Orkambi 100 mg/125 mg granules and 150 mg/188 mg granules

Summary of changes 

• To align the PI to the latest QRD template (v. 10.2)
• Trial numbers updated to reflect study numbers 

Summary of changes 

• Correction in spelling mistakes
• To update the Greek address in the local representative table

Hepatobiliary events changed to Hepatobiliary adverse reactions throughout

Respiratory events changed to Respiratory adverse reactions throughout

4.1 Therapeutic Indications

Changed language from children to patients and added definition of CFTR gene- cystic fibrosis transmembrane conductance regulator

Posology

Added language stating that treatment can be started on any day of the week

Special Populations -Removed Elderly section

Hepatic Impairment- Added language about using Orkambi with caution in patients with severe hepatic impairment

4.4 Special warnings and precautions for use

Bronchospasm added as a common adverse reaction and spelled out forced expiratory volume (FEV)

4.6 Fertility, pregnancy and lactation

Fertility

Added language “No human data on the effects of lumacaftor and/or ivacaftor on fertility are available”

Removed language “No effects on male or female fertility and reproductive performance indices were observed at ≤100 mg/kg/day”

4.8 Undesirable effects

Summary of the safety profile

Removed language about the frequency of serious adverse reactions

Table 4- added bronchospasm adverse reaction under respiratory, thoracic and mediastinal disorders

Paediatric population- Removed language about additional adverse reactions from trial 6

5.1 Pharmacodynamic Properties

Pharmacodynamic effects- Added Cardiac electrophysiology Section stating, “No meaningful changes in QTc interval or blood pressure were observed in a thorough QT clinical study evaluating lumacaftor 600 mg once daily/ivacaftor 250 mg q12h and lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h.”

5.3 Preclinical safety data

Safety Pharmacology- removed, “No meaningful changes in QTc interval or blood pressure were observed in a thorough QT clinical study evaluating either lumacaftor 600 mg once daily/ivacaftor 250mg q12h or lumacaftor 1000mg once daily/ivacaftor 450 mg q12h, demonstrating a lack of translation of these non-clinical findings to the clinic.”

Peri- and post-natal development- added sentence, “yielding exposures that were approximately 4 times those obtained with the maximum recommended human dose of the ivacaftor component of Orkambi based on summed AUCs of ivacaftor and its metabolites”

6.6 Special precautions for disposal

Removed “no special requirements” to add, “Any unused medicinal product or waste material should be disposed of in accordance with local requirements.”

Updated language to be “your child” throughout

1. What Orkambi is and what it is used for

Added “homozygotes” at the end of the indication statement

Removed, “While taking Orkambi, you may notice that your child’s breathing is easier, that they do not get ill as often, and/or that it is easier to gain weight.”

2. What you need to know before taking Orkambi Warnings and Precautions

Added that narrowing of the airways were seen in patients

Updated that Orkambi contains sodium

4. Possible side effects

Updated a header to be “Other side effects”

Under Common side effects added narrowing of the airways and high levels of liver enzymes, shown by a blood test

Under uncommon side effects added “in males” after enlargement of the breast

Addition of local representative details for marketing authorisation holder.

Orkambi SmPC

Administrative edits throughout to change “Trials” to “trials”, “Week” to “week” and “Day” to “day” where applicable.

Section 4.4

Update to include information on conducting through investigation regarding the causes of a significant elevation of ALT or AST.

Previous text:

Hepatobiliary events

……….

In the event of significant elevation of ALT or AST, with or without elevated bilirubin (either ALT or AST > 5 x the upper limit of normal [ULN], or ALT or AST > 3 x ULN with bilirubin > 2 x ULN), dosing with lumacaftor/ivacaftor should be discontinued and laboratory tests closely followed until the abnormalities resolve.Following resolution of transaminase elevations, the benefits and risks of resuming dosing should be considered (see sections 4.2, 4.8, and 5.2).

Updated text:

Hepatobiliary events

……….

In the event of significant elevation of ALT or AST, with or without elevated bilirubin (either ALT or AST > 5 x the upper limit of normal [ULN], or ALT or AST > 3 x ULN with bilirubin > 2 x ULN and/or clinical jaundice), dosing with lumacaftor/ivacaftor should be discontinued and laboratory tests closely followed until the abnormalities resolve. A thorough investigation of potential causes should be conducted and patients should be followed closely for clinical progression. Following resolution of transaminase elevations, the benefits and risks of resuming dosing should be considered (see sections 4.2, 4.8, and 5.2).

Section 4.5

Table 3

Update to advice on dose recommendation for patients taking clarithromycin or telithromycin to reduce  to one sachet every other day instead of once daily.

Update to advice on dose recommendation for patients taking itraconazole, ketoconazole, posaconazole, voriconazole to one sachet every other day instead of once daily.

Section 4.8

Under paediatric population addition of long-term safety data from the 96-week rollover extension study in patients 2 yrs and older. Statement that data was generally consistent with the parent study has been added. Also the addition of long-term safety data from 96-week rollover study in patients 6 yrs and older. Statement that data was generally consistent with 24-week parent studies.

Addition of text:

Paediatric population

……….

Long-term safety data from a 96-week rollover extension study in 57 patients aged 2 years and older who were homozygous for the F508del mutation in the CFTR gene were generally consistent with the24-week parent study in patients aged 2 to 5 years (trial 8) and safety data in patients aged 6 to 11 years.

Long-term safety data from a 96-week rollover extension study in 239 patients aged 6 years and older who were homozygous for the F508del mutation in the CFTR gene (trial 9) were generally consistent with the 24-week parent studies in patients aged 6 to 11 years (trial 6 and trial 7).

Section 5.1

Addition of data related to Trial 9 (rollover extension study) including the addition of Table 8 Long-term effect of lumacaftor/ivacaftor in trial 9

Addition of text:

Patients with CF aged 6 years and older from trial 6 and trial 7 were included in a phase 3, multicentre, rollover extension study (trial 9). This extension trial was designed to evaluate the safety and efficacy of long-term treatment of lumacaftor/ivacaftor. Of the 262 patients who received any treatment in trial 6 or trial 7, 239 (91%) were dosed and received active treatment (patients 6 to <12 years of age received lumacaftor 200 mg q12h/ivacaftor 250 mg q12h; patients ≥12 years of age received lumacaftor 400 mg q12h/ivacaftor 250 mg q12h) in the extension study for up to an additional 96 weeks (i.e., up to a total of 120 weeks) (see section 4.8). Secondary efficacy results and pulmonary exacerbation event rate per patient year are presented in Table 8.

Update to section 2. header from “Do not take Orkambi” to “Do not use Orkambi”.

Administrative edit to “Common” side effect to change “Increase of an enzyme in your blood (blood creatine phosphokinase)” to “Increase of an enzyme in the blood (blood creatine phosphokinase)”

Update to possible side effects section “uncommon” side effects to clarify enlargement of the breast can be observed in males when ivacaftor is used alone.

Update to section 5, to add the word “child” in the statement regarding disposal of medicines.

Update to Orkambi 100/125 mg granules in sachet and Orkambi 150/ 188 mg granules in sachet SmPC:

Change from 2 year to 3 years shelf life in section 6.3 of SmPC.

Correction made to file to include granules information only.

Update to Orkambi 100/125 mg granules in sachet and Orkambi 150/ 188 mg granules in sachet SmPC:

Change from 2 year to 3 years shelf life in section 6.3 of SmPC.

• A new SmPC has been created for the granule formulation which follows on from the tablet formulation SmPC
• Sections 1 to 4.2 (name, composition, pharmaceutical form,  indication, posology and administration, dose adjustments for special populations):l new information regarding the granule formulation
• Inclusion of Trial 8 (809-115; 2-5 year olds) in section 4.8
• Undesirable effects to highlight the consistency of the safety profile in ages 2-5
• Inclusion of Trial 8 in section 5.1 Pharmacological properties, pharmacodynamics effects
• Addition of pharmacokinetic properties in children aged 2-5 (consistent exposures to the adult population)
• Update to section 6. Pharmaceutical Particulars to incorporate information for the granule formulation

6.4 Special precautions for storage, this has now been updated to state that no special storage conditions are required, as per EMA requirements