

5. What should I know while using ORKAMBI?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using ORKAMBI. Use ORKAMBI exactly as your doctor has prescribed Take ORKAMBI with fat containing food Tell your doctor if you become pregnant or plan to become pregnant while using ORKAMBI.
Things you should not do	Do not stop using ORKAMBI or change the dose without first checking with your doctor. Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.
Looking after your medicine	Store below 30°C, in a dry place away from moisture, heat or sunlight. Keep this medicine where young children cannot reach it.

For more information, see Section 5. What should I know while using ORKAMBI? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. Sometimes they are serious, most of the time they are not. Tell your doctor straight away if you feel unwell while using ORKAMBI. Some side effects may need medical attention.
Common side effects include shortness of breath, diarrhoea and nausea. If you experience significant pain or discomfort in the upper right stomach (abdominal) area, yellowing of your skin or the white parts of your eyes, loss of appetite, nausea, vomiting, dark urine or confusion this may indicate problems with your liver and you should see your doctor straight away or go to the emergency department at your nearest hospital.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI

FULL CMI

ORKAMBI^® (or-KAM-bee)

Active ingredient(s): Lumacaftor/ Ivacaftor

Consumer Medicine Information (CMI)

This leaflet provides important information about using ORKAMBI. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ORKAMBI.

Where to find information in this leaflet:

1. Why am I using ORKAMBI?
2. What should I know before I use ORKAMBI?
3. What if I am taking other medicines?
4. How do I use ORKAMBI?
5. What should I know while using ORKAMBI?
6. Are there any side effects?
7. Product details

1. Why am I using ORKAMBI?

ORKAMBI contains the active ingredients lumacaftor and ivacaftor.

ORKAMBI is used for the treatment of cystic fibrosis (CF) in patients aged 1 year or older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

What is cystic fibrosis?

Cystic fibrosis is caused by genetic defects that limit the flow of chloride and water through cell membranes. As a result, the mucus in the lungs (and other organs) becomes thick and sticky, clogs the lungs and makes it easier for germs to grow. ORKAMBI is a medicine that works by improving the flow of chloride and water in patients with cystic fibrosis who have a certain genetic defect.

ORKAMBI helps your breathing by improving your lung function. You may also notice that you do not get ill as often, or that it is easier to maintain a healthy weight.

How ORKAMBI works

ORKAMBI belongs to a group of medicines called “cystic fibrosis transmembrane conductance regulator (CFTR) modulators”.

The CFTR protein is a chloride ion channel that is normally present at the cell surface of epithelial cells where it transports chloride ions out of the cell in multiple organs. In people who have two copies of the F508del mutation in the CFTR gene, the amount of CFTR protein at the cell surface is much lower than normal. The small amount of CFTR protein that reaches the cell surface does not function properly, as the chloride ion channel remains closed more often than normal.

ORKAMBI is a combination product that contains a CFTR corrector (lumacaftor) which increases the amount of working CFTR at the cell surface, and a CFTR potentiator (ivacaftor), which makes the CFTR protein at the cell surface function better because the chloride channel is open more often.

ORKAMBI therefore allows more chloride ions to get transported out of cells in multiple organs.

ORKAMBI is not addictive.

2. What should I know before I use ORKAMBI?

Warnings

Do not use ORKAMBI if:

you are allergic to any medicine containing lumacaftor or ivacaftor, the active ingredients in ORKAMBI, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

have any other medical conditions
take any medicines for any other condition (see Section 3. What if I am taking other medicines?)

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is unknown whether ORKAMBI is excreted in human breast milk. If you plan to breast-feed, ask your doctor for advice before taking ORKAMBI.

Check with your doctor if you are using or plan to use hormonal birth control (oral, injectable, skin patches and implantable products) as this type of birth control may not work when taking ORKAMBI (see Section 3. What if I am taking other medicines?)

Use in children

Do not give ORKAMBI to children under 1 year of age.

It is not known if ORKAMBI is safe and effective in children under 1 year of age.

Tell your doctor if you:

have been told you have liver or kidney disease.

Worsening of liver function has been seen in patients with severe liver disease and can be serious or fatal.

Laboratory testing

Your doctor will do some blood tests to check your liver before you start taking and while you are taking ORKAMBI, particularly in the first year (every 3 months) and once a year after that.

Abnormal blood tests of the liver have been seen in some people receiving ORKAMBI. If you have had abnormal blood tests of the liver in the past, your doctor may adjust your dose of ORKAMBI and may order blood tests to test your liver more often.

Other testing

Lungs

Respiratory events such as shortness of breath or chest tightness 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.

Blood Pressure

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.

Eyes

Abnormality of the eye lens (cataract) without any effect on vision has been noted in some children receiving ORKAMBI. Your doctor may perform eye examinations before and during treatment with ORKAMBI.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may be affected by ORKAMBI or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

Tell your doctor or pharmacist if you are taking any of the following:

Anti-allergic medicines used for the relief and treatment of allergies	montelukast, fexofenadine
Antifungal medicines used for the treatment of fungal infections	ketoconazole, itraconazole, posaconazole, voriconazole, fluconazole
Antibiotic medicines used for treatment of bacterial infections	telithromycin, clarithromycin, erythromycin, rifampicin, rifabutin, rifapentine
Anticonvulsant medicines used for the treatment of epileptic seizures	phenobarbital, carbamazepine, phenytoin
Anti-inflammatory medicines used for the treatment of pain associated with inflammation	ibuprofen
Herbal medicine	St. John's wort (Hypericum perforatum)
Anti-allergic medicines used for the relief and treatment of allergies	montelukast, fexofenadine
Benzodiazepines used for the treatment of anxiety, insomnia, agitation etc	midazolam, triazolam
Immunosuppressants used after organ transplantation	ciclosporin, everolimus, sirolimus, tacrolimus
Cardiac glycosides used for the treatment of mild to moderate congestive heart failure and an abnormal heart rhythm	digoxin
Anticoagulants used to prevent blood clots from forming or growing larger in blood and blood vessels	warfarin, dabigatran
Hormonal contraceptives used to prevent pregnancy	oral, injectable, skin patches (transdermal) and implantable products
Glucocorticoids used to treat inflammation	prednisone, methylprednisolone
Antidepressants used to treat depression	citalopram, escitalopram, sertraline, bupropion
Oral hypoglycemics used to treat Type 2 diabetes	repaglinide
Medicines used to treat acid reflux disease and ulcers	Proton pump inhibitors such as omeprazole, esomeprazole, lansoprazole, H2 blockers such as ranitidine

Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking ORKAMBI.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ORKAMBI.

4. How do I use ORKAMBI?

How much to take/use

Your doctor will tell you how much ORKAMBI you need to take each day. This may depend on your condition and whether or not you are taking any other medicines.

The recommended dose of ORKAMBI for patients aged 1 year and older is as follows:

Patients aged 1 to less than 2 years and weighing 7 kg to less than 9 kg:

Morning: One sachet of 75 mg lumacaftor/94 mg ivacaftor granules taken orally.

Evening (12 hours later): One sachet of 75 mg lumacaftor/94 mg ivacaftor granules taken orally.

Patients aged 1 to less than 2 years and weighing 9 kg to less than 14 kg:

Morning: One sachet of 100 mg lumacaftor/125mg ivacaftor granules taken orally.

Evening (12 hours later): One sachet of 100 mg lumacaftor/125 mg ivacaftor granules taken orally.

Patients aged 1 to less than 2 years and weighing less than or equal to 14 kg:

Morning: One sachet of 150 mg lumacaftor/188 mg ivacaftor granules taken orally.

Evening (12 hours later): One sachet of 150 mg lumacaftor/188 mg ivacaftor granules taken orally.

Patients aged 2 to 5 years and weighing less than 14 kg:

One sachet of 100 mg lumacaftor/125 mg ivacaftor granules taken orally every 12 hours (total daily dose of 200mg lumacaftor/ 250mg ivacaftor).

Patients aged 2 to 5 years and weighing greater than or equal to 14 kg:

One sachet of 150 mg lumacaftor/ 188 mg ivacaftor granules taken orally every 12 hours (total daily dose of 300 mg lumacaftor/ 376 mg ivacaftor).

Patients 6-11 years:

Two tablets (100 mg lumacaftor/125 mg ivacaftor in each tablet) taken orally every 12 hours (total number of tablets is 4 per day for a total of 400 mg lumacaftor/500 mg ivacaftor).

Patients 12 years and over:

Two tablets (200 mg lumacaftor/125 mg ivacaftor in each tablet) taken orally every 12 hours (the total number of tablets is 4 per day for a total of 800 mg lumacaftor/500 mg ivacaftor).

When to take / use ORKAMBI

ORKAMBI should be used every day for as long as your doctor tells you to.
Your doctor will determine if your treatment should be stopped.

If you have liver problems, your doctor may need to reduce your dose of ORKAMBI.

How to take ORKAMBI

ORKAMBI is for oral use.

Take ORKAMBI with fat-containing food.

Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs.

Other fat-containing foods are:

Cheese, whole milk, breast milk, infant formula, whole-milk dairy products, yoghurt, chocolate
Meats, oily fish
Eggs
Avocados, soy-based products (tofu)
Nuts

Taking ORKAMBI with fat-containing food is important to get the right levels of medicine in your body.

Tablets:

Take 2 tablets of ORKAMBI every 12 hours by mouth with a fat-containing meal or snack.

Granules:

Each sachet is for single use only. Take one sachet of ORKAMBI every 12 hours.

Giving ORKAMBI to your child:

Hold sachet of granules with cut line on top.
Shake sachet gently to settle contents.
Tear or cut sachet open along cut line.
Mix the entire content of a sachet with 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 or liquids include puréed fruits or vegetables, yogurt, water, milk, breast milk, infant formula or juice.
Once mixed, give the product to your child immediately. If this is not possible, give it within one hour after mixing. Ensure that the mixture is completely and immediately consumed.
A fat-containing meal or snack should be given to your child just before or just after dosing.

If you forget to use ORKAMBI

ORKAMBI should be used regularly at the same time each day.

If less than 6 hours have passed since you missed a dose, take the dose as soon as possible and then go back to your regular schedule.

If more than 6 hours have passed since you missed a dose then skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, talk to your doctor or pharmacist.

If you use too much ORKAMBI

If you think that you have used too much ORKAMBI, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using ORKAMBI?

Things you should do

Keep all of your doctor's appointments so that your progress can be checked.

Use ORKAMBI exactly as your doctor has prescribed.
Take ORKAMBI with fat-containing food
Tell your doctor if you become pregnant while using ORKAMBI.
Tell your doctor if, for any reason, you have not used ORKAMBI exactly as prescribed.
Tell your doctor or pharmacist as soon as possible if you do not feel well while taking ORKAMBI.

Things you should not do

Do not stop using ORKAMBI or change the dose without first checking with your doctor.
Do not let yourself run out of medicine over the weekend or on holidays.
Do not give ORKAMBI to anyone else even if they have the same condition as you.
Do not use ORKAMBI to treat other complaints unless your doctor tells you to.
Do not start taking any other medicines, whether they require a prescription or not without telling your doctor first or consulting a pharmacist.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ORKAMBI affects you.

Looking after your medicine

Store below 30°C
Keep it where young children cannot reach it.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Getting rid of any unwanted medicine

If your doctor tells you to stop using ORKAMBI or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects

What to do

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

shortness of breath
diarrhoea
nausea

Common side effects (may affect up to 1 in 10 people)

chest tightness
sore throat
upper respiratory tract infection
gas
rash
stuffy or runny nose
vomiting
irregular periods (menses) or pain with menses

Uncommon side effects (may affect up to 1 in 100 people)

abnormal or irregular periods, including the absence or infrequent menses, or more frequent or heavier menstrual bleeding
increase in blood pressure

Additional side effects in children:

cough with sputum
stuffy nose
headache
stomach pain
increase in sputum

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects	What to do
The side effects listed below may indicate problems with your liver. You may need urgent medical attention if you experience: significant pain or discomfort in the upper right stomach (abdominal) area. yellowing of your skin or the white parts of your eyes. loss of appetite nausea or vomiting dark urine confusion	Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What ORKAMBI contains

Tablets:

Active ingredients
(main ingredient)

lumacaftor
ivacaftor

Other ingredients
(inactive ingredients)

microcrystalline cellulose

croscarmellose sodium

hypromellose acetate succinate

povidone

sodium lauryl sulfate

magnesium stearate

OPADRY II Pink 85F140026 (PI# 110227)

OPACODE monogramming ink S-1-17823 BLACK (PI# 12108)

Granules:

Active ingredients
(main ingredient)

lumacaftor
ivacaftor

Other ingredients
(inactive ingredients)

microcrystalline cellulose

hypromellose acetate succinate

croscarmellose sodium

sodium lauryl sulfate

povidone

Do not take this medicine if you are allergic to any of these ingredients.

What ORKAMBI looks like

ORKAMBI 100/125 mg Tablets (AUST R 289715):

Pink, oval-shaped tablets, printed with "1V125" in black ink on one side and plain on the other.

ORKAMBI 200/125 mg Tablets (AUST R 235759):

Pink, oval-shaped tablets, printed with "2V125" in black ink on one side and plain on the other.

ORKAMBI 75/94 mg Granules (AUST R 389450),

ORKAMBI 100/125 mg Granules (AUST R 305011),

and ORKAMBI 150/188 mg Granules (AUST R 305012)

White to off-white granules enclosed in unit dose sachets

Availability

Tablets:

ORKAMBI tablets are available in the following pack sizes:

112-count tablet box (contains a 4-week supply in 4 weekly cartons of 7 daily blister strips with 4 tablets per strip)

ORKAMBI tablets are available in the following strength:

200 mg of lumacaftor and 125 mg of ivacaftor
100 mg of lumacaftor and 125 mg of ivacaftor

Granules:

ORKAMBI granules are available in the following pack size:

56 sachets (containing 4 individual wallets with 14 sachets per wallet)

ORKAMBI granules are available in the following strengths:

75 mg of lumacaftor and 94 mg of ivacaftor
100 mg of lumacaftor and 125 mg of ivacaftor
150 mg of lumacaftor and 188 mg of ivacaftor

Who distributes ORKAMBI

Vertex Pharmaceuticals (Australia) Pty Ltd
Suite 3, Level 3
601 Pacific Highway
St Leonards NSW 2065
Australia
Telephone: 1800 179 987
e-mail: [email protected]

This leaflet was prepared in May 2023.

VERTEX and the VERTEX triangle logo are registered trademarks and ORKAMBI is a trademark of Vertex Pharmaceuticals Incorporated.

Published by MIMS July 2023

BRAND INFORMATION

Brand name

Orkambi

Active ingredient

Lumacaftor; Ivacaftor

Schedule

1 Name of Medicine

Lumacaftor and ivacaftor.

2 Qualitative and Quantitative Composition

Tablets.

Orkambi 100/125 film-coated tablets contain 100 mg of lumacaftor and 125 mg of ivacaftor.
Orkambi 200/125 film-coated tablets contain 200 mg of lumacaftor and 125 mg of ivacaftor.

Granules.

Orkambi 75/94 granules contain 75 mg lumacaftor and 94 mg ivacaftor per sachet.
Orkambi 100/125 granules contain 100 mg lumacaftor and 125 mg ivacaftor per sachet.
Orkambi 150/188 granules contain 150 mg lumacaftor and 188 mg ivacaftor per sachet.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Orkambi 100/125 (lumacaftor/ivacaftor) film-coated tablets are supplied as pink, oval-shaped tablets. Each tablet is printed with "1V125" in black ink on one side and plain on the other.
Orkambi 200/125 (lumacaftor/ivacaftor) film-coated tablets are supplied as pink, oval-shaped tablets. Each tablet is printed with "2V125" in black ink on one side and plain on the other.
Orkambi (lumacaftor/ivacaftor) granules are supplied as white to off-white granules enclosed in unit dose sachets.

4 Clinical Particulars

4.1 Therapeutic Indications

Orkambi is indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene.

4.2 Dose and Method of Administration

Orkambi should only be prescribed by physicians with experience in the treatment of CF. If the patient's genotype is unknown, an accurate and validated genotyping method should be performed to confirm the presence of the F508del mutation on both alleles of the CFTR gene.
Adults, adolescents, and children aged 1 year and older should be dosed according to Table 1.
A fat containing meal or snack should be consumed just before or just after dosing.
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, cheeses, nuts, chocolate, whole-milk, whole milk dairy products, breast milk, infant formula, meats, avocados, oily fish, and soy-based products (tofu) (see Section 5.2 Pharmacokinetic Properties).

Film-coated tablets.

For oral use. Patients should be instructed to swallow the tablets whole (i.e. patients should not chew, break, or dissolve the tablet).

Granules.

For oral use. The entire content of each sachet of granules should be mixed with one teaspoon (5 mL) of age-appropriate soft food or liquid and the mixture completely consumed. Some examples of soft foods or liquids include puréed fruits or vegetables, flavored yogurt or pudding, water, milk, breast milk, infant formula or juice. Food should be at room temperature or below. Each sachet is for single use only. Once mixed, the product has been shown to be stable for one hour, and therefore should be ingested during this period.

Use in renal insufficiency.

No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution is recommended while using Orkambi in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease (see Section 5.2 Pharmacokinetic Properties).

Use in hepatic insufficiency.

No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A dose reduction is recommended for patients with moderate hepatic impairment (Child-Pugh Class B).
Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, after weighing the risks and benefits of treatment, Orkambi should be used with caution at a reduced dose (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
For dose adjustments for patients with hepatic impairment see Table 2.

Use in patients with advanced lung dysfunction.

Clinical experience in patients with ppFEV₁ < 40 is limited, and additional monitoring of these patients is recommended during initiation of therapy. In Study 809-106, patients aged 12 years and older with advanced lung disease (ppFEV₁ < 40) initiated at a reduced dose (1 tablet every 12 hours for up to 2 weeks and subsequently increased to the full dose) experienced fewer respiratory events than patients initiated on the full dose (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Use in combination with strong CYP3A inhibitors.

No dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking Orkambi. However, when initiating Orkambi in patients currently taking strong CYP3A inhibitors (e.g. itraconazole), reduce Orkambi dose to 1 tablet daily or 1 sachet every other day for the first week of treatment. Following this period, continue with the recommended daily dose.
If Orkambi is interrupted for more than 1 week and then re-initiated while taking strong CYP3A inhibitors, reduce Orkambi dose to 1 tablet daily or 1 sachet every other day for the first week of treatment re-initiation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Following this period, continue with the recommended daily dose.

Use in combination with ciprofloxacin.

No dose adjustment is required when Orkambi is used with ciprofloxacin.

4.3 Contraindications

In cases of hypersensitivity to the active substance or to any component of this medication, patients should not be treated with this medicine.

4.4 Special Warnings and Precautions for Use

Patients with CF who are heterozygous for the F508del mutation in the CFTR gene.

Orkambi is not effective in patients with CF who have the F508del mutation on one allele plus a second allele with a mutation predicted to result in the lack of CFTR production or that is not responsive to ivacaftor in vitro.

Patients with CF who have a gating (class III) mutation in the CFTR gene.

Orkambi is not recommended for use in patients with CF who are heterozygous for the F508del mutation on one allele, with an ivacaftor-responsive mutation on the second allele, since the exposure of ivacaftor is very significantly reduced when dosed in combination with lumacaftor.

Use in hepatic impairment.

Patients with advanced liver disease.

Abnormalities in liver function, including advanced liver disease, can be present in patients with CF. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension receiving Orkambi. Use Orkambi with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If Orkambi is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration).

Hepatobiliary events.

Elevated transaminases have been reported in patients with CF, including some receiving Orkambi. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin (see Section 4.8 Adverse Effects (Undesirable Effects)).
Because an association with liver injury cannot be excluded, assessments of liver function tests (ALT, AST and bilirubin) are recommended before initiating Orkambi every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered.
In the event of significant elevation of ALT or AST, with or without elevated bilirubin [either ALT or AST > 5 x the upper limit of normal (ULN), or ALT or AST > 3 x ULN with bilirubin > 2 x ULN], dosing with Orkambi should be discontinued and laboratory tests closely followed until the abnormalities resolve. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration). The dose should be reduced in moderate or severe hepatic impairment (see Section 4.2 Dose and Method of Administration, Use in hepatic insufficiency).

Respiratory events.

Respiratory events (e.g. chest discomfort, dyspnoea, and respiration abnormal) were observed more commonly in patients during initiation of Orkambi compared to those who received placebo. These events have led to drug discontinuation and can be serious, particularly in patients with percent predicted FEV₁ (ppFEV₁) < 40. Clinical experience in patients with ppFEV₁ < 40 is limited, and additional monitoring of these patients is recommended during initiation of therapy (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials). There is no experience of initiating treatment with Orkambi in patients having pulmonary exacerbations and this is not advisable.

Cardiovascular effects.

Effect on blood pressure.

Increased blood pressure has been observed in some patients treated with Orkambi. Blood pressure should be monitored periodically in all patients during treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).

Decrease in heart rate.

During the 24-week, placebo-controlled, Phase 3 studies, a maximum decrease in mean heart rate of 6 beats per minute (bpm) from baseline was observed on Day 1 and Day 15. After Week 4, the mean change in heart rate ranged from 1 to 2 bpm below baseline among patients treated with lumacaftor/ivacaftor. The percentage of patients with heart rate values < 50 bpm on treatment was 11% for patients who received lumacaftor/ivacaftor, compared to 4.9% for patients who received placebo. Decreased in heart rate observed in clinical studies were not considered clinically relevant.

Cataracts.

Cases of non-congenital lens opacities without impact on vision have been reported in paediatric patients treated with Orkambi and ivacaftor monotherapy. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in paediatric patients initiating treatment with Orkambi.

Patients after organ transplantation.

Orkambi has not been studied in patients with CF who have undergone organ transplantation. Therefore, use in transplanted patients is not recommended. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) for interactions with ciclosporin or tacrolimus.

Interactions with medicinal products.

Based on exposure and indicated doses, the drug interaction profile is considered to be the same for all dosage strengths and forms.

Substrates of CYP3A.

Lumacaftor is a strong inducer of CYP3A. Administration of Orkambi may decrease systemic exposure of medicinal products which are substrates of CYP3A, which may decrease their therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Orkambi may substantially decrease hormonal contraceptive exposure, reducing effectiveness. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with Orkambi (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Strong CYP3A inducers.

Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of Orkambi with strong CYP3A inducers, such as rifampicin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of Orkambi. Therefore, co-administration with strong CYP3A inducers (e.g. rifampicin, St. John's wort [Hypericum perforatum]) is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in renal impairment.

Caution is recommended while using Orkambi in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease (see Section 4.2 Dose and Method of Administration, Use in renal insufficiency; Section 5.2 Pharmacokinetic Properties, Renal impairment).

Use in the elderly.

Clinical studies of Orkambi did not include patients aged 65 years and older. Thus, the efficacy and safety of Orkambi in elderly patients have not been evaluated.

Paediatric use.

The data to support use in 6-11 years included pivotal clinical studies in patients 12 years and older with a partial extrapolation to children (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Limited data is available in children aged less than 6 years of age.

Effects on laboratory tests.

See Section 4.4 Special Warnings and Precautions for Use, Hepatobiliary events.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Lumacaftor is a strong inducer of CYP3A. Ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. The net effect of lumacaftor/ivacaftor therapy is expected to be strong CYP3A induction.
Drug interaction studies were performed in adults with lumacaftor/ivacaftor and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies.

Effects of other medicines on lumacaftor/ivacaftor.

CYP3A inhibitors.

Co-administration of lumacaftor/ivacaftor with itraconazole, a strong CYP3A inhibitor, did not impact the exposure of lumacaftor, but increased ivacaftor exposure by 4.3-fold. Due to the induction effect of lumacaftor on CYP3A, at steady-state, the net exposure of ivacaftor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg every 12 hours, the approved dose of ivacaftor monotherapy. Therefore, no dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking Orkambi.
However, when initiating Orkambi in patients currently taking strong CYP3A inhibitors, the dose should be reduced as per Section 4.2 Dose and Method of Administration, Use in combination with strong CYP3A inhibitors.
Examples of strong CYP3A inhibitors include: ketoconazole, itraconazole, posaconazole, voriconazole; telithromycin, clarithromycin.
No dose adjustment is recommended when used with moderate or weak CYP3A inhibitors.

CYP3A inducers.

Co-administration of lumacaftor/ivacaftor with rifampicin, a strong CYP3A inducer, had minimal effect on the exposure of lumacaftor, but decreased ivacaftor exposure (AUC) by 57%. Therefore, co-administration of Orkambi is not recommended with strong CYP3A inducers such as: rifampicin, rifabutin; phenobarbital, carbamazepine, and phenytoin; St. John's wort (Hypericum perforatum).
No dose adjustment is recommended when used with moderate or weak CYP3A inducers.
Other recommendations.

Ciprofloxacin.

Co-administration of lumacaftor/ivacaftor with ciprofloxacin had minimal to mild effect on exposures of lumacaftor and ivacaftor. Therefore, no dose adjustment is required when Orkambi is used with ciprofloxacin.

Effects of lumacaftor/ivacaftor on other medicines.

CYP3A and P-gp substrates.

Lumacaftor is a strong inducer of CYP3A. Co-administration of lumacaftor with ivacaftor, a sensitive CYP3A substrate, decreased ivacaftor exposure by approximately 80%.
Administration of Orkambi may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect of the medicinal product. Co-administration of Orkambi is not recommended with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index such as: midazolam, triazolam; ciclosporin, everolimus, sirolimus, and tacrolimus.
Based on in vitro results which showed P-gp inhibition and pregnane-X-receptor (PXR) activation, lumacaftor has the potential to both inhibit and induce P-gp. Additionally, a clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of Orkambi with P-gp substrates may alter the exposure of these substrates. When co-administration with sensitive P-gp substrates such as digoxin is required, caution and appropriate monitoring are recommended.

CYP2B6 and CYP2C substrates.

In vitro studies suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; however, inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in vitro studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of Orkambi with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates. When coadministration is required, monitoring is recommended, such as the international normalised ratio with warfarin.

Established and other potentially significant drug interactions.

Table 3 provides the established or predicted effect of lumacaftor/ivacaftor on other medicinal products or the effect of other medicinal products on lumacaftor/ivacaftor. The information reported in Table 3 mostly derives from in vitro studies. The recommendations provided under "Clinical comment" in Table 3 are based on drug interaction studies, clinical relevance, or predicted interactions due to elimination pathways. Drug interactions that have the most clinical relevance are listed first.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Lumacaftor had no effects on fertility and reproductive performance indices in male and female rats at an oral dose of 1000 mg/kg/day [approximately 3 and 6.5 times, respectively, the maximum recommended human dose (MRHD) of the lumacaftor component of Orkambi on an AUC basis].
Ivacaftor impaired fertility and reproductive performance indices in male and female rats at an oral dose of 200 mg/kg/day (yielding approximately 15 and 7 times, respectively, the systemic exposure anticipated in patients at the maximum recommended human dose (MRHD) of the ivacaftor component of Orkambi based on summed AUCs of ivacaftor and its major metabolites) when dams were dosed prior to and during early pregnancy. The pregnancy rate was decreased, oestrus cycling was disrupted and pre-implantation loss was increased. These effects occurred in the presence of significant maternal toxicity. No effects on male or female fertility and reproductive performance indices were observed at ≤ 100 mg/kg/day (yielding approximately 8 and 5 times, respectively, the exposure at the MRHD of the ivacaftor component of Orkambi based on summed AUCs of ivacaftor and its metabolites).
(Category B3)
Category B3 drugs have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
No adequate and well-controlled studies of Orkambi in pregnant women have been conducted. Adverse effects on embryofetal development have been observed in studies in animals, conducted with the individual active components. Lumacaftor, ivacaftor, and/or their metabolites were shown to cross the placenta in rats and rabbits.
Lumacaftor produced no teratogenicity or other adverse effects on embryofetal development in rats receiving oral doses up to 2000 mg/kg/day (yielding 8 times the plasma AUC for lumacaftor in patients at the maximum recommended dose) or in rabbits at up to 100 mg/kg/day (relative exposure based on AUC, 3). At 200 mg/kg/day, treatment with lumacaftor was associated with abortions and a slight increase in the incidence of minor skeletal abnormalities in rabbits (relative exposure based on AUC, 5). This occurred in conjunction with significant maternal toxicity, and the findings are not considered to reflect a direct effect of lumacaftor on the developing fetus.
Developmental toxicity studies with ivacaftor revealed no teratogenicity in rats at oral doses up to 200 mg/kg/day (yielding 7 times the summed AUC for ivacaftor and its major metabolites anticipated in patients) or in rabbits at up to 100 mg/kg/day (relative exposure based on summed AUCs, ≥ 4). Fetal weight was decreased and the incidence of minor fetal skeletal abnormalities was increased in rats treated at 200 mg/kg/day; these effects were observed in conjunction with maternal toxicity.
Because animal reproduction studies are not always predictive of human response, and given the limited experience with Orkambi in pregnancy, Orkambi should only be used during pregnancy if the expected benefits justify the potential risks to the fetus.
It is unknown whether lumacaftor and/or ivacaftor and metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of both lumacaftor and ivacaftor into the milk of lactating female rats. As such, risks to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from lumacaftor/ivacaftor therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.

4.7 Effects on Ability to Drive and Use Machines

Orkambi is not expected to have an impact on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Experience from clinical trials.

The safety profile of Orkambi is based primarily on the pooled data from 1108 patients with CF 12 years and older who are homozygous for the F508del mutation in the CFTR gene and who received at least 1 dose of study drug in two double-blind, placebo-controlled, Phase 3 clinical studies, each with 24 weeks of treatment [Study 809-103 (TRAFFIC) and Study 809-104 (TRANSPORT)]. A total of 738 patients received lumacaftor/ivacaftor (369 patients received lumacaftor 400 mg q12h in combination with ivacaftor 250 mg q12h and 369 patients received lumacaftor 600 mg qd in combination with ivacaftor 250 mg q12h) and 370 patients received placebo. Of the 1108 patients, 49% were female and 99% were Caucasian.
The proportion of patients who prematurely discontinued study drug due to adverse events was 4.2% for lumacaftor/ivacaftor-treated patients and 1.6% for placebo-treated patients. The only adverse events which resulted in discontinuation in at least 0.5% of patients receiving lumacaftor/ivacaftor were increased blood creatine phosphokinase (0.5%) and hepatobiliary events (0.5%).
The most common adverse effects reactions experienced by patients who received lumacaftor/ivacaftor in the pooled, placebo-controlled, Phase 3 studies were dyspnoea (14.0% versus 7.8% on placebo), diarrhoea (11.0% versus 8.4% on placebo), and nausea (10.2% versus 7.6% on placebo).
The only serious adverse reactions occurring in at least 0.5% of patients on lumacaftor/ivacaftor and greater than placebo were hepatobiliary events, including 4 reported as transaminase elevations, 2 as cholestatic hepatitis, and 1 as hepatic encephalopathy.
Table 4 shows adverse events-effects with an incidence of at least 10% in any treatment group from the two double-blind, placebo-controlled, Phase 3 clinical studies.

Tabulated list of adverse reactions.

Adverse reactions identified in patients aged 6 years and older who are homozygous for the F508del mutation in the CFTR gene are presented in Table 5 and are listed by system organ class, preferred term, and frequency. Adverse reactions are ranked under the MedDRA frequency classification: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (frequency cannot be estimated using the available data).

Safety data from a 96-week rollover extension study [Study 809-105 (PROGRESS)] in 1029 patients aged 12 years and older who were homozygous for the F508del mutation in the CFTR gene, were consistent with in Studies 809-103 (TRAFFIC) and 809-104 (TRANSPORT) (see Section 5.1 Pharmacodynamic Properties). The respiratory events in treatment naïve patients who were initiated on Orkambi in Study 809-105 (PROGRESS) were comparable to those who were initiated on Orkambi in preceding Studies 809-103 (TRAFFIC) and 809-104 (TRANSPORT).

Studies in patients aged 6 through 11 years.

The safety profile observed in studies in patients 6-11 years old [Study 809-109 and 809-011 (Part B)] was similar to that observed in Studies 809-103 (TRAFFIC) and 809-104 (TRANSPORT).
Adverse reactions that are not listed in Table 5, and that occurred in ≥ 5% of lumacaftor/ivacaftor-treated patients with an incidence of ≥ 3% higher than placebo (Study 809-11(Part B) included: productive cough (17.5% vs. 5.9%), nasal congestion (16.5% vs. 7.9%), headache (12.6% vs. 8.9%), abdominal pain upper (12.6% vs. 6.9%), and sputum increased (10.7% vs. 2.0%).
Safety data from a 96-week rollover extension study in 239 patients aged 6 years and older who were homozygous for the F508del mutation in the CFTR gene (Study 809-110) were generally consistent with Studies 809-109 and 809-011 (Part B) (see Section 5.1 Pharmacodynamic Properties).

Studies in patients aged 2 through 5 years.

In a 24-week, open-label, multicenter Phase 3 study in 60 patients aged 2 through 5 years with CF who are homozygous for the F508del-CFTR mutation (Study 809-115) the safety profile was generally consistent to that observed in studies in patients aged 6 years and older (see Section 5.1 Pharmacodynamic Properties).
Safety data from a 96-week rollover extension study in 57 patients aged 2 years and older who were homozygous for the F508del mutation in the CFTR gene (Study 809-116) were generally consistent with Study 809-115 and patients aged 6 years and older (see Section 5.1 Pharmacodynamic Properties).

Studies in patients aged 1 to less than 2 years.

The safety profile from a 24-week, open-label, multicenter Phase 3 study in 46 patients aged 1 to less than 2 years with CF who are homozygous for the F508del-CFTR mutation (Study 809-122) was generally consistent with the established safety profile of lumacaftor/ivacaftor observed in patients aged 2 years and older.

Detailed description of selected adverse reactions.

Hepatobiliary events.

Patients over 12 years of age.

During the 24-week, placebo-controlled, Phase 3 studies (Studies 809-103 (TRAFFIC) and 809-104 (TRANSPORT)), the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and > 3 x ULN was 0.8%, 2.0%, and 5.2% in the patients receiving lumacaftor/ivacaftor, and 0.5%, 1.9%, and 5.1% in the placebo-treated patients. The incidence of transaminase-related adverse drug reactions was 5.1% and 4.6% in lumacaftor/ivacaftor-treated patients and those who received placebo, respectively. Seven patients who received lumacaftor/ivacaftor had liver-related serious adverse events with elevated transaminases, including 3 with concurrent elevation in total bilirubin. Following discontinuation of lumacaftor/ivacaftor, liver function tests returned to baseline or improved substantially in all patients. While alternative etiologies were present, the potential for liver injury associated with lumacaftor/ivacaftor cannot be excluded (see Section 4.4 Special Warnings and Precautions for Use).
Among seven patients with pre-existing cirrhosis and/or portal hypertension who received lumacaftor/ivacaftor in the placebo-controlled Phase 3 studies, worsening liver function with increased ALT, AST, bilirubin, and hepatic encephalopathy was observed in one patient. The event occurred within 5 days of the start of dosing and resolved following discontinuation of lumacaftor/ivacaftor (see Section 4.4 Special Warnings and Precautions for Use).

Patients aged 6 through 11 years.

Abnormal transaminases were more commonly observed in children.
During the 24-week, open-label Phase 3 clinical study in 58 patients aged 6 through 11 years (Study 809-011 (Part B)), the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and > 3 x ULN was 5.3%, 8.8%, and 19.3%. No patients had an increase in total bilirubin levels > 2 x ULN. Lumacaftor/ivacaftor dosing was maintained or successfully resumed after interruption in all patients with transaminase elevations, except 1 patient who discontinued treatment.
During the 24 week, placebo-controlled Phase 3 clinical study in 204 patients aged 6 through 11 years (Study 809-109), the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and > 3 x ULN was 1.0%, 4.9%, and 12.6% in the lumacaftor/ivacaftor patients, and 2.0%, 3.0%, and 7.9% in the placebo treated patients. No patients had total bilirubin levels > 2 x ULN. Two patients in the lumacaftor/ivacaftor group and two patients in the placebo group discontinued treatment due to transaminase elevations.

Patients aged 2 through 5 years.

During the 24-week, open-label Phase 3 clinical study in 60 patients aged 2 through 5 years (Study 809-115), the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and > 3 x ULN was 8.3% (5/60), 11.7% (7/60), and 15.0% (9/60). No patients had total bilirubin levels > 2 x ULN. Three patients discontinued lumacaftor/ivacaftor treatment due to transaminase elevations.

Patients aged 1 to less than 2 years.

During the 24-week, open-label Phase 3 clinical study in 46 patients aged 1 to less than 2 years (Study 809-122), the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and > 3 x ULN was 2.2% (1/46), 4.3% (2/46), and 10.9% (5/46), respectively. No patients had total bilirubin levels > 2 x ULN. One patient discontinued lumacaftor/ivacaftor treatment due to transaminase elevations.
Respiratory events.

Patients over 12 years of age.

During the 24-week, placebo-controlled, Phase 3 studies [Studies 809-103 (TRAFFIC) and 809-104 (TRANSPORT)], incidence of respiratory adverse reactions (e.g. chest discomfort, dyspnoea, and respiration abnormal such as respiratory chest tightness) was 26.3% in lumacaftor/ivacaftor-treated patients compared to 17.0% in patients who received placebo. The incidence of these events were more common in patients treated with lumacaftor/ivacaftor with lower pre-treatment FEV₁. Approximately three-quarters of the events began during the first week of treatment, and in most patients the events resolved without dosing interruption. The majority of events were mild or moderate in severity, non-serious, and did not result in treatment discontinuation.
During a 24-week, open label, Phase 3b clinical study (Study 809-106) in 46 patients aged 12 years and older with advanced lung disease (ppFEV₁ < 40) [mean ppFEV₁ 29.1 at baseline (range: 18.3 to 42.0)], the incidence of respiratory events was 65.2%. In the subgroup of 28 patients who were initiated at the full dose of lumacaftor/ivacaftor (2 tablets every 12 hours), the incidence was 71.4%, and in the 18 patients who were initiated at a reduced dose of lumacaftor/ivacaftor (1 tablet every 12 hours for up to 2 weeks, and subsequently increased to the full dose), the incidence was 55.6%. Of the patients who were initiated lumacaftor/ivacaftor at the full dose, one patient had a serious respiratory event, three patients subsequently had their dose reduced, and three patients discontinued treatment. No serious respiratory events, dose reductions or discontinuations were seen in patients who were initiated at the half dose (see Section 4.4 Special Warnings and Precautions for Use).

Patients aged 6 through 11 years.

During the 24-week, open-label Phase 3 clinical study (Study 809-011 (Part B)) in 58 patients aged 6 through 11 years (mean baseline ppFEV₁ was 91.4), the incidence of respiratory adverse reactions was 6.9% (4/58).
During the 24 week, placebo-controlled Phase 3 clinical study (Study 809-109) in patients aged 6 through 11 years (mean baseline ppFEV₁ was 89.8), the incidence of respiratory adverse reactions was 18.4% in lumacaftor/ivacaftor patients and 12.9% in placebo patients. A decline in ppFEV₁ at initiation of therapy was observed during serial post dose spirometry assessments. The absolute change from pre-dose at 4-6 hours post-dose was -7.7 on Day 1 and -1.3 on Day 15 in lumacaftor/ivacaftor patients. The post-dose decline was resolved by Week 16.
Menstrual abnormalities. During the 24 week, placebo-controlled, Phase 3 studies, the incidence of combined menstrual abnormality events (amenorrhoea, dysmenorrhoea, menorrhagia, menstruation irregular, metrorrhagia, oligomenorrhoea, and polymenorrhoea) was 9.9% in lumacaftor/ivacaftor-treated female patients and 1.7% in placebo-treated females. These menstrual events occurred more frequently in the subset of female patients who were taking hormonal contraceptives (25.0%) compared to patients who were not taking hormonal contraceptives (3.5%) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Most of these reactions were mild or moderate in severity and non-serious.
Increased blood pressure. During the 24-week, placebo-controlled, Phase 3 studies [Study 809-103 (TRAFFIC) and 809-104 (TRANSPORT)], adverse reactions related to increased blood pressure (e.g. hypertension, blood pressure increased) were reported in 0.9% (7/738) of patients treated with lumacaftor/ivacaftor and in no patients who received placebo.
In patients treated with lumacaftor/ivacaftor the maximum increase from baseline (114 mmHg systolic and 69 mmHg diastolic) in mean systolic and diastolic blood pressure was 3.1 mmHg and 1.8 mmHg, respectively. In patients who received placebo the maximum increase from baseline (114 mmHg systolic and 69 mmHg diastolic) in mean systolic and diastolic blood pressure was 0.9 mmHg and 0.9 mmHg, respectively.
The proportion of patients who experienced a systolic blood pressure value > 140 mmHg or a diastolic blood pressure > 90 mmHg on at least two occasions was 3.4% and 1.5% in patients treated with lumacaftor/ivacaftor, respectively, compared with 1.6% and 0.5% in patients who received placebo (see Section 4.4 Special Warnings and Precautions for Use).

Post-marketing experience.

Hepatic impairment. Post-marketing cases of liver function decompensation including liver failure leading to death have been reported in CF patients with pre-existing cirrhosis with portal hypertension who were treated with lumacaftor/ivacaftor (see Section 4.4 Special Warnings and Precautions for Use).
Respiratory events. Post-marketing reports of respiratory events were more common in patients with lower ppFEV₁. Some of these events were serious and led to lumacaftor/ivacaftor treatment discontinuation (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
No specific antidote is available for overdose with Orkambi. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. The F508del mutation impacts the CFTR protein in multiple ways, primarily by causing a defect in cellular processing and trafficking that reduces the quantity of CFTR at the cell surface. The small amount of F508del-CFTR that reaches the cell surface has low channel open probability (defective channel gating). Lumacaftor is a CFTR corrector that acts directly on F508del-CFTR to improve its cellular processing and trafficking, thereby increasing the quantity of functional CFTR at the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel open probability (or gating) of the CFTR protein at the cell surface. The combined effect of lumacaftor and ivacaftor is increased quantity and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport.

Effects on sweat chloride.

Changes in sweat chloride in response to lumacaftor/ivacaftor were evaluated in a 24-week, open-label Phase 3 clinical study [Study 809-011 (Part B)] and as part of a 24-week, placebo-controlled Phase 3 clinical study (Study 809-109) in patients with CF, aged 6 through 11 years old who were homozygous for the F508del mutation in the CFTR gene. There was no direct correlation between the decrease in sweat chloride levels and improvement in lung function.
In Study 809-011 (Part B), treatment with lumacaftor/ivacaftor lumacaftor 200 mg/ivacaftor 250 mg q12h for 24 weeks, demonstrated a reduction in sweat chloride as early as Day 15 that was sustained through Week 24. The within-group least square (LS) mean absolute change from baseline in sweat chloride was -20.4 mmol/L (95% CI: -23.9, -16.9; P < 0.0001) at Day 15 and -24.8 mmol/L (95% CI: -29.1, -20.5; P < 0.0001) at Week 24. In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The within-group LS mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was 21.3 mmol/L (95% CI: 18.6, 24.0; P < 0.0001). This change represents a return to baseline after treatment washout.
In Study 809-109, treatment with lumacaftor 200 mg/ivacaftor 250 mg q12h for 24 weeks demonstrated a decrease in sweat chloride compared to placebo that was sustained through 24 weeks of treatment. The treatment difference (LS mean) in sweat chloride for the average absolute change at Day 15 and at Week 4 as compared to placebo was -20.8 mmol/L (95% CI: -23.4, -18.2). The treatment difference (LS mean) in sweat chloride for the absolute change at Week 24 as compared to placebo was -24.9 mmol/L.
Changes in sweat chloride in response to lumacaftor/ivacaftor were evaluated in a 24-week, open label Phase 3 clinical study (Study 809-115) in 60 patients with CF, aged 2 through 5 years (homozygous for F508del) who received either lumacaftor 100 mg/ivacaftor 125 mg every 12 hours or lumacaftor 150 mg/ivacaftor 188 mg every 12 hours for 24 weeks. Treatment with lumacaftor/ivacaftor demonstrated a reduction in sweat chloride at Week 4 through Week 24. The mean absolute change from baseline in sweat chloride was -31.7 mmol/L (95% CI: -35.7, -27.6; P < 0.0001) at Week 24. In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was an increase of 33.0 mmol/L (95% CI: 28.9, 37.1; P < 0.0001). This change represents a return to baseline after treatment washout.
Changes in sweat chloride in response to lumacaftor/ivacaftor were evaluated in a 24 week, open label Phase 3 clinical study (Study 809-122) in 46 patients with CF, aged 1 to less than 2 years (homozygous for F508del) who received lumacaftor 75 mg/ivacaftor 94 mg (patient weighing 7 kg to < 9 kg at screening), lumacaftor 100 mg/ivacaftor 125 mg (patient weighing 9 kg to < 14 kg at screening), lumacaftor 150 mg/ivacaftor 188 mg (patient weighing ≥ 14 kg at screening), every 12 hours for 24 weeks. Treatment with lumacaftor/ivacaftor demonstrated a reduction in sweat chloride at Week 4 which was sustained through Week 24. The mean absolute change from baseline in sweat chloride at Week 24 was -29.1 (13.5) mmol/L (95% CI: -34.8, -23.4). In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The mean (SD) absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was 27.3 (11.1) mmol/L (95% CI: 22.3, 32.3). This change represents a return towards baseline after treatment washout.

Clinical trials.

Studies 809-103 (TRAFFIC) and 809-104 (TRANSPORT) in patients with CF who are homozygous for the F508del mutation in the CFTR gene. The efficacy of Orkambi in patients with CF who are homozygous for the F508del mutation in the CFTR gene was evaluated in two randomised, double-blind, placebo-controlled clinical trials of 1108 clinically stable patients with CF, in which 737 patients were randomised to and dosed with lumacaftor/ivacaftor. Patients in both trials were randomised 1:1:1 to receive lumacaftor 600 mg once daily/ivacaftor 250 mg q12h; lumacaftor 400 mg q12h/ivacaftor 250 mg q12h; or placebo. Patients took the study drug with fat-containing food for 24 weeks in addition to their prescribed CF therapies (e.g. bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). Patients from these trials were eligible to roll over into a blinded extension study.
Study 809-103 (TRAFFIC) evaluated 549 patients with CF who were aged 12 years and older (mean age 25.1 years) with percent predicted FEV₁ (ppFEV₁) at screening between 40-90 [mean ppFEV₁ 60.7 at baseline (range: 31.1 to 94.0)]. Study 809-104 (TRANSPORT) evaluated 559 patients aged 12 years and older (mean age 25.0 years) with ppFEV₁ at screening between 40-90 [mean ppFEV₁ 60.5 at baseline (range: 31.3 to 99.8)]. Patients with a history of colonisation with organisms associated with a more rapid decline in pulmonary status such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus, or who had 3 or more abnormal liver function tests at screening (ALT, AST, AP, GGT ≥ 3 times the ULN or total bilirubin ≥ 2 times the ULN) were excluded.
The primary efficacy endpoint in both studies was the absolute change from baseline in ppFEV₁ at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24. Other efficacy variables included relative change from baseline in ppFEV₁ at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24; absolute change from baseline in BMI at Week 24; absolute change from baseline in CFQ-R Respiratory Domain at Week 24; the proportion of patients achieving ≥ 5% relative change from baseline in ppFEV₁ using the average of Week 16 and Week 24; and number of pulmonary exacerbations (including those requiring hospitalisation or IV antibiotic therapy) through Week 24.
In both studies, treatment with Orkambi resulted in a statistically significant improvement in ppFEV₁ (Table 6). The treatment difference between lumacaftor/ivacaftor 400 mg/250 mg q12h and placebo for the mean absolute change (95% CI) in ppFEV₁ from baseline at Week 24 (assessed as the average of the treatment effects at Week 16 and at Week 24) was 2.6 percentage points (1.2, 4.0) in Study 809-103 (TRAFFIC) (P=0.0003) and 3.0 percentage points (1.6, 4.4) in Study 809-104 (TRANSPORT) (P < 0.0001). Mean improvement in ppFEV₁ was rapid in onset (Day 15) and sustained throughout the 24-week treatment period (Figure 1). Improvements in ppFEV₁ were observed regardless of age, disease severity, sex, and geographic region. The Phase 3 trials of lumacaftor/ivacaftor included 81 patients with ppFEV₁ < 40 at baseline (including 29 who received lumacaftor 400 mg/ivacaftor 250 mg q12h). The treatment difference in this subgroup was comparable to that observed in patients with ppFEV₁ ≥ 40. See Table 6 for a summary of primary and key secondary outcomes in Studies 809-103 and 809-104.

At Week 24, the proportion of patients who remained free from pulmonary exacerbations was significantly higher for patients treated with Orkambi compared with placebo. In the pooled analysis, the rate ratio of exacerbations through Week 24 in subjects treated with lumacaftor 400 mg/ivacaftor 250 mg q12h; (n = 369) was 0.61 (P < 0.0001), representing a reduction relative to placebo of 39%. The event rate per year, annualised to 48 weeks, was 0.70 in the active group and 1.14 in the placebo group. Treatment with Orkambi significantly decreased the risk for exacerbations requiring hospitalisation vs. placebo by 61% (rate ratio=0.39, P < 0.0001; event rate per 48 weeks was 0.17 for active and 0.45 for placebo) and reduced exacerbations requiring treatment with intravenous antibiotics by 56% (rate ratio=0.44, P < 0.0001; event rate per 48 weeks 0.25 for active and 0.58 for placebo). See Figure 2.

Study 809-102, cohort 4: patients with CF who are heterozygous for the F508del mutation in the CFTR gene. Study 809-102 was a multicenter, double-blind, randomised, placebo-controlled, Phase 2 trial in 125 patients with CF aged 18 years and older who had a ppFEV₁ of 40 to 90, inclusive. All patients were tested for the CF genotype at screening; eligible patients had the F508del mutation on one allele plus a second allele with a mutation predicted to result in the lack of CFTR production or a CFTR that is not responsive to ivacaftor in vitro.
Patients received either Orkambi (n=62) or placebo (n=63) q12h in addition to their prescribed CF therapies. The median age of patients enrolled was 28 years and the mean baseline ppFEV₁ was 61.47. Patients with a history of colonisation with organisms such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus, or who had 3 or more abnormal liver function tests (ALT, AST, AP, GGT ≥ 3 times the ULN or total bilirubin ≥ 2 times the ULN) were excluded.
The primary endpoint was improvement in lung function as determined by the mean absolute change from baseline at Day 56 in ppFEV₁. Treatment with Orkambi resulted in no significant improvement in ppFEV₁ relative to placebo in patients with CF heterozygous for the F508del mutation in the CFTR gene [treatment difference 0.60 (P=0.5978)]. There were no meaningful differences between patients treated with Orkambi compared to placebo for the following secondary endpoints: relative change in ppFEV₁, BMI, and weight; however, there was a nominally statistically significant change in the CF respiratory symptom score.
Study 809-105: long-term safety and efficacy rollover trial. Study 809-105 (PROGRESS), a Phase 3, parallel-group, multicenter, rollover extension study was conducted in patients with CF aged 12 years and older, that included patients from Study 809-103 1 (TRAFFIC) and Study 809-104 (TRANSPORT). This 96 week extension study was designed to evaluate the safety and efficacy of long-term treatment of lumacaftor/ivacaftor. Of the 1108 patients who received any treatment in Study 809-103 1 (TRAFFIC) or Study 809-104 (TRANSPORT), 1029 patients (93%) were dosed and received active treatment in Study 809-105 (PROGRESS) for up to an additional 96 weeks (i.e. up to a total of 120 weeks). A total of 82% (421 of 516 eligible patients) completed 72 weeks of this study; 42% completed 96 weeks. Majority of patients discontinued for reasons other than safety. The efficacy analysis of this extension study included data up to Week 72 with a sensitivity analysis that included data up to Week 96.
The absolute change in ppFEV₁ observed in patients treated with Orkambi in Study 809-103 (TRAFFIC) or Study 809-104 (TRANSPORT) remained above baseline at week 72 (LS mean 0.5, 95% CI -0.4 to 1.5). In patients who transitioned from placebo to Orkambi, an improvement in ppFEV₁ was observed on initiation of active treatment which was maintained above baseline through week 72 (LS mean change 1.5, 95% CI 0.2 to 2.9). At week 96 the LS mean change in ppFEV₁ for patients continuing Orkambi was 0.5, 95% CI -0.7 to 1.6 and for patients transitioning from placebo to Orkambi was 0.8, 95% CI -0.8 to 2.3 (Figure 3).

Patients treated with Orkambi for 24 weeks in Study 809-103 (TRAFFIC) or Study 809-104 (TRANSPORT) continued to show improvement in BMI through Study 809-105 (PROGRESS). At baseline the BMI (SD) was 21.5 kg/m² (3.0). At week 72, the LS mean of absolute change from baseline was 0.69 (95% CI 0.56-0.81) in patients who remained on Orkambi and in patients who transitioned to Orkambi, was 0.62 (95% CI 0.45-0.79). Similar improvement in BMI was observed up to week 96 in both treatment groups (Figure 4).

The absolute change in CFQ-R respiratory domain score (points) for patients treated with Orkambi for 24 weeks in Study 809-103 (TRAFFIC) or Study 809-104 (TRANSPORT) remained above baseline at week 72 (LS mean was 5.7, 95% CI 3.8 to 7.5). For patients who transitioned to Orkambi, a similar initial response was observed, with improvement at week 72 (LS mean 3.3, 95% CI 0.7 to 5.9). Mean respiratory domain score remained above pretreatment baseline in both groups up to week 96 (Figure 5).

Through extension Week 96, the annualized rate (to 48 weeks) of pulmonary exacerbations remained low in patients that continued on Orkambi from Study 809-103 (TRAFFIC) or Study 809-104 (TRANSPORT) (0.65, 95% CI 0.56-0.75 events per patient year). For patients who transitioned from placebo to active treatment, the rate was reduced to a similar level (0.69, 95% CI 0.56-0.85). Similarly, the subsets of pulmonary exacerbations that required hospital admission remained low in patients that continued on Orkambi from Study 809-103 (TRAFFIC) or Study 809-104 (TRANSPORT) (0.24, 95% CI 0.19-0.29 events per patient year). For patients who transitioned from placebo to active treatment, the rate was reduced to a similar level (0.30, 95% CI 0.22-0.40). The subsets of pulmonary exacerbations that required intravenous antibiotics remained low in patients that continued on Orkambi from Study 809-103 or Study 809-104 (0.32, 95% CI 0.26-0.38 events per patient year). For patients who transitioned from placebo to active treatment, the rate was reduced to a similar level (0.37, 95% CI 0.29-0.49) (Figure 6).

Studies in patients aged 6 through 11 years.

The pharmacokinetic profile, safety, and efficacy of lumacaftor/ivacaftor in patients aged 6 through 11 years with CF who are homozygous for the F508del mutation in the CFTR gene are supported by a partial extrapolation from adequate and well-controlled studies of lumacaftor/ivacaftor in patients 12 years and older [Study 809-103 (TRAFFIC) and Study 809-104 (TRANSPORT)], with additional data from two 24-week (an open-label, Phase 3 clinical study in 58 patients aged 6 through 11 years and a placebo-controlled, Phase 3 clinical study in 204 patients with CF aged 6 through 11 years).
Study 809-109: study in patients 6 through 11 years old with CF who are homozygous for the F508del mutation in the CFTR gene. Study 809-109 was a 24-week, placebo-controlled, Phase 3 clinical study in 204 patients with CF aged 6 through 11 years old (mean age 8.8 years). Study 809-109 evaluated subjects with lung clearance index (LCI_2.5) ≥ 7.5 at the initial screening visit (mean LCI_2.5 10.28 at baseline [range: 6.55 to 16.38]) and ppFEV₁ ≥ 70 at screening (mean ppFEV₁ 89.8 at baseline [range: 48.6 to 119.6]). Lung Clearance Index (LCI) is a measure of lung function via exhalation and removal of a tracer gas and is calculated using multiple breath washout (MBW) technique. LCI is sensitive for early disease progression and small airway abnormalities.
Patients received either lumacaftor 200 mg/ivacaftor 250 mg every 12 hours (N=103) or placebo (N=101) in addition to their prescribed CF therapies. Patients who had 2 or more abnormal liver function tests (ALT, AST, AP, GGT ≥ 3 times the ULN), or ALT or AST > 5 times ULN, or total bilirubin > 2 times ULN were excluded.
The primary efficacy endpoint was absolute change in LCI_2.5 from baseline through Week 24. Key secondary endpoints included average absolute change from baseline in sweat chloride at Day 15 and Week 4 and at Week 24 (see Section 5.1 Pharmacodynamic Properties), absolute change from baseline in BMI at Week 24, absolute change from baseline in CFQ-R Respiratory Domain through Week 24. These results are presented in Table 7.

Study 809-011 (part B): safety and tolerability study in paediatric patients with CF aged 6 through 11 years homozygous for the F508del mutation in the CFTR gene. Study 809-011 evaluated subjects aged 6 through 11 years at screening, with a screening ppFEV₁ ≥ 40 and weight > 15 kg. Subjects had a mean baseline ppFEV₁ of 91.4 (range: 55 to 122.7) and a mean baseline LCI_2.5 of 9.99.
Patients were administered lumacaftor 200 mg/ivacaftor 250 mg every 12 hours with fat-containing food for 24 weeks in addition to their prescribed CF therapies (e.g. bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). In order to evaluate off drug effects, patients had a safety follow-up visit following a 2-week washout period.
Secondary endpoints evaluated were average absolute change from baseline in sweat chloride at Day 15 and Week 4 (see Section 5.1 Pharmacodynamic Properties), absolute change from baseline in weight, body mass index (BMI), height and their z-scores, Cystic Fibrosis Questionnaire-Revised (CFQ-R) at 24 weeks of treatment, and absolute change in sweat chloride from Week 24 at Week 26. Lung Clearance Index (LCI_2.5) was assessed as an exploratory endpoint. Spirometry (ppFEV₁) was assessed as a planned safety endpoint. These results are presented in Table 8.

Study 809-110: long-term safety and efficacy rollover trial. Study 809-110 was a Phase 3, parallel-group, multicenter, rollover extension study in patients with CF that included patients aged 6 years and older from Studies 809-109 and 809-011 (Part B). This extension trial was designed to evaluate the safety and efficacy of long-term treatment of lumacaftor/ivacaftor. Of the 262 patients who received any treatment in Studies 809-109 and 809-011 (Part B), 239 (91%) were dosed and received active treatment (lumacaftor 200 mg q12h/ivacaftor 250 mg q12h or lumacaftor 400 mg q12h/ivacaftor 250 mg q12h) in Study 809-110 for up to an additional 96 weeks (i.e. up to a total of 120 weeks).
Patients treated with lumacaftor/ivacaftor in Studies 809-109 or 809-011 (Part B) showed that the effect on secondary efficacy endpoints was consistent with parent studies, from Studies 809-109 and 809-011 (Part B) baseline after an additional 96 weeks through Study 809-110. For patients who transitioned from placebo to active treatment, similar effects on secondary efficacy endpoints as those observed in patients treated with lumacaftor/ivacaftor in parent Study 809-109 or 809-011 (Part B) were seen.
Study 809-115: safety and tolerability study in paediatric patients with CF aged 2 through 5 years homozygous for the F508del mutation in the CFTR gene. Study 809-115 evaluated 60 patients aged 2 through 5 years for 24 weeks. Patients were administered granules every 12 hours, at a dose of lumacaftor 100 mg/ivacaftor 125 mg granules for patients weighing less than 14 kg or lumacaftor 150 mg/ivacaftor 188 mg for patients weighing 14 kg or greater, in addition to their prescribed CF therapies. Secondary endpoints are included in Table 9. PK effects are described in Table 11; effects on sweat chloride are described in Section 5.1 Pharmacodynamic Properties; safety data are described in Section 4.8 Adverse Effects (Undesirable Effects).

Study 809-116: long-term safety and pharmacodynamic rollover study. Study 809-116 was a Phase 3, open-label, multicenter, rollover extension study in patients with CF that included patients aged 2 years and older from Study 809-115. This study was designed to evaluate the safety and pharmacodynamics of long-term treatment of lumacaftor/ivacaftor. Of the 60 patients who received any treatment in Study 809-115, 57 were dosed and received active treatment (lumacaftor 100 mg/ivacaftor 125 mg q12h, lumacaftor 150 mg/ivacaftor 188 mg q12h, or lumacaftor 200 mg/ivacaftor 250 mg q12h depending on age and weight of the patient) in Study 809-116 for up to an additional 96 weeks (i.e. up to a total of 120 weeks).
Patients treated with lumacaftor/ivacaftor in Study 809-115 showed that the change in sweat chloride was maintained with respect to Study 809-115 baseline after an additional 96 weeks through Study 809-116. In addition, improvements in growth parameters (BMI, weight, stature and associated z-scores) were maintained through Study 809-116.
Study 809-122: safety and pharmacokinetic study in patients aged 1 to less than 2 years with CF who are homozygous for the F508del-CFTR mutation. Trial 122 was a single-arm, uncontrolled, trial evaluating the pharmacokinetic profile, pharmacodynamic effects and safety of lumacaftor/ivacaftor in 46 patients with CF aged 1 to less than 2 years (mean age at baseline 18.1 months). The pharmacodynamic effects observed in this study are similar to effects observed in patients aged 12 years and older (studies 809-103 and 809-104). The efficacy of lumacaftor/ivacaftor in patients aged 1 to less than 2 years is extrapolated from patients aged 12 years and older.
In Study 809-122 Part B the primary endpoint of safety and tolerability was evaluated across 24 weeks. Secondary endpoints evaluated were pharmacokinetics and absolute change from baseline in sweat chloride at Week 24. According to their weight at screening, patients were administered granules mixed with food every 12 hours for 24 weeks, at a dose of lumacaftor 75 mg/ivacaftor 94 mg granules (patients weighing 7 kg to < 9 kg) or lumacaftor 100 mg/ivacaftor 125 mg (patients weighing 9 kg to < 14 kg) or lumacaftor 150 mg/ivacaftor 188 mg (patients weighing ≥ 14 kg), in addition to their prescribed CF therapies. In order to evaluate off-drug effects, patients had a safety follow-up visit following a 2-week washout period.
Secondary endpoints included absolute change from baseline in sweat chloride at Week 24 (see Section 5.1 Pharmacodynamic Properties). Summary of additional endpoints listed in Table 10.

5.2 Pharmacokinetic Properties

Absorption.

Following multiple oral doses of lumacaftor given in combination with ivacaftor, the exposure of lumacaftor generally increased proportional to dose over the range of 200 mg to 800 mg every 24 hours. The exposure of lumacaftor increased approximately 2-fold when given with fat-containing food relative to fasted conditions. The median (range) t_max of lumacaftor is approximately 4.0 hours (2.0; 9.0) in the fed state.
Following multiple oral dose administration of ivacaftor in combination with lumacaftor, the exposure of ivacaftor generally increased with doses from 150 mg every 12 hours to 250 mg every 12 hours. The exposure of ivacaftor when given in combination with lumacaftor increased approximately 3-fold when given with fat-containing food. Therefore, Orkambi should be administered with fat-containing food. The median (range) t_max of ivacaftor is approximately 4.0 hours (2.0; 6.0) in the fed state.

Distribution.

Lumacaftor is more than 99% bound to plasma proteins, primarily to albumin. After oral administration of 400 mg every 12 hours in patients with CF in a fed state, the typical apparent volumes of distribution for the central and peripheral compartments (CV) were estimated to be 23.5 L (48.7%) and 33.3 L (30.5%), respectively.
Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. After oral administration of ivacaftor 250 mg every 12 hours in combination with lumacaftor, the typical apparent volumes of distribution for the central and peripheral compartments (CV) were estimated to be 95.0 L (53.9%) and 201 L (26.6%), respectively.

Metabolism.

Lumacaftor is not extensively metabolised in humans with the majority of lumacaftor excreted unchanged in the faeces. In vitro and in vivo data indicate that lumacaftor is mainly metabolised via oxidation and glucuronidation, with CYP3A4 and CYP2C8 involved. The main metabolite formed, M28, is not pharmacologically active.
Ivacaftor is extensively metabolised in humans. In vitro and in vivo data indicate that ivacaftor is primarily metabolised by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active.

Excretion.

Following oral administration of lumacaftor, the majority of lumacaftor (51%) is excreted unchanged in the faeces. There was negligible urinary excretion of lumacaftor as unchanged drug. The apparent terminal half-life is approximately 26 hours. The typical apparent clearance, CL/F (CV), of lumacaftor was estimated to be 2.38 L/hr (29.4%) for patients with CF.
Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the faeces after metabolic conversion. There was negligible urinary excretion of ivacaftor as unchanged drug. In healthy subjects, the half-life of ivacaftor when given with lumacaftor is approximately 9 hours. The typical CL/F (CV) of ivacaftor when given in combination with lumacaftor was estimated to be 25.1 L/hr (40.5%) for patients with CF.

Special populations.

The exposures are similar between adults and the paediatric population based on population pharmacokinetics (PK) analyses. Data for patients aged 1 to less than 18 years are presented in Table 11.

Hepatic impairment.

Following multiple doses of lumacaftor/ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had higher exposures (AUC_0-12hr by approximately 50% and C_max by approximately 30%) compared with healthy subjects matched for demographics. The impact of mild hepatic impairment (Child-Pugh Class A, score 5 to 6) on pharmacokinetics of lumacaftor given in combination with ivacaftor has not been studied, but the increase in exposure is expected to be less than 50% (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration.
Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C, score 10 to 15), but exposure is expected to be higher than in patients with moderate hepatic impairment. (See Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration).

Renal impairment.

Pharmacokinetic studies have not been performed with Orkambi in patients with renal impairment. In a human pharmacokinetic study with lumacaftor alone, there was minimal elimination of lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine with 0.18% as unchanged parent). In a human pharmacokinetic study with ivacaftor alone, there was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine) (see Section 4.2 Dose and Method of Administration).

Gender.

The effect of gender was evaluated using a population pharmacokinetics analysis of data from clinical studies of lumacaftor given in combination with ivacaftor. Results indicate no clinically relevant difference in pharmacokinetic parameters for lumacaftor and ivacaftor between males and females. No dose adjustments of Orkambi are necessary based on gender.

5.3 Preclinical Safety Data

Genotoxicity.

Both lumacaftor and ivacaftor were negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus test.

Carcinogenicity.

A two-year study in Sprague-Dawley rats and a 26-week study in transgenic Tg.rasH2 mice were conducted to assess the carcinogenic potential of lumacaftor. No evidence of tumourigenicity by lumacaftor was observed in rats at oral doses up to 1000 mg/kg/day (yielding approximately 5 and 13 times the plasma AUC for lumacaftor in patients at the MRHD in males and females, respectively). No evidence of tumourigenicity was observed in Tg.rasH2 mice at lumacaftor oral doses up to 1500 and 2000 mg/kg/day in female and male mice, respectively. Plasma exposures to lumacaftor in mice at these doses were approximately 5- and 3.5-fold higher than the plasma levels of lumacaftor measured in humans following lumacaftor/ivacaftor therapy.
Two-year studies in mice and rats to assess carcinogenic potential of ivacaftor demonstrated that ivacaftor was not carcinogenic in either species. Plasma exposures to ivacaftor in mice at the non-carcinogenic dose (200 mg/kg/day, the highest dose tested) were approximately 10- to 18-fold higher than the plasma levels measured in 6-11 years old children following Orkambi therapy, and at least 1.1- to 2.2-fold higher with respect to the summed AUCs for ivacaftor and its major metabolites. Plasma exposures to ivacaftor in rats at the non-carcinogenic dose (50 mg/kg/day, the highest dose tested) were approximately 41- to 74-fold higher than the plasma levels measured in humans following Orkambi therapy, and 6- to 8-fold higher with respect to the summed AUCs for ivacaftor and its major metabolites. As Orkambi therapy in ≥ 12 years old patients is associated with lower exposure to ivacaftor and its major metabolites than in 6-11 years old, higher exposure margins (increased by a factor of 1.6) apply to older children and adults.

Juvenile rats toxicity.

Cataracts were seen in juvenile rats treated with ivacaftor from postnatal Day 7 through 35 at oral dose levels of 10 mg/kg/day and higher, yielding exposure to ivacaftor and its major metabolites approximately 4-6.5 times lower than in 6-11 years old patients and 2.5-4 times lower than in older patients at the maximum recommended human dose with Orkambi (based on summed AUCs). This finding has not been observed in older animals. The potential relevance of these findings in humans is unknown.

6 Pharmaceutical Particulars

6.1 List of Excipients

Orkambi tablets contain the following inactive ingredients: microcrystalline cellulose; croscarmellose sodium; hypromellose acetate succinate; povidone; sodium lauryl sulfate; magnesium stearate; Opadry II Pink 85F140026 (PI# 110227); Opacode monogramming ink S-1-17823 Black (PI# 12108).
Orkambi granules contain the following inactive ingredients: microcrystalline cellulose; hypromellose acetate succinate; croscarmellose sodium; sodium lauryl sulfate; povidone.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the ARTG. The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Tablets.

Orkambi 100/125 tablets and Orkambi 200/125 tablets are packaged in a thermoform [polychlorotrifluoroethylene (PCTFE)] blister with a paper-backed foil lidding. There are four tablets in each blister strip. Seven strips are included in each weekly carton (28 tablets). Four cartons are contained in each Orkambi 100/125 or 200/125 box, totalling 112 tablets.

Granules.

Orkambi 75/94, Orkambi 100/125 and Orkambi 150/188 granules in sachet are packaged in a foil laminate [biaxially-oriented polyethylene terephthalate/polyethylene/foil/polyethylene (BOPET/PE/Foil/PE)] sachet. There are 14 sachets in a wallet, and 4 wallets in a carton, totalling 56 sachets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

The active ingredients in Orkambi tablets are lumacaftor, which has the following chemical name: 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl) cyclopropyl]carbonyl}amino)- 3-methylpyridin-2-yl] benzoic acid, and ivacaftor, which has the following chemical name: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide.

Chemical structure.

The structural formulas are:

The empirical formula for lumacaftor is C₂₄H₁₈F₂N₂O₅ and for ivacaftor is C₂₄H₂₈N₂O₃.
The molecular weights for lumacaftor and ivacaftor are 452.41 and 392.49, respectively.
The pKa values of lumacaftor are 2.51 and 4.28. The log-D value of lumacaftor is 2.29 at pH=7.4 and 25°C. The pKa values of ivacaftor are 9.40 and 11.60. The log-D value of ivacaftor is 5.68 at pH=7.4 and 25°C.
Lumacaftor is a white to off-white powder that is practically insoluble in water (0.02 mg/mL). Ivacaftor is a white to off-white powder that is practically insoluble in water (< 0.05 microgram/mL).

CAS number.

Lumacaftor.

936727-05-8.

Ivacaftor.

873054-44-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

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Orkambi

Lumacaftor; Ivacaftor

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BRAND INFORMATION

Orkambi 100 mg/125 mg Tablets

Orkambi 200 mg/125 mg Tablets