Consumer medicine information

Kalydeco

Ivacaftor

BRAND INFORMATION

Brand name

Kalydeco

Active ingredient

Ivacaftor

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kalydeco.

SUMMARY CMI

KALYDECO®

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 KALYDECO?

KALYDECO contains the active ingredient ivacaftor. KALYDECO is used for the treatment of cystic fibrosis (CF) in patients aged 4 months and older who have at least one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data.

For more information, see Section 1. Why am I using KALYDECO? in the full CMI.

2. What should I know before I use KALYDECO?

Do not use if you have ever had an allergic reaction to KALYDECO 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 KALYDECO? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with KALYDECO 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 KALYDECO?

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

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

5. What should I know while using KALYDECO?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using KALYDECO.
  • Use KALYDECO exactly as your doctor has prescribed.
  • Take KALYDECO with fat-containing food and avoid food containing grapefruit.
  • Tell your doctor if you become pregnant while using KALYDECO.
Things you should not do
  • Do not stop using KALYDECO 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 KALYDECO? in the full CMI.

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. Ask your doctor or pharmacist if you have any further questions about side effects.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking KALYDECO.

Some common side effects experienced by patients taking KALYDECO include the common cold, sore throat and nasal congestion, headache, abdominal pain, diarrhoea and rash.

If you experience significant pain or discomfort in the upper right abdominal area, or yellowing of your skin or the white parts of your eyes these may be indicative of serious side effects. 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

KALYDECO® (kuh-LYE-deh-koh)

Active ingredient(s): Ivacaftor


Consumer Medicine Information (CMI)

This leaflet provides important information about using KALYDECO. 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 KALYDECO

Where to find information in this leaflet:

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

1. Why am I using KALYDECO?

KALYDECO contains the active ingredient ivacaftor.

KALYDECO is used for the chronic treatment of cystic fibrosis (CF) in patients aged 4 months and older who have at least one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data.

KALYDECO belongs to a group of medicines called "cystic fibrosis transmembrane conductance regulator (CFTR) modulators."

In people with a G551D or other gating (class III) mutation and in people with an R117H mutation, the CFTR protein is present in normal amounts but its ability to allow chloride to pass through is reduced. KALYDECO is a CFTR potentiator, which is a drug that increases the opening of the CFTR protein, allowing more chloride to pass through.

KALYDECO is not addictive.

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. KALYDECO is a medicine that works by improving the flow of chloride and water in patients with cystic fibrosis who have a certain genetic defect.

2. What should I know before I use KALYDECO?

Warnings

Do not use KALYDECO if:

  • you are allergic to ivacaftor, 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:

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.

Your doctor will help you decide what is best for you or your child.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is unknown whether KALYDECO is excreted in human milk. If you plan to breast-feed, ask your doctor for advice before taking KALYDECO.

Use in children

Do not give KALYDECO to children weighing less than 5 kg or under 4 months of age.

The safety and efficacy of this medicine in children aged less than 4 months have not been established.

Abnormality of the eye lens (cataract) without any effect on vision has been noted in some children receiving KALYDECO.

Your doctor may perform some eye examinations prior to and during the treatment with KALYDECO.

Laboratory Testing

Your doctor will do some blood tests to check your liver prior to and while you are taking KALYDECO, particularly during the first year and especially if you have had high liver enzymes in the past.

Talk to your doctor if you have been told you have liver or kidney disease or if you are taking any other medicine, as your doctor may need to adjust the dose of KALYDECO.

Increased liver enzymes in the blood have been seen in some people receiving KALYDECO. Tell your doctor right away if you have any of these symptoms, which may be a sign of liver problems:

  • pain or discomfort in the upper right abdominal area
  • yellowing of the skin or the white part of the eyes
  • loss of appetite
  • nausea or vomiting
  • dark urine

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 interfere with KALYDECO and affect how it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

Take KALYDECO with fat-containing food and avoid food containing grapefruit.

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

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
Anticonvulsant medicines
used for the treatment of epileptic seizures
phenobarbital, carbamazepine, phenytoin
Anti-inflammatory medicines
used for the treatment of inflammation
dexamethasone, high-dose prednisone
Herbal medicineSt. John's wort (Hypericum perforatum)
Benzodiazepines
used for the treatment of anxiety, insomnia, agitation, etc.
midazolam, alprazolam, diazepam, triazolam
Immunosuppressants
used after organ transplantation
ciclosporin, 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

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

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

4. How do I use KALYDECO?

How much to take

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

KALYDECO dosing recommendations for patients aged 4 months and older are as follows:

AgeWeightDoseTotal daily dose
4 months to less than 6 months≥5 kgOne sachet of 25 mg granules taken orally every 12 hours50 mg (two sachets)
6 months and older≥5 kg to
<7 kg
One sachet of 25 mg granules taken orally every 12 hours50 mg (two sachets)
≥7 kg to
<14 kg
One sachet of 50 mg granules taken orally every 12 hours100 mg (two sachets)
≥14 kg to
<25 kg
One sachet of 75 mg granules taken orally every 12 hours150 mg (two sachets)
≥25 kgOne 150 mg tablet taken orally every 12 hours300 mg (two tablets)

If you have liver problems, your doctor may need to reduce the dose as your liver is not clearing ivacaftor as fast as in people who do not have problems with liver function.

When to take KALYDECO

  • KALYDECO should be taken every 12 hours.

How to take KALYDECO

KALYDECO is for oral use.

Tablets

Take 1 tablet (150 mg) of KALYDECO every 12 hours by mouth with a fat-containing meal or snack.

Granules

Take 1 sachet of KALYDECO every 12 hours by mouth with a fat-containing meal or snack. Each sachet is for single use only.

Giving KALYDECO 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 one teaspoon (5 mL) of age-appropriate soft food or liquid. Food or liquid should be at room temperature or below. Some examples of age-appropriate soft foods or liquids include puréed fruits or vegetables, yogurt, water, breast milk, infant formula, whole milk, 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.
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, breast milk, infant formula, whole milk, whole-milk dairy products, yogurt, chocolate
- Meats, oily fish
- Avocados, hummus, soy-based products (tofu)
- Nuts, fat-containing nutritional bars or drinks

If you forget to take KALYDECO

KALYDECO should be used regularly at the same time each day. If you miss your dose at the usual time, take the missed dose if less than 6 hours have passed since the time you missed the dose. Otherwise, wait until your next scheduled dose as you normally would.

Do not take a double dose to make up for the 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 take too much KALYDECO

If you think that you have used too much KALYDECO, 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 KALYDECO?

Things you should do

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

  • Use KALYDECO exactly as your doctor has prescribed.
  • Take KALYDECO with fat-containing food and avoid food containing grapefruit.
  • Tell all doctors, dentists and pharmacists who are treating you that you are using KALYDECO.
  • Tell your doctor if you become pregnant while using KALYDECO.
  • Tell your doctor if, for any reason, you have not used KALYDECO exactly prescribed.

Remind any doctor, dentist or pharmacist you visit that you are using KALYDECO.

Things you should not do

  • Do not stop using KALYDECO 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 KALYDECO to anyone else even if they have the same condition as you.
  • Do not use KALYDECO to treat other complaints unless your doctor tells you to.
  • Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.

Things to be careful of

  • Avoid food containing grapefruit during treatment with KALYDECO as they may increase the amount of KALYDECO in your body.
  • KALYDECO tablets contains lactose. KALYDECO granules contains lactose, mannitol and sucralose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Driving or using machines

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

KALYDECO may cause dizziness in some people. Do not drive or use machines unless you are sure that you are not affected.

If your child is taking KALYDECO, it is advised that he/she does not ride his/her bike or do anything else's that needs his/her full attention unless you are sure that your child is not affected.

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.

Do not store it:

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

Follow the instructions in the carton on how to take care of your medicine properly.

Granules

Once mixed with food, KALYDECO granules are stable for one hour.

Getting rid of any unwanted medicine

If you no longer need to use this medicine 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.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking KALYDECO.

Less serious side effects

Less serious side effectsWhat to do

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

  • upper respiratory tract infection (the common cold), including sore throat and nasal congestion
  • headache
  • abdominal pain
  • diarrhoea
  • rash

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

  • sinus congestion
  • red throat
  • runny nose
  • dizziness
  • changes in the type of bacteria in mucus
  • ear pain, ear discomfort
  • ringing in the ears
  • redness inside the ear

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

  • ear congestion
  • breast inflammation
  • breast mass
  • enlargement of the breast
  • nipple changes or pain
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Significant pain or discomfort in the upper right abdominal area.
  • Yellowing of your skin or the white parts of your eyes.
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.

These may be indicative of serious side effects. You may need urgent medical attention. Serious side effects are uncommon.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell, even if it is not on the list.

This is not a complete list of all possible side effects. Your doctor or pharmacist has a more complete list. Others may occur in some people and there may be some side effects not yet known.

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 KALYDECO tablets contain

Active ingredient
(main ingredient)
ivacaftor
Other ingredients
(inactive ingredients)
microcrystalline cellulose, lactose monohydrate, hypromellose acetate succinate, croscarmellose sodium, sodium lauryl sulfate, silicon dioxide, magnesium stearate, carnauba wax, Opadry II complete film coating system 85F90614 Blue (PI# 108371), OPACODE monogramming ink S-1-17823 BLACK (PI# 12108).
Potential allergensLactose monohydrate

What KALYDECO granules contain

Active ingredient
(main ingredient)
ivacaftor
Other ingredients
(inactive ingredients)
silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, mannitol, sucralose, sodium lauryl sulfate.
Potential allergensLactose monohydrate, mannitol and sucralose

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

What KALYDECO looks like

KALYDECO 150 mg film-coated tablets are light blue, capsule-shaped tablets, 16.5 mm x 8.4 mm, printed with "V 150" in black ink on one side and plain on the other. (150 mg blister pack: Aust R 198655).

KALYDECO 25 mg, 50 mg and 75 mg granules are white to off-white sweetened, unflavoured granules approximately 2 mm in diameter.

(25 mg sachet: Aust R 342815; 50 mg sachet: Aust R 267390; 75 mg sachet: Aust R 269661)

Availability

Tablets

  • KALYDECO 150 mg tablets are available in in a blister pack containing 56 film-coated tablets.

Granules

  • KALYDECO 25 mg, 50 mg and 75 mg granules are available in the following pack size:
    - 56 sachets (containing 4 individual wallets with 14 sachets per wallet)

Who distributes KALYDECO

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 February 2023.

©2023 Vertex Pharmaceuticals Incorporated

KALYDECO, VERTEX and the VERTEX triangle logo are registered trademarks of Vertex Pharmaceuticals Incorporated.

Published by MIMS April 2023

BRAND INFORMATION

Brand name

Kalydeco

Active ingredient

Ivacaftor

Schedule

S4

 

1 Name of Medicine

Ivacaftor.

2 Qualitative and Quantitative Composition

Tablets.

Kalydeco (ivacaftor) film-coated tablets contain 150 mg of ivacaftor per tablet.
Excipient with known effect: lactose monohydrate.

Granules.

Kalydeco (ivacaftor) granules contain 25 mg, 50 mg or 75 mg of ivacaftor per sachet.
Excipient with known effect: lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Kalydeco (ivacaftor) film-coated tablets are light blue, capsule-shaped tablets (16.5 mm x 8.4 mm in modified caplet shape). Each tablet is printed with "V 150" in black ink on one side only.
Kalydeco (ivacaftor) granules are white to off-white sweetened, unflavoured granules (approximately 2 mm in diameter) enclosed in unit dose sachets.

4 Clinical Particulars

4.1 Therapeutic Indications

Kalydeco is indicated for the treatment of cystic fibrosis (CF) in patients aged 4 months and older who have at least one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

4.2 Dose and Method of Administration

Kalydeco should only be prescribed by physicians with experience in the treatment of cystic fibrosis. If the patient's genotype is unknown, an accurate and validated genotyping method should be performed to confirm the presence of an indicated mutation in at least one allele of the CFTR gene before starting treatment (see Section 5.1 Pharmacodynamic Properties).
In patients with R117H mutation, analysis of the poly-T variants should be performed. In asymptomatic patients with R117H-7T, a sweat test should be conducted and a diagnosis of CF confirmed prior to starting treatment.
Adults, adolescents, and children aged 4 months and older should be dosed according to Table 1.
A fat-containing meal or snack should be consumed just before or just after dosing of Kalydeco. Meals and snacks recommended in CF guidelines or meals recommended in standard nutritional guidelines contain adequate amounts of fat. A serving size of foods appropriate for age from a typical CF diet should be given. Examples of meals that contain fat are those prepared with butter or oils or those containing eggs, cheeses, nuts, avocados, whole milk, breast milk, infant formula, full-fat yoghurt, or meats. Food containing grapefruit should be avoided during treatment with Kalydeco (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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. Food or liquid 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. Some examples of soft foods or liquids include puréed fruits or vegetables, yoghurt, applesauce, water, milk, breast milk, infant formula, or juice.

Use in the elderly.

The efficacy and safety of Kalydeco in patients age 65 years or older have not been evaluated.

Use in renal impairment.

No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution is recommended while using Kalydeco in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Use in hepatic impairment.

Patients aged 4 months to less than 6 months.

Due to variability in maturation of cytochrome (CYP) enzymes involved in ivacaftor metabolism, treatment with ivacaftor is not recommended in patients aged 4 months to less than 6 months with hepatic impairment, unless the benefits outweigh the risks. In such cases, the recommended dose is one sachet of 25 mg granules once daily or less frequently (see Table 2). Dosing intervals should be modified according to clinical response and tolerability (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Patients aged 6 months and older.

No dose adjustment is necessary for patients aged 6 months and older with mild hepatic impairment (Child-Pugh Class A). A reduced dose of Kalydeco is recommended for patients with moderate hepatic impairment (Child-Pugh Class B) (see Table 2).
There is no experience with the use of Kalydeco in patients aged 6 months and older with severe hepatic impairment (Child-Pugh Class C). The use of Kalydeco in these patients is therefore not recommended, unless the benefits outweigh the risks. In such cases, Kalydeco should be used with caution at a reduced dose (see Table 2). Dosing intervals should be modified according to clinical response and tolerability (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Concomitant use of CYP3A inhibitors.

Patients aged 4 months to less than 6 months.

Due to variability in maturation of cytochrome (CYP) enzymes involved in ivacaftor metabolism, treatment with ivacaftor is not recommended when co-administered with moderate or strong inhibitors of CYP3A in patients aged 4 months to less than 6 months, unless the benefits outweigh the risks. In such cases, the recommended dose is one sachet of 25 mg granules twice weekly or less frequently (see Table 3; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Dosing intervals should be modified according to clinical response and tolerability (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Patients aged 6 months and older.

When co-administered with strong inhibitors of CYP3A (e.g. ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin) in patients aged 6 months and older, Kalydeco should be administered as follows: in patients with body weight 5 kg to less than 7 kg, one 25 mg sachet twice a week; in patients with body weight 7 kg to less than 14 kg, one 50 mg sachet of granules twice a week; in patients with body weight 14 kg to less than 25 kg, one 75 mg sachet of granules twice a week; and in patients with body weight 25 kg or greater, one 150 mg tablet twice a week (see Table 3).
When co-administered with moderate inhibitors of CYP3A (e.g. fluconazole, erythromycin) in patients 6 months and older, Kalydeco should be administered as follows: in patients with body weight 5 kg to less than 7 kg, one 25 mg sachet once daily; in patients with body weight 7 kg to less than 14 kg, one 50 mg sachet of granules once daily; in patients with body weight 14 kg to less than 25 kg, one 75 mg sachet of granules once daily; and in patients with body weight 25 kg or greater, one 150 mg tablet once daily (see Table 3; Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.3 Contraindications

In cases of hypersensitivity to the active substance or to any component of these medicines, patients should not be treated with the medicines.

4.4 Special Warnings and Precautions for Use

Use in hepatic impairment.

Patients aged 4 months to less than 6 months.

No safety data are available in infants aged 4 to less than 6 months of age with moderate or severe hepatic impairment treated with ivacaftor. Treatment with ivacaftor is not recommended in patients aged 4 months to less than 6 months with hepatic impairment, unless the benefits outweigh the risks. In such cases, the starting dose interval should be reduced, and dosing intervals should be modified according to clinical response and tolerability (see Table 2; Section 4.2 Dose and Method of Administration).

Patients aged 6 months and older.

No safety data are available in infants aged 6 to less than 12 months of age with moderate or severe hepatic impairment treated with ivacaftor. A reduced dose of Kalydeco is recommended for patients with moderate hepatic impairment (Child-Pugh Class B).
There is no experience of the use of Kalydeco in patients aged 6 months and older with severe hepatic impairment (Child-Pugh Class C). Use of Kalydeco is not recommended in patients with severe hepatic impairment unless the benefits are expected to outweigh the risks of over exposure. In such cases, the starting dose interval should be reduced and dosing intervals should be modified according to clinical response and tolerability (see Table 2; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Interactions with medicinal products.

CYP3A inducers.

Exposure to ivacaftor is significantly decreased by the concomitant use of CYP3A inducers, potentially resulting in the loss of ivacaftor efficacy; therefore, co-administration of ivacaftor with strong CYP3A inducers is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

CYP3A inhibitors.

Exposure to ivacaftor is increased when co-administered with strong or moderate CYP3A inhibitors. The dose of ivacaftor must be adjusted when used concomitantly with strong or moderate CYP3A inhibitors (see Table 3; Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). No safety data are available in infants aged 4 to less than 12 months of age who are treated with ivacaftor and moderate or strong CYP3A inhibitors (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in renal impairment.

Caution is recommended while using Kalydeco 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; Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

Clinical studies of ivacaftor did not include a sufficient number of patients age 65 years and older to evaluate the efficacy and safety of ivacaftor in this age range. Thus, the efficacy and safety of Kalydeco in elderly patients have not been evaluated.

Paediatric use.

The efficacy of Kalydeco in patients 4 months to less than 6 years was extrapolated from patients 6 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels between patients 4 months to less than 6 years, and adults and children 6 years of age and older. The safety and efficacy of Kalydeco in children aged less than 4 months have not been established. Efficacy was not demonstrated in patients less than 18 years of age with CF who have an R117H mutation in clinical trials. Currently available data are described, see Section 5.2 Pharmacokinetic Properties; Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.8 Adverse Effects (Undesirable Effects); Section 4.2 Dose and Method of Administration.

Cataracts.

Cases of non-congenital lens opacities without impact on vision have been reported in paediatric patients treated with ivacaftor. 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 Kalydeco treatment.
Cataracts were seen in juvenile rats treated with ivacaftor from postnatal day 7-35 at oral doses ≥ 10 mg/kg/day, yielding exposure to ivacaftor and its major metabolites approximately 3.5-6 times lower than that in patients at the maximum recommended human dose (MRHD) based on summed AUCs. This finding has not been observed in older animals. The potential relevance of these findings in humans is unknown.

Patients after organ transplantation.

Kalydeco 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).

Lactose.

Kalydeco contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Effects on laboratory tests.

Liver function tests.

Moderate transaminase (alanine transaminase [ALT] or aspartate transaminase [AST]) elevations are common in patients with CF. In Studies 1, 2, and 3, the incidence and clinical features of transaminase elevations in clinical trials were similar between patients in the ivacaftor and placebo treatment groups (see Section 4.8 Adverse Effects (Undesirable Effects)). In the subset of patients with a medical history of elevated transaminases, increased ALT or AST has been reported more frequently in patients receiving ivacaftor compared to placebo. Therefore, liver function tests are recommended for all patients prior to initiating Kalydeco, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, consider more frequent monitoring of liver function tests (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients who develop unexplained increased transaminase levels during treatment should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consideration should be given to the continuation of treatment after assessment of the individual benefits and risks.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Medicinal products that inhibit or induce CYP3A activity may impact the pharmacokinetics of ivacaftor. The dose of Kalydeco must be adjusted when concomitantly used with strong and moderate CYP3A inhibitors. Exposure to ivacaftor may be reduced by the concomitant use of CYP3A inducers, potentially resulting in the loss of efficacy of Kalydeco.
Ivacaftor is a weak CYP3A and P-glycoprotein (P-gp) inhibitor and may modify the pharmacokinetics of medicinal products that are substrates of CYP3A and/or P-gp. In vitro studies indicated that ivacaftor has the potential to inhibit CYP2C9.

Medicinal products affecting the pharmacokinetics of Kalydeco.

CYP3A inhibitors.

Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, increased ivacaftor exposure (measured as area under the curve [AUC]) by 8.5-fold and increased hydroxymethyl-ivacaftor (M1) to a lesser extent than ivacaftor. A reduction of the Kalydeco dose is recommended for co-administration with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin (see Section 4.2 Dose and Method of Administration).
Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold and increased M1 to a lesser extent than ivacaftor.
A reduction of the Kalydeco dose is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin (see Section 4.2 Dose and Method of Administration).
Co-administration of Kalydeco with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure to ivacaftor. Food containing grapefruit should be avoided during treatment with Kalydeco.

CYP3A inducers.

Co-administration of Kalydeco with rifampicin, a strong CYP3A inducer, decreased ivacaftor exposure (AUC) by 89% and decreased M1 to a lesser extent than ivacaftor.
Co-administration with strong CYP3A inducers, such as rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin and St. John's wort (Hypericum perforatum), is not recommended. Concomitant use of weak to moderate inducers of CYP3A (e.g. dexamethasone, high-dose prednisone) may decrease the exposure of ivacaftor and thus may reduce Kalydeco efficacy.

Other recommendations.

Co-administration of ciprofloxacin with Kalydeco did not affect the exposure of ivacaftor. No dose adjustment is required when Kalydeco is co-administered with ciprofloxacin.

Medicinal products affected by Kalydeco.

CYP3A, P-gp, or CYP2C9 substrates.

Based on in vitro results, ivacaftor and its M1 metabolite have the potential to inhibit CYP3A and P-gp. Co-administration with (oral) midazolam, a sensitive CYP3A substrate, increased midazolam exposure 1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor.
Co-administration with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold, consistent with weak inhibition by P-gp by ivacaftor. Administration of Kalydeco may increase systemic exposure of medicinal products that are substrates of CYP3A and/or P-gp, which may increase or prolong their therapeutic effect and adverse reactions. Use with caution and monitor for benzodiazepine-related side effects when using concomitant oral midazolam, alprazolam, diazepam, or triazolam. Use with caution and appropriate monitoring when using concomitant digoxin, cyclosporine, or tacrolimus.
Ivacaftor may inhibit CYP2C9. Therefore, monitoring of the INR during co-administration with warfarin is recommended.
Ivacaftor has been studied with an oestrogen/progesterone oral contraceptive and was found to have no significant effect on the exposures of the oral contraceptive. Kalydeco is not expected to modify the efficacy of oral contraceptives. Therefore, no dose adjustment of oral contraceptives is necessary.
Ivacaftor has been studied with the CYP2C8 substrate rosiglitazone. No significant effect on rosiglitazone exposure was found. Therefore, no dose adjustment of CYP2C8 substrates such as rosiglitazone is necessary.
Ivacaftor has been studied with the CYP2D6 substrate desipramine. No significant effect on desipramine exposure was found. Therefore, no dose adjustment of CYP2D6 substrates such as desipramine is necessary.
Interaction studies have only been performed in healthy adults.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Ivacaftor impaired fertility and reproductive performance indices in male and female rats at an oral dose of 200 mg/kg/day (yielding approximately 10 and 5 times, respectively, the systemic exposure anticipated in patients at the MRHD 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 6 and 3 times, respectively, the exposure at the MRHD 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.
There are no adequate and well-controlled studies of Kalydeco in pregnant women. Developmental toxicity studies in animals revealed no teratogenicity in rats at oral doses up to 200 mg/kg/day (yielding 5 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, ≥ 3). 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. Ivacaftor and/or its metabolites were shown to cross the placenta in rats and rabbits.
As animal reproduction studies are not always predictive of human response, and given the limited experience with Kalydeco in pregnancy, Kalydeco should only be used during pregnancy if the expected benefits to the mother justify the potential risks to the fetus.
It is unknown whether ivacaftor and/or its metabolites are excreted in human milk. Ivacaftor and/or its metabolites were shown to be excreted into the milk of lactating rats. The safe use of Kalydeco during breast-feeding has not been established. Kalydeco should only be used during breast-feeding if the potential benefit outweighs the potential risk.

4.7 Effects on Ability to Drive and Use Machines

Dizziness has been reported in patients receiving Kalydeco, which could influence the ability to drive or operate machines (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients experiencing dizziness should be advised not to drive or operate machines until symptoms abate.

4.8 Adverse Effects (Undesirable Effects)

Experience from clinical trials.

The safety profile of Kalydeco is based on seven clinical trials: two pooled, placebo-controlled Phase 3 clinical trials (Study 1 STRIVE and Study 2 ENVISION) conducted in 213 CF patients (109 received ivacaftor and 104 received placebo up to 48 weeks) who had a G551D mutation in the CFTR gene; a 96-week open-label extension study (Study 4 PERSIST) that included 192 patients with a G551D mutation; an 8-week, Phase 3, placebo-controlled crossover design study (Study 5 KONNECTION) in 39 patients with CF who had a non-G551D gating (class III) mutation in the CFTR gene; a 24-week, placebo-controlled trial (Study 6 KONDUCT) involving 69 patients with an R117H mutation in the CFTR gene; and a 24-week, open-label study (Study 7 KIWI) that included 34 patients with a G551D or another gating (class III) mutation in the CFTR gene; and a cohort of 19 patients aged 12 months to less than 24 months, a cohort of 11 patients aged 6 months to less than 12 months, and a cohort of 6 patients aged 4 months to less than 6 months, in a 24-week, open label, Phase 3 clinical study in patients with CF (Study 8 ARRIVAL). Patients with a gating mutation or R117H mutation were eligible for this study. Patients treated with Kalydeco in these trials were between the ages of 4 months and 68 years.
The most common adverse reactions that were more frequent in patients with a G551D mutation who received ivacaftor for 48 weeks in the placebo-controlled Phase 3 trials were abdominal pain (15.6% versus 12.5% on placebo), diarrhoea (12.8% versus 9.6% on placebo), dizziness (9.2% versus 1.0% on placebo), rash (12.8% versus 6.7% on placebo), upper respiratory tract reactions (including upper respiratory tract infection, nasal congestion, pharyngeal erythema, oropharyngeal pain, rhinitis, sinus congestion, and nasopharyngitis) [63.3% versus 50.0% on placebo], headache (23.9% versus 16.3% on placebo) and bacteria in sputum (7.3% versus 3.8% on placebo). One patient in the ivacaftor group reported a serious adverse reaction: abdominal pain.
Adverse events were identified based on the pooled data of the 48-week, placebo-controlled Studies 1 (STRIVE) and 2 (ENVISION) in patients aged 6 years and older who had a G551D mutation in the CFTR gene.
Table 4 shows adverse events with an incidence of at least 10% in any treatment group from the two double-blind, placebo-controlled Phase 3 trials.
Table 5 presents the adverse reactions identified in patients aged 6 years and older who had a G551D mutation in at least one allele 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).

Description of selected adverse reactions.

Rash. During 48-week, placebo-controlled clinical trials, the incidence of rash was 12.8% in Kalydeco-treated patients. Including data from all clinical trial and post-marketing data, most of these events were non-serious and most of these patients did not discontinue the treatment because of rash.
Ear and labyrinth disorders. During 48-week, placebo-controlled clinical trials, the incidence of ear and labyrinth disorders was 9.2% in Kalydeco-treated patients. Most events were described as mild to moderate in severity, one event of ear pain was described as severe, none were serious, and no patients discontinued treatment because of ear and labyrinth disorder.
Nervous system disorders.

Headache.

During 48-week, placebo-controlled clinical trials, the incidence of headache was 23.9% in Kalydeco-treated patients. Including data from all clinical trial and post-marketing data, most of these events were non-serious and most of these patients did not discontinue the treatment because of headache.

Dizziness.

During 48-week, placebo-controlled clinical trials, the incidence of dizziness was 9.2% in the Kalydeco-treated patients. Including data from all clinical trial and post-marketing data, most of these events were non-serious and most of these patients did not discontinue the treatment because of dizziness.
Upper respiratory tract reactions. During 48-week, placebo-controlled clinical trials, the incidence of upper respiratory tract reactions (upper respiratory tract infection, nasal congestion, pharyngeal erythema, oropharyngeal pain, rhinitis, sinus congestion, and nasopharyngitis) was 63.3% in Kalydeco-treated patients. Most events were described as mild to moderate in severity, one event of upper respiratory tract infection and one event of nasal congestion were considered to be severe, none were serious, and no patients discontinued treatment because of upper respiratory tract reactions.
Laboratory abnormalities.

Transaminase elevations.

During the placebo-controlled Studies 1 (STRIVE), 2 (ENVISION), and 3 (DISCOVER), up to 48 weeks, in patients with a G551D mutation in the CFTR gene or who were homozygous for the F508del mutation, the incidence of maximum transaminase (ALT or AST) > 8, > 5 or > 3 x ULN was 1.8%, 2.3%, and 5.9% in Kalydeco-treated patients and 1.5%, 2.3%, and 8.3% in placebo-treated patients, respectively. Three patients, 2 (1.5%) on placebo and 1 (0.5%) on Kalydeco, permanently discontinued treatment for elevated transaminases, which were all > 8 x ULN. No Kalydeco-treated patients experienced a transaminase elevation > 3 x ULN associated with elevated total bilirubin > 1.5 x ULN. In Kalydeco-treated patients, most transaminase elevations up to 5 x ULN resolved without treatment interruption. Kalydeco dosing was interrupted in most patients with transaminase elevations > 5 x ULN. In all instances where dosing was interrupted for elevated transaminases, Kalydeco dosing was able to be resumed (see Section 4.4 Special Warnings and Precautions for Use).

Long-term safety (study 4-VX08-770-105, PERSIST): open-label extension study in patients ≥ 6 years.

Among 192 patients with the G551D mutation treated with Kalydeco for 96 weeks in an open-label extension study (Study 4 PERSIST) following the placebo-controlled Phase 3 studies (96 to 144 weeks cumulatively), the nature of adverse events was similar to those reported in the placebo-controlled Phase 3 studies. Serious adverse reactions observed during the 96-week extension study included abdominal pain (1%), headache (1%), and vestibular disorder (0.5%).

Non-G551D gating population (study 5 - VX12-770-111, KONNECTION): study in patients (≥ 6 years) with CF with non-G551D gating mutations.

In an 8-week, two-part, randomised, double-blind, placebo-controlled, crossover Phase 3 clinical trial of 39 patients with CF aged 6 and older who had a non-G551D gating mutation in the CFTR gene (Study 5 KONNECTION), the safety results were consistent with those observed in studies in patients with CF who had the G551D mutation. In the non-G551D gating population, one adverse reaction occurred in more patients during treatment with Kalydeco, compared with placebo: rhinitis (7.9% versus 5.4% on placebo).

R117H population (study 6 - (VX11-770-110, KONDUCT): study in patients with CF with an R117H mutation in the CFTR gene).

In a 24-week, placebo-controlled trial (Study 6 KONDUCT) involving 69 patients with CF aged 6 and older who had an R117H mutation in the CFTR gene, the safety results were consistent with those observed in studies in patients with CF who had the G551D mutation.

Paediatric population.

The safety data were evaluated in 6 patients aged 4 months to less than 6 months, 11 patients aged 6 months to less than 12 months, 19 patients aged 12 months to less than 24 months, 34 patients aged 2 years to less than 6 years of age, 52 patients between 6 to less than 12 years of age and 93 patients between 12 to less than 18 years of age. The safety profile is generally consistent among children and adolescents and is also consistent with adult patients.
Paediatric safety and efficacy study in patients aged 2 to less than 6 years of age (study 7 - VX11-770-108, KIWI): study in paediatric patients with CF aged 2 to less than 6 years with G551D or another gating mutation. In this paediatric population, transaminase elevation and vomiting were observed more frequently as compared to the adults; however, it is unknown if these effects were due to Kalydeco. In this study the incidence of patients experiencing transaminase elevations (ALT or AST) > 3 x ULN was 14.7% (5/34). All 5 patients had maximum ALT or AST levels > 8 x ULN, which returned to baseline levels following interruption of ivacaftor dosing. Ivacaftor was discontinued permanently in one patient (see Section 4.4 Special Warnings and Precautions for Use, Liver function tests).
Paediatric safety study in patients aged 4 months to < 24 months (Study 8 - VX15- 770-124, ARRIVAL): safety study in paediatric patients with CF aged less than 24 months.

Patients aged 12 months to less than 24 months.

During the 24-week, open-label, Phase 3 clinical study in 19 patients aged 12 months to less than 24 months, the incidence of patients experiencing transaminase elevations (ALT or AST) > 3, > 5, and > 8 x ULN was 27.8% (5/18), 11.1% (2/18) and 11.1% (2/18), respectively. No patients had elevations in total bilirubin. No subjects discontinued ivacaftor treatment due to transaminase elevations. The two patients with elevations of ALT or AST > 8 x ULN interrupted treatment and subsequently resumed ivacaftor successfully.

Patients aged 4 months to less than 12 months.

In the cohort of patients aged 6 months to less than 12 months (N = 11), one patient (9.1%) had elevated ALT of > 3 to ≤ 5 x ULN. In the cohort of patients aged 4 months to less than 6 months (N = 6), no patients had elevated ALT or AST (> 3 x ULN). No patients had elevations in total bilirubin or discontinued ivacaftor treatment due to transaminase elevations in any cohort (see Section 4.4 Special Warnings and Precautions for Use, Management of elevated transaminases).

Post-marketing experience.

There are no relevant updates from the post-marketing experience.

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).
The highest repeated dose was 450 mg (in a tablet formulation) every 12 hours for 4.5 days (9 doses) in a trial evaluating the effect of Kalydeco on ECGs in healthy subjects. Adverse events reported at a higher incidence compared to placebo included dizziness and diarrhoea.
No specific antidote is available for overdose with Kalydeco. Treatment of overdose with Kalydeco consists of general supportive measures including monitoring of vital signs, liver function tests, and observation of the clinical status of the patient.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ivacaftor is a selective potentiator of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. In vitro, ivacaftor increases the open probability of the CFTR channel gate to enhance chloride transport. This has been demonstrated in normal CFTR and in mutant forms of CFTR that have reduced channel-open probability, such as G551D-CFTR and R117H-CFTR. The exact mechanism leading ivacaftor to prolong the gating activity of some mutant CFTR forms has not been completely elucidated.
The chloride transport response of mutant CFTR protein to ivacaftor was determined in Ussing chamber electrophysiology studies using a panel of Fisher Rat Thyroid (FRT) cell lines transfected with individual cell mutations. Ivacaftor increases chloride transport in FRT cells expressing CFTR mutations that result in CFTR protein being delivered to the cell surface.
The in vitro CFTR chloride transport response threshold was designated as at least a 10% net increase in chloride transport over baseline as a percent of normal CFTR because it is predictive or reasonably expected to predict clinical benefit. For individual mutations, the magnitude of the net change over baseline in CFTR-mediated chloride transport in vitro is not correlated with the magnitude of clinical response.
The G970R mutation was previously classified as a gating mutation; however, it was found to cause a splicing defect resulting in little-to-no CFTR protein at the cell surface.
Table 6 lists mutations that are responsive to ivacaftor based on 1) a positive clinical response and/or 2) in vitro data in FRT cells indicating that ivacaftor increases chloride transport to at least 10% over baseline (% of normal).
In clinical trials (Study 1 STRIVE and Study 2 ENVISION) in patients with the G551D mutation in one allele of the CFTR gene administered 150 mg of ivacaftor tablets every 12 hours, Study 1 STRIVE in patients 12 years and older and Study 2 ENVISION in patients 6 to 11 years of age, ivacaftor led to rapid (15 days), substantial (the mean change in sweat chloride from baseline through Week 24 was -48 mmol/L [95% CI -51, -45] and -54 mmol/L [95% CI -62, -47], respectively), and sustained (through 48 weeks) reduction in sweat chloride concentration.
In a clinical trial in patients aged 6 years and older administered 150 mg of ivacaftor tablets every 12 hours who had a non-G551D gating mutation in the CFTR gene (Study 5 KONNECTION, Part 1), treatment with ivacaftor led to a rapid (15 days) and substantial mean change in sweat chloride from baseline of -49 mmol/L (95% CI -57, -41) after 8 weeks of treatment. However, in patients with the G970R-CFTR mutation, the mean (SD) absolute change in sweat chloride at Week 8 was -6.25 (6.55) mmol/L. Clinical efficacy has not been established in patients with the G970R mutation (see Section 4.4 Special Warnings and Precautions for Use).
In a clinical trial (Study 6 KONDUCT) in 69 patients age 6 years or older with CF who had an R117H mutation in the CFTR gene, the treatment difference in mean change in sweat chloride from baseline through 24 weeks of treatment was -24 mmol/L (95% CI -28, -20) and in patients 18 years or older it was -22 mmol/L (95% CI -26, -17). The mean sweat chloride change was consistent across subgroups, including age, poly-T status, and FEV1.
In an open-label, Phase 3 clinical study in 34 patients aged 2 to less than 6 years with G551D or another gating mutation, administered either 50 mg or 75 mg of ivacaftor granules every 12 hours (Study 7 KIWI), the mean absolute change from baseline in sweat chloride was -47 mmol/L (95% CI -58, -36) at Week 24.
In a 24 week, open-label, Phase 3 clinical study in patients with CF aged less than 24 months with a gating mutation or an R117H mutation (Study 8 ARRIVAL), the mean absolute change from baseline in sweat chloride for patients aged 12 months to less than 24 months (n = 10) was -73.5 mmol/L (SD: 17.5) at Week 24.
The mean absolute change from baseline in sweat chloride for patients aged 6 months to less than 12 months (n = 6) was -58.6 mmol/L (SD: 16.5) at Week 24, and the mean absolute change from baseline in sweat chloride for patients aged 4 months to less than 6 months (n = 3) was -50 mmol/L (SD: 17.3) at Week 24. Patients with a gating mutation or R117H mutation were eligible for this study.

Clinical trials.

The efficacy of Kalydeco has been evaluated in eight clinical trials including two Phase 3, randomised, double-blind, placebo-controlled, multi-centre studies of clinically stable patients with CF who had the G551D mutation in the CFTR gene on at least 1 allele and had FEV1 (forced expiratory volume exhaled in the first second) ≥ 40% predicted.
Patients in both studies were randomised 1:1 to receive either 150 mg of ivacaftor tablets or placebo every 12 hours with fat-containing food for 48 weeks in addition to their prescribed CF therapies (e.g. tobramycin, dornase alfa). The use of inhaled hypertonic saline was not permitted.
Efficacy results from a Phase 2 study in patients with CF who were homozygous for the F508del mutation in the CFTR gene (Study 3 DISCOVER) showed no statistically significant difference in FEV1 over 16 weeks of ivacaftor treatment compared to placebo. Therefore, use of Kalydeco in these patients is not recommended.

Study 1 (VX08-770-102, STRIVE): study in patients with CF (≥ 12 years) with a G551D-CFTR mutation.

Study 1 STRIVE evaluated 161 patients who were 12 years of age or older; 122 (75.8%) patients had the F508del mutation in the second allele. At the start of the study, patients in the placebo group used some medicinal products at a higher frequency than the ivacaftor group.
These medications included dornase alfa (73.1% versus 65.1%), salbutamol (53.8% versus 42.2%), tobramycin (44.9% versus 33.7%), and salmeterol/fluticasone (41.0% versus 27.7%). At baseline, mean predicted FEV1 was 63.6% (range: 31.6% to 98.2%) and mean age was 26 years (range: 12 to 53 years).

Study 2 (VX08-770-103, ENVISION): study in patients with CF (6 to 11 years) with a G551D-CFTR mutation.

Study 2 ENVISION evaluated 52 patients who were 6 to 11 years of age at screening; mean (SD) body weight was 30.9 (8.63) kg; 42 (80.8%) of patients had the F508del mutation in the second allele. At baseline, mean predicted FEV1 was 84.2% (range: 44.0% to 133.8%) and mean age was 9 years (range: 6 to 11 years); 8 (30.8%) patients in the placebo group and 4 (15.4%) patients in the ivacaftor group had an FEV1 less than 70% predicted at baseline.
The primary efficacy endpoint in both studies was the mean absolute change from baseline in percent predicted FEV1 through 24 weeks of treatment.
The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) in percent predicted FEV1 from baseline through Week 24 was 10.6 percentage points (8.6, 12.6) in Study 1 STRIVE and 12.5 percentage points (6.6, 18.3) in Study 2 ENVISION (see Figure 1).
The treatment difference between ivacaftor and placebo for the mean relative change (95% CI) in percent predicted FEV1 from baseline through Week 24 was 17.1% (13.9, 20.2) in Study 1 STRIVE and 15.8% (8.4, 23.2) in Study 2 ENVISION. The mean change from baseline through Week 24 in FEV1 (L) was 0.37 L in the ivacaftor group and 0.01 L in the placebo group in Study 1 STRIVE and 0.30 L in the ivacaftor group and 0.07 L in the placebo group in Study 2 ENVISION. In both studies, improvements in percent predicted FEV1 were rapid in onset (Day 15 P < 0.0001 and P = 0.0004 for Study 1 STRIVE and Study 2 ENVISION, respectively) and durable through 48 weeks (P < 0.0001 and P = 0.0017 for Study 1 STRIVE and Study 2 ENVISION, respectively).
FEV1 results at 24 and 48 weeks by age subgroups are shown in Table 7.
The results for clinically relevant secondary endpoints are shown in Table 8.

Study 3 (VX08-770-104, DISCOVER): study in patients (≥ 12 years) with CF with the F508del mutation in CFTR gene.

Study 3 DISCOVER (Part A) was a 16-week, 4:1 randomised, double-blind, placebo-controlled, parallel-group, Phase 2 study of ivacaftor (150 mg tablets every 12 hours) in 140 patients with CF age 12 years and older who were homozygous for the F508del mutation in the CFTR gene and who had FEV1 ≥ 40% predicted.
The mean absolute change from baseline through Week 16 in percent predicted FEV1 (primary efficacy endpoint) was 1.5 percentage points in the ivacaftor group and -0.2 percentage points in the placebo group. The estimated treatment difference for ivacaftor versus placebo was 1.7 percentage points (95% CI -0.6, 4.1); this difference was not statistically significant (P = 0.15).

Study 4 (VX08-770-105, PERSIST): open-label extension study in patients ≥ 6 years.

Study 4 PERSIST is an open-label extension study to evaluate the safety and efficacy of long-term treatment of orally administered ivacaftor (150 mg tablets every 12 hours) in patients continuing from Studies 1 and 2. It enrolled 144 adolescents/adults who completed Study 1 STRIVE (age ≥ 12 years) and 48 children who completed Study 2 ENVISION (age 6 to 11 years). The percent predicted FEV1 range at the beginning of Study 4 PERSIST was 29.1% to 126.7%. The use of inhaled hypertonic saline was permitted. A pre-specified analysis of all patients' data was performed after all patients from Study 1 STRIVE and Study 2 ENVISION who had not discontinued received 96 weeks of treatment with ivacaftor in Study 4 (for a total exposure of 144 weeks for patients who received ivacaftor in Study 1 STRIVE and Study 2 ENVISION).
In Study 4 PERSIST, the substantial lung function improvement and weight gain (as seen in Study 1 STRIVE and Study 2 ENVISION) (see Table 9) and CFQ-R changes (as seen in Study 1 STRIVE) persisted through 144 weeks of cumulative ivacaftor treatment. The time-to-first pulmonary exacerbation showed a consistent trend across 144 weeks for patients treated with ivacaftor from Study 1 STRIVE. Too few patients experienced pulmonary exacerbations in Study 2 ENVISION to perform a meaningful statistical analysis. See Figures 2, 3 and 4.

Study 5 (VX12-770-111, KONNECTION): study in patients (≥ 6 years) with CF with non-G551D gating mutations.

Study 5 KONNECTION was a Phase 3, two-part, randomised, double-blind, placebo-controlled, crossover study (Part 1) with an open-label extension period (Part 2) to evaluate the efficacy and safety of ivacaftor in patients with CF who have a non-G551D gating mutation in the CFTR gene (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D). Patients who completed Part 1 of this study (randomised, double-blind, placebo-controlled, 8-week crossover) continued into the 16-week open-label Part 2 of the study. Four patients with a G970R mutation were also represented in this study. Clinical efficacy in patients with the G970R mutation could not be established.
Study 5 KONNECTION evaluated 39 patients with CF who were 6 years of age or older (mean age 23 years) with baseline FEV1 ≥ 40% predicted (mean FEV1 78% predicted [range: 43% to 119%]).
In Part 1, patients were randomised 1:1 to receive either 150 mg of ivacaftor tablets or placebo every 12 hours with fat-containing food for 8 weeks in addition to their prescribed CF therapies during the first Treatment Period and crossed over to the other treatment for the second 8 weeks. The two 8-week Treatment Periods were separated by a 4- to 8-week Washout Period. The use of inhaled hypertonic saline was not permitted.
The primary efficacy endpoint was improvement in lung function as determined by the mean absolute change from baseline in percent predicted FEV1 through 8 weeks of treatment.
In Part 1 of Study 5 KONNECTION, the observed treatment difference between ivacaftor and placebo for the mean absolute change in percent predicted FEV1 from baseline through Week 8 was 10.7 percentage points (P < 0.0001). Improvements in percent predicted FEV1 were observed regardless of age, disease severity, sex, geographic region, and Pseudomonas aeruginosa infection status at baseline. Improvement in percent predicted FEV1 was rapid in onset (Day 15, P < 0.0001) and durable through 8 weeks (P < 0.0001) of treatment with ivacaftor.
Treatment with ivacaftor resulted in substantial, consistent, and statistically significant treatment effects across the secondary endpoints of the absolute change from baseline in BMI and BMI-for-age z-score at Week 8 was 0.7 kg/m2 (P < 0.0001) and 0.3 points (P = 0.0010), respectively, and CFQ-R respiratory domain score through Week 8 was 9.6 points (P = 0.0004; Minimum Clinically Important Difference = 4 units) when compared to placebo. Together, these results demonstrate the positive effects of ivacaftor treatment on pulmonary and extrapulmonary measures.

Study 6 (VX11-770-110, KONDUCT): study in patients with CF with an R117H mutation in the CFTR gene.

The efficacy and safety of Kalydeco in patients with CF who have an R117H mutation in the CFTR gene were evaluated in a randomised, double-blind, placebo-controlled, parallel-group clinical trial of patients aged 6 years and older with cystic fibrosis. Fifty-nine of 69 patients completed 24 weeks of treatment. Two patients discontinued and 8 patients did not complete treatment due to study termination. Patients who were 12 years and older had FEV1 at screening between 40-90% predicted, and patients who were 6-11 years of age had FEV1 at screening between 40-105% predicted. The patients had well preserved BMIs (mean overall: 23.76 kg/m2) and a high proportion were pancreatic sufficient as assessed by a low rate of pancreatic enzyme replacement therapy use (pancreatin: 11.6%; pancrelipase: 5.8%). Patients who had persistent Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus isolated from sputum at screening, and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥ 3 times the ULN, were excluded. Patients were randomised 1:1 to receive either 150 mg of Kalydeco (n = 34) or placebo (n = 35) every 12 hours with food containing fat for 24 weeks in addition to their prescribed CF therapies.
The primary efficacy endpoint was improvement in lung function as determined by the mean absolute change from baseline in percent predicted FEV1 through 24 weeks of treatment. The treatment difference for absolute change in percent predicted FEV1 through Week 24 was 2.1 percentage points (analysis conducted with the full analysis set which included all 69 patients), and did not reach statistical significance. The treatment difference in mean change in sweat chloride from baseline through 24 weeks of treatment was -24 mmol/L (95% CI -28, -20) and in patients 18 years or older it was -22 mmol/L (95% CI -26, -17). The mean sweat chloride change was consistent across subgroups, including age, poly-T status, and FEV1.
In a subgroup analysis in patients 18 years and older, the treatment difference for the mean absolute change from baseline through Week 24 in percent predicted FEV1 was 5.0 percent points (95% CI 1.1, 8.8). In a subgroup analysis in patients 6-11 years of age, the treatment difference for the mean absolute change from baseline through Week 24 in percent predicted FEV1 was -6.3 percentage points (95% CI -12.0, -0.7).
No statistical analysis was conducted for subjects 12 to 17 years of age because only 2 patients were enrolled in the clinical study (see Table 10).
Other efficacy variables that were analysed included absolute change in sweat chloride from baseline through Week 24, improvement in cystic fibrosis respiratory symptoms through Week 24 as assessed by the CFQ-R respiratory domain score (see Table 10), absolute change in body mass index (BMI) at Week 24, and time to first pulmonary exacerbation. The overall treatment difference for the absolute change from baseline in BMI at Week 24 was 0.3 kg/m2 and the calculated hazard ratio for time to first pulmonary exacerbation was 0.93, which were not statistically significant.
Statistically significant improvements in clinical efficacy (FEV1, CFQ-R respiratory domain) were seen in several subgroup analyses, and decreases in sweat chloride were observed in all subgroups. Subgroups analyzed included those based on age, lung function, and poly-T status (see Table 10).
The efficacy of ivacaftor beyond 2 years of treatment has not been examined in clinical trials in children with R117H mutation.

Study 7 (VX11-770-108, KIWI): study in paediatric patients with CF aged 2 to less than 6 years with G551D or another gating mutation.

The pharmacokinetic profile, safety and efficacy of ivacaftor granules in patients aged 2 through less than 6 years with CF who have a G551D mutation or other gating (class III) mutation in the CFTR gene were studied in a 2-part, 24-week, open-label, Phase 3 clinical study in 34 patients (efficacy was a tertiary endpoint). The results of studies 1, 2 and 5 which examined ivacaftor in older subjects were used as supportive data.
Patients in Study 7 KIWI were 2 to less than 6 years of age (mean age 3 years). The majority of the study population had pancreatic insufficiency; 25 of the 27 patients with available data had Faecal Elastase-1 values < 50 microgram/g at baseline. The mean Fecal Elastase-1 value at baseline was 28 microgram/g.
Patients with evidence of colonisation with Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥ 3 x ULN at screening were excluded.
Patients were assigned to the ivacaftor 50 mg or ivacaftor 75 mg groups according to their weight at enrolment (patients weighing less than 14 kg received ivacaftor 50 mg granules and patients weighing more than 14 kg received ivacaftor 75 mg granules). Ivacaftor was administered orally every 12 hours with fat-containing food in addition to their prescribed CF therapies.
Efficacy endpoints evaluated were absolute change from baseline in sweat chloride through 24 weeks of treatment, measures of nutritional status including absolute change from baseline in weight, body mass index (BMI), and stature (supported by weight, BMI, and stature-for-age z-scores) at 24 weeks of treatment, and measures of pancreatic function including Fecal Elastase-1 and Immunoreactive Trypsinogen (IRT) results at 24 weeks.
Overall, sweat chloride, and mean absolute changes from baseline in nutritional status (weight, BMI, stature; supported by weight, BMI, and stature-for-age z-scores), showed improvement from baseline in Study 7 KIWI. Changes in weight and BMI z-scores are consistent with results shown in 6- to 11-year-olds in Study 2 ENVISION and Study 5 KONNECTION. Substantial increases from baseline in Faecal Elastase-1 were observed at Week 24. The mean (SD) overall change from baseline in Faecal Elastase-1 (n = 27) was 99.8 microgram/g (138.4). Six patients with initial levels below 200 microgram/g achieved, at week 24, a level of ≥ 200 microgram/g. Changes from baseline in IRT (mean baseline value 33.58 nanogram/mL) showed decreases at Week 24. Results are shown in Table 11. Data on percent predicted FEV1 (exploratory endpoint) were available for 3 patients in the ivacaftor 50 mg group and 17 patients in the 75 mg dosing group. The mean (SD) overall change in percent predicted FEV1 from baseline at week 24 (exploratory endpoint) was 1.8 (17.81).

Study 8 (VX15-770-124, ARRIVAL): safety study in paediatric patients with CF aged less than 24 months.

The use of ivacaftor in patients with CF aged 4 months to less than 24 months is based on the extrapolation of evidence from studies of ivacaftor in patients aged 6 years and older, and supported by additional PK and safety data from clinical trial (Study 8 ARRIVAL). Study 8 ARRIVAL was a 24 week open label, phase 3 clinical study including data of a cohort of 19 patients aged 12 months to less than 24 months, a cohort of 11 patients aged 6 months to less than 12 months, and a cohort of 6 patients aged 4 months to less than 6 months. Patients with a gating mutation, or R117H mutation were eligible to participate.
In part B of Study 8 ARRIVAL, patients received ivacaftor 25 mg, 50 mg or 75 mg according to their age and weight at each study visit (patients weighing 5 kg to less than 7 kg received ivacaftor 25 mg, patients weighing 7 kg to less than 14 kg received ivacaftor 50 mg, and patients weighing more than 14 kg received ivacaftor 75 mg). Ivacaftor was administered orally every 12 hours with fat-containing food in addition to standard-of-care CF therapies.
The primary endpoint of safety was evaluated through 24 weeks (see Section 4.8 Adverse Effects (Undesirable Effects)). Secondary endpoints were evaluation of pharmacokinetics and the absolute change from baseline in sweat chloride. Sweat chloride showed improvement from baseline as early as Week 2, which was sustained through 24 weeks of treatment. Mean measures of nutritional status were normal at baseline and generally maintained through 24 weeks of treatment.
The mean (SD) Faecal Elastase-1 (a measure of exocrine pancreatic function) values at baseline and Week 24 are shown in Table 12.

Long term safety study.

In a 5 year observational safety surveillance study using real-world data from US and UK CF patient registries, key clinical outcomes were compared annually between ivacaftor-treated patients and untreated comparator patients matched on age, gender and disease severity as assessed by genotype. In the US registry there was a lower incidence of death, organ transplant, pulmonary exacerbations and hospitalisations in ivacaftor-treated versus untreated comparator patients. Results from the UK registry were similar.
In a disease progression analysis over the course of the study, a sub-set of patients with a record of continuous ivacaftor treatment (the majority of patients had the G551D mutation) had better preservation of lung function and improved BMI relative to untreated comparator patients.

Study 9 (VX17-770-128): post-marketing observational study.

The use of ivacaftor in patients with CF who have ivacaftor-responsive CFTR mutations, based on in vitro FRT testing (see Section 5.1 Pharmacodynamic Properties, Mechanism of action) is supported with additional post-marketing observational data (Study 9). Study 9 was a 3-year observational study evaluating the real-world clinical response to ivacaftor in CF patients with mutations that are ivacaftor-responsive based on in vitro and/or clinical evidence. The data used in the analysis were collected by the United States Cystic Fibrosis Foundation Patient Registry (US CFFPR).
The study included data from 349 patients aged 2 years and older with selected FDA-approved ivacaftor-responsive CFTR mutations and a new record of ivacaftor initiation between 17 May 2017 and 31 December 2017. Analyses were performed using data for up to 36 months before and 36 months after initiation of ivacaftor treatment. Of the 349 patients in the ivacaftor cohort, 232 (66.5%) remained in the cohort at the beginning of the second year of follow-up, and 167 (47.9%) remained in the cohort at the beginning of the third year. The most common reason for cohort attrition was initiating use of another CFTR modulator.
The study endpoints included lung function measurements (ppFEV1), PEx, hospitalizations, nutritional parameters (weight, BMI, and z-scores for weight and BMI), death, organ transplantation, selected CF complications, and selected pulmonary pathogens. The results of the observational study support the effectiveness of ivacaftor in patients with CF with ivacaftor-responsive CFTR mutations.
Nineteen ivacaftor-responsive mutations were represented in the enrolled patient population. At ivacaftor initiation, the mean age of patients was 27.6 years and they had a mean ppFEV1 of 77.5. The most common mutation subgroups were D1152H (21.2%), A455E (16.9%), L206W and S945L (11.7% each), R347H (9.2%), P67L (7.4%), and R117C (5.2%).
For each of the 12-month periods after ivacaftor initiation, in patients 6 years and older, ppFEV1 was increased compared to the pre-treatment period. A subgroup analysis was performed in individual CFTR mutation subgroups where there were at least 5 patients with available ppFEV1 data. There were 12 evaluable mutation subgroups and consistent ppFEV1 increases were observed in all mutation sub-groups in the year after ivacaftor initiation. These improvements were generally maintained in the subsequent follow-up years.

5.2 Pharmacokinetic Properties

The pharmacokinetics of ivacaftor are similar between healthy adult volunteers and patients with CF. After oral administration of a single 150 mg dose to healthy volunteers in a fed state, the mean (±SD) for AUC and Cmax were 10,600 (5260) nanogram*hr/mL and 768 (233) nanogram/mL, respectively. The apparent terminal half-life was approximately 12 hours following a single dose in the fed state. The apparent clearance (CL/F) of ivacaftor was similar for healthy subjects and patients with CF. The mean (±SD) of CL/F for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects at steady state. After every 12-hour dosing, steady-state plasma concentrations of ivacaftor were reached by Days 3 to 5, with an accumulation ratio ranging from 2.2 to 2.9.

Absorption.

Following multiple oral dose administrations of ivacaftor, the exposure of ivacaftor generally increased with a dose from 25 mg every 12 hours to 450 mg every 12 hours. The exposure of ivacaftor increased approximately 2.5- to 4-fold when given with fat-containing food. Therefore, ivacaftor should be administered with fat-containing food. The median tmax (range) is approximately 4.0 (3.0, 6.0) hours in the fed state.
Ivacaftor granules (2 x 75 mg sachets) had similar bioavailability to the 150 mg ivacaftor tablet when given with fat-containing food to adult patients. The effect of food on ivacaftor absorption is similar for ivacaftor granules and the 150 mg tablet formulation.

Distribution.

Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells. After oral administration of 150 mg every 12 hours for 7 days in healthy volunteers in a fed state, the mean (±SD) apparent volume of distribution was 353 (122) L.

Metabolism.

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, the majority of ivacaftor (88%) was excreted in the faeces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of the total dose excreted with 22% as M1 and 43% as M6. There was negligible urinary excretion of ivacaftor as unchanged parent and minimal urinary excretion (6.6%) of ivacaftor plus metabolites.

Special populations.

Children and adolescents.

Predicted ivacaftor exposure based on observed ivacaftor concentrations in Phase 2 and 3 studies as determined using population pharmacokinetic (PK) analysis is presented by age group (and body weight for patients less than 12 years of age) in Table 13. Exposures in 6- to 11-year-olds are predictions based on simulations from the population PK model using data obtained for this age group.

Gender.

The effect of gender on ivacaftor pharmacokinetics was evaluated using population pharmacokinetics of data from clinical studies of ivacaftor. No dose adjustments are necessary based on gender.

Renal impairment.

Pharmacokinetic studies have not been performed with ivacaftor in patients with renal impairment. In a human pharmacokinetic study, there was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine).
There was negligible urinary excretion of ivacaftor as unchanged parent (less than 0.01% following a single oral dose of 500 mg). Therefore, no dose adjustments are recommended for mild and moderate renal impairment. However, caution is recommended when administering Kalydeco to 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; Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

Following a single dose of 150 mg of ivacaftor, adult patients with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had similar ivacaftor Cmax (mean [±SD] of 735 [331] nanogram/mL), but an approximately 2-fold increase in ivacaftor AUC0-∞ (mean [±SD] of 16800 [6140] nanogram.hr/mL) compared with healthy subjects matched for demographics.
Simulations for predicting the steady-state exposure of ivacaftor showed that by reducing the dosage from 150 mg q12h to 150 mg once daily, adults with moderate hepatic impairment would have comparable steady-state Cmin values as those obtained with a dose of 150 mg q12h in adults without hepatic impairment. Therefore, a reduced dose of ivacaftor is recommended in patients with moderate hepatic impairment (see Section 4.2 Dose and Method of Administration). The impact of mild hepatic impairment (Child-Pugh Class A, score 5 to 6) on the pharmacokinetics of ivacaftor has not been studied, but the increase in ivacaftor AUC0-∞ is expected to be less than two-fold. Therefore, no dose adjustment is necessary for patients with mild hepatic impairment.
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. The use of Kalydeco in patients with severe hepatic impairment is therefore not recommended unless the benefits outweigh the risks. In such cases, the starting dose of ivacaftor should be reduced and dosing intervals should be modified according to clinical response and tolerability (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity.

Ivacaftor was 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.

Two-year oral studies in mice and rats to assess the carcinogenic potential of ivacaftor demonstrated that ivacaftor was not carcinogenic in either species. Plasma exposures to ivacaftor in mice at the non-carcinogenic dosage (200 mg/kg/day, the highest dosage tested) were approximately 4- to 7-fold higher than the plasma levels measured in humans following ivacaftor therapy, and at least 1.2 to 2.4 times higher with respect to the summed AUC for ivacaftor and its major metabolites. Plasma exposures to ivacaftor in rats at the non-carcinogenic dosage (50 mg/kg/day, the highest dosage tested) were approximately 16- to 29-fold higher than the plasma levels measured in humans following ivacaftor therapy, and 6- to 9-fold higher with respect to the summed AUC for ivacaftor and its major metabolites.

6 Pharmaceutical Particulars

6.1 List of Excipients

Kalydeco tablets.

Each tablet contains the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, hypromellose acetate succinate, croscarmellose sodium, sodium lauryl sulfate, silicon dioxide, magnesium stearate, carnauba wax, Opadry II complete film coating system 85F90614 Blue (PI# 108371), Opacode monogramming ink S-1-17823 Black (PI# 12108).

Kalydeco granules.

Each sachet contains the following inactive ingredients: lactose monohydrate, hypromellose acetate succinate, croscarmellose sodium, sodium lauryl sulfate, silicon dioxide, magnesium stearate, mannitol, sucralose.

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 (150 mg).

Kalydeco tablets are packaged in a thermoform (polychlorotrifluoroethylene [PCTFE]/foil) blister pack or a child-resistant high-density polyethylene (HDPE) bottle with a polypropylene, foil-lined induction seal closure and molecular sieve desiccant.
The following pack sizes are available:
Blister pack containing 56 film-coated tablets;
Bottle containing 56 film-coated tablets.

Granules (25 mg, 50 mg and 75 mg).

Kalydeco granules are packaged in a Biaxially Oriented Polyethylene Terephthalate/Polyethylene/Foil/Polyethylene (BOPET/PE/Foil/PE) sachet.
A pack size of 56 sachets (containing 4 individual wallets with 14 sachets per wallet) is available.

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

Chemical structure.


The empirical formula of ivacaftor is C24H28N2O3 and its molecular weight is 392.49. 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.
Ivacaftor is a white to off-white powder that is practically insoluble in water (< 0.05 microgram/mL).

CAS number.

873054-44-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes