• Addition of Depression text in 4.4
• Revision to breast-feeding text in 4.6
• Addition of Depression in Table 4: Adverse reactions in 4.8
• Updated revision date

Kalydeco granules PI

Minor typographical changes and text updates throughout the PI

Update to revise the word “medicine/s” with “medicinal product/s” throughout the PI.

Section 5: Pharmacological Properties

5.1 Pharmacodynamics Properties

Mechanism of action - Update to specify the reference to study 5 to include safety.

Section 9:

Date of latest renewal: 29 April 2022

Section 10:

Date of revision of the text: 04/2022

Minor correction (section 5.1) change 6 months to 4 months for study 8 study in paediatric patients with CF aged less than 24 months.

Section 6.

Clarification in the manufacturer’s address that Almac Craigavon is in Northern Ireland within the United Kingdom.

Updated date

Date updated

Updated date

Updated date

Minor administrative edits throughout the label
4.2    Posology and method of administration

• Some minor administrative updates in this section.
• Missed dose
• Editorial updates to instructions to patients who may have missed a dose.

4.8    Undesirable effects

• Table 2 title header amended.
• Paediatric population section updated to include information on peak LFT elevations being generally higher in paediatric patients than in older patients.

Minor typographical changes throughout the SmPC and spelling correction.

4.1. Therapeutic indications

Updated indication to state that Kalydeco granules are indicated for the treatment of patients aged at least 4 months.

4.2          Posology and method of administration

Update to dosing recommendations table (Table 1) to add information for patients 4 months to less than 6 months, which is 25 mg granules taken orally every 12 hours with fait-containing food, for patients weighing at least 5kgs, with a total daily dose of 50 mg.

Update to subsection on concomitant use of CYP3A inhibitors to amend the dose recommendation for use with moderate and strong CYP3A inhibitors to patients aged 6 months and older.

Additional information added to state that 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 of age.

Text added:Due to the variability in maturation of the 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 packet of 25 mg granules twice weekly or less frequently (see sections 4.4 and 4.5). Dosing intervals should be modified according to clinical response and tolerability (see sections 4.4 and 5.2)

Update to the dose adjustment section for hepatically impaired to amend the dose recommendation for use with mild and moderate impairment to patients aged 6 months and older. Also the age of 6 months have been added to state there is no experience of the use of ivacaftor in patients with severe hepatic impairment (Child-Pugh class C).

Seville oranges removed from method of administration section and food or drink to be avoided during treatment.

​​​​​​​4.5 Interaction with other medicinal products and other forms of interaction

Removed Seville oranges as a food to be avoided during treatment with ivacaftor in the CYP3A inhibitors subsection.

4.8 Undesirable effects

Adverse events table header (Table 2) amended to patients 4 months and older.

Addition of the patient cohort information for patients between 4 months to less than 6 months of age who were studied as part of the paediatric population.

Amended the safety profile sentence in the paediatric population section to confirm the safety profile is generally consistent among paediatric patients aged 4 months and older.

Table 3 amended to add transaminase elevations data in patients 4 to less than 6 months of age.

​​​​​​​​​​​​​​5.1 Pharmacodynamic properties

Updated figures for mean absolute change from baseline in sweat chloride in study 8 and addition of the 4 months to less than 6 months age cohort data for study 8.

Table 7 and summary of data updated to include data for patients 4 months to less than 6 months. Patient numbers figure amended, in addition to the baseline and week 24 values showing the effect of ivacaftor on growth parameters.

​​​​​​​​​​​​​​5.2 Pharmacokinetic properties

Addition of mean ivacaftor exposure data for the 4 months to less than 6 months age group in Table 8.

Update to section 1. to update the therapeutic indication to state that Kalydeco granules are indicated for the treatment of babies and children and 4 months and older.

Update to section 2. warnings and precautions section (children) to state that it is not known if ivacaftor is safe and effective in children under 4 months of age.

Update to section 2. “Kalydeco with food and drink” to remove Seville oranges.

Section 3. How to take Kalydeco updated to include dose recommendation for children aged 4months to less than 6 months (Table 1).

Clarifications made on dose reduction and use of Kalydeco granules in children with moderate, severe liver problems. Addition of information for children with liver problems aged between 4 months and 6 months that use is not recommended, but your doctor will decide if it is appropriate for the child to use and what dose they should have.

Minor edits throughout SmPC to amend  “Kalydeco” to “Ivacaftor”.

Update to Section 2. QUALITATIVE AND QUANTITATIVE COMPOSITION

• Revised excipient with known effect text to remove “as” to “lactose monohydrate”.

Update to Section 4.2 Posology and method of administration

• Minor revision to “Missed dose” section to add clarifying text around existing language.

Update to Section 4.4 Special warnings and precautions for use

• Interactions with medicinal products edited to clarify that exposure to ivacaftor is significantly decreased by concomitant use of CYP3A inducers.
• Additionally for strong or moderate CYP3A inhibitors, exposure to ivacaftor is increased.
• “Cataracts” header updated to “Paediatric population”.
• “Potential for ivacaftor to interact with transporters” subsection moved location within this section.

Update to Section 4.8 Undesirable effects

• Section updated to include additional data for transaminase elevations.
• Addition of table for transaminase elevations in patients 6 months to < 12 years treated with ivacaftor as monotherapy.

Updates to section 5.2 Pharmacokinetic properties

• Minor administrative edits.
• Updates to the Biotransformation subsections.

Warnings and Precautions

• Reformatting of “other medicines and Kalydeco” section to include medicines in alphabetical order, simplify descriptors and amend subheaders to “Antibiotic medicines” instead of antibacterial agents and Epilepsy medicines from “anticonvulsant medicines”.

Section 3. How to take Kalydeco

• Addition of “Kalydeco” to dosing recommendation table for sachets.

Section 4. Possible side effects

• Minor administrative edits.
• Subsection “Possible signs of liver problems” included.

• Updates to section 4.1 amd 4.2 associated with indication update for infants aged at least 6 months and over with an R117H mutation.
• Updates to section 4.4 and 5.1 due to addition of data from Study 6 ( a study in patients with CF with an R117H mutation in the CTFR gene.

Updates to PIL associated with indication update to include that Kalydeco granules can be used in the treatment of infants, toddlers and children who have an R117H CFTR mutation and weight 5kg to less than 25 kg with Cystic Fibrosis (CF).

Previous text:

1. What Kalydeco is and what it is used for

Kalydeco contains the active ingredient ivacaftor. Ivacaftor acts at the level of the cystic fibrosis transmembrane conductance regulator (CFTR), a protein that forms a channel at the cell surface that allows the movement of particles such as chloride in and out of the cell. Due to mutations in the CFTR gene (see below), chloride movement is reduced in those with cystic fibrosis (CF). Ivacaftor helps certain abnormal CFTR proteins open more often to improve chloride movement in and out of the cell.

Kalydeco granules are indicated for the treatment of babies and children aged 6 months and older and weighing 5 kg to less than 25 kg with cystic fibrosis (CF) who have one of the following gating mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R.

Updated text:

1. What Kalydeco is and what it is used for

Kalydeco contains the active ingredient ivacaftor. Ivacaftor acts at the level of the cystic fibrosis transmembrane conductance regulator (CFTR), a protein that forms a channel at the cell surface that allows the movement of particles such as chloride in and out of the cell. Due to mutations in the CFTR gene (see below), chloride movement is reduced in those with cystic fibrosis (CF). Ivacaftor helps certain abnormal CFTR proteins open more often to improve chloride movement in and out of the cell.

Kalydeco granules are indicated for the treatment of babies and children aged 6 months and older and weighing 5 kg to less than 25 kg with cystic fibrosis (CF) who have an R117H CFTR mutation or one of the following gating mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R.

Previous text:

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

Children

Do not give this medicine to children under 6 months of age with gating mutations as it is not known if ivacaftor is safe and effective in these children.

Updated text:

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

Children

Do not give this medicine to children under 6 months of age as it is not known if ivacaftor is safe and effective in these children.

PIL updated to reflect license expansion to 6 months of age and new 25mg dose.

Dosing table updated to include lower weight group

Lisence expanded to include Kalydeco 25 mg granules in sachet.

Indicated age from 6 months and dosing table 1 updated to reflect this change.

Table 7 updated to include younger age group

Note removal of black triangle

Section 4.1: age change from 2 years to 12 months and weight to 7 kilos.

Section 4.2 age change

Section 4.8: Tables updated to reflect age change and addition of the following wording:

During the 24‑week, open‑label, Phase 3 clinical study of ivacaftor in patients aged 12 months to less than 24 months (Study 8), 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 patients 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 (see section 4.4 for management of elevated transaminases). 

Section 5.1 new data on Study 8 added.

Section 5.2 Table updated to reflect age change

Section 7 MAH address changed

Wording updated to reflect new data

In section 3: minor editorial changes

In section 4.2: minor editorial changes

In section 4.4: Removal of the warning regarding limited data in patients with FEV1 <40%. Other minor editorial changes

In section 4.5: Removal of the drug-drug interaction information for CYP2C8 substrates. Other minor editorial changes

In section 4.6: minor editorial changes

In section 4.7: minor editorial changes

In section 4.8: minor editorial changes

In section 4.9: minor editorial changes

In section 5.1: minor editorial changes

In section 5.2: minor editorial changes

In section 6.5: minor editorial changes

In section 8: minor editorial changes

In section 9: minor editorial changes

Section 2: minor editorial changes
Section 4.4: minor editorial changes
Section 4.5: minor editorial changes
Section 4.6: changes in relation to pre-clinical pregnancy, breast-feeding and fertility data
Section 5.1: minor editorial changes
Section 5.2: minor editorial changes
Section 5.3: changes to pre-clinical data on teratogenicity, carcinogenicity and findings of cataracts