Orkambi 200 mg/125 mg tablets and 100mg/125mg tablets

Summary of changes 

• To align the PI to the latest QRD template (v. 10.2)
• Trial numbers updated to reflect study numbers 
• To remove the 28-tablet 200 mg/125 mg presentation (EU/1/15/1059/003) for Orkambi Film-coated tablet
• Section 6.3 Shelf life update for Orkambi 100mg/125mg film coated tablets
• Section 8 Marketing Authorisation number deleted (EU/1/15/1059/003)

Summary of changes 

• Correction on spelling mistakes
• To remove the 28-tablet 200 mg/125 mg presentation (EU/1/15/1059/003) for Orkambi Film-coated tablet
• To update the Greek address in the local representative table

Use of word “treatment” when talking about this product more widely used throughout

Hepatobiliary events changed to Hepatobiliary adverse reactions throughout

Respiratory events changed to Respiratory adverse reactions throughout

Changed “Day” to day and “Week” to week and “Trial” to trial throughout

4.1 Therapeutic Indications

Added definition of CFTR gene- cystic fibrosis transmembrane conductance regulator

4.2 Posology and method of administration

Removed “for standard dosing recommendations see Table 1” line

Table 1

Amended table to use the number 2 instead of the word two

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)

Removed the word “drug” from Established and other potentially significant interactions sub-section title

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”

6.1 List of excipients

Printing Ink- changed Ammonium hydroxide to Ammonia solution, concentrated

Addition of local representative details for marketing authorisation holder.

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 4.8

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.

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 4.8

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

Summary of the changes:

• 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
• The MAH has been updated

Commission Decision for the Orkambi MAH transfer (dated 26 Nov 2018)Marketing Authorisation Holder changed

New text added to section 4.5:

False Positive Urine Tests for THC

There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving Orkambi. An alternative confirmatory method should be considered to verify results

4.8 Undesirable effects:
Addition of ‘Blood creatine phosphokinase increased’ with frequency ‘common’
Table 4 has been updated to reflect this change

Orkambi 200 mg/125 mg film-coated tablets

4 years (PREVIOUSLY 2 YEARS)

Section 1:

Addition of new dose: Orkambi 100 mg/125 mg film coated tablets

Section 2:

Addition of new composition details:

Orkambi 100 mg/125 mg film-coated tablets

Each film coated tablet contains 100 mg of lumacaftor and 125 mg of ivacaftor.

Orkambi 200 mg/125 mg film-coated tablets

Section 3:

Addition of new text describing pharmaceutical form:

Orkambi 100 mg/125 mg film-coated tablets

Pink, oval shaped tablets (dimensions 14 × 7.6 × 4.9 mm) printed with “1V125” in black ink on one side.

Orkambi 200 mg/125 mg film-coated tablets

Section 4.2:

New Table 1with doses

Addition of wording:

Updated working regarding Concomitant use of CYP3A inhibitors

No dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking Orkambi. However, when initiating Orkambi in patients taking strong CYP3A inhibitors, the dose should be reduced to one tablet daily (lumacaftor 100 mg/ivacaftor 125 mg total daily dose for patients aged 6 to 11 years; lumacaftor 200 mg/ivacaftor 125 mg total daily dose for patients aged 12 years and older) for the first week of treatment to allow for the steady state induction effect of lumacaftor. Following this period, the recommended daily dose should be continued.

If Orkambi is interrupted for more than one week and then re initiated while taking strong CYP3A inhibitors, the Orkambi dose should be reduced to one tablet daily for the first week of treatment re initiation. Following this period, the recommended daily dose should be continued (see section 4.5).

Addition of Table 2 regarding dose adjustments for patients with hepatic impairment

Updated wording for Paediatric population

The safety and efficacy of Orkambi in children aged less than 6 years have not yet been established

Method of administration updated working:

Patients may start taking Orkambi on any day of the week

Section 4.4

Updated information for Respiratory events:

A transient decline in FEV1 has also been observed in some patients following initiation of lumacaftor/ivacaftor.

initiating treatment in patients having a pulmonary exacerbation is not advisable

Section 4.5

Addition of information:

The drug interaction profile for lumacaftor 200 mg/ivacaftor 250 mg every 12 hours is considered to be the same as that for lumacaftor 400 mg/ivacaftor 250 mg every 12 hours, based on exposure at the indicated doses.

Addition of information for Paediatric population and interaction studies:

Interaction studies have only been performed in adults.

Section 4.7:

Deletion of text regarding influence on ability to drive or use machinery

Section 4.8

Updated wording to include long-term safety data:

The safety data from 1029 patients aged 12 years and older who were homozygous for the F508del mutation in the CFTR gene treated with lumacaftor/ivacaftor for up to an additional 2496

Tabulated list of adverse reactions updated to include the 24-week, placebo-controlled study in patients aged 6 to 11 years (Trial 7).

Table 4 updated to include productive cough, sputum increased and abdominal pain upper

Description of selected adverse reactions: wording updated to refer to Trials 1 and 2 rather that Phase 3 studies.

Paediatric population section updated to include new data:

Safety data were collected forevaluated in 161 paediatric patients aged 6 to 11 years (Trials 6 and 7) and in 194 paediatric patients with CFaged 12 to 17 years with CF who are homozygous for the F508del mutation and who received lumacaftor/ivacaftor in the placebo controlled, Phase 3clinical studies. Patients aged 12 to 17 years were included in Trials 1 and 2.

The safety profile in these paediatric patients is generally consistent with that in adult patients. Additional adverse reactions from Trial 6 are included in Table 4.

Description of selected adverse reactions for patients aged 6 to 11 years

Hepatobiliary events

During the 24 week, open label Phase 3 clinical study in 58 patients aged 6 to 11 years (Trial 6), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 5.3%, 8.8%, and 19.3%. No patients had total bilirubin levels > 2 x ULN. Lumacaftor/ivacaftor dosing was maintained or successfully resumed after interruption in all patients with transaminase elevations, except 1 patient who discontinued treatment permanently.

During the 24 week, placebo-controlled Phase 3 clinical study in 204 patients aged 6 to 11 years (Trial 7), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 1.0%, 4.9%, and 12.6% in the lumacaftor/ivacaftor patients, and 2.0%, 3.0%, and 7.9% in the placebo treated patients. No patients had total bilirubin levels >2 x ULN. Two patients in the lumacaftor/ivacaftor group and two patients in the placebo group discontinued treatment permanently due to transaminase elevations.

Respiratory events

During the 24 week, open label Phase 3 clinical study (Trial 6) in 58 patients aged 6 to 11 years (mean baseline ppFEV1 was 91.4), the incidence of respiratory adverse reactions was 6.9% (4/58).

During the 24 week, placebo-controlled Phase 3 clinical study (Trial 7) in patients aged 6 to 11 years (mean baseline ppFEV1 was 89.8), the incidence of respiratory adverse reactions was 18.4% in lumacaftor/ivacaftor patients and 12.9% in placebo patients. A decline in ppFEV1 at initiation of therapy was observed during serial post dose spirometry assessments. The absolute change from pre-dose at 4-6 hours post-dose was -7.7 on Day 1 and -1.3 on Day 15 in lumacaftor/ivacaftor patients. The post-dose decline was resolved by Week 16.

Section 5

New information in Pharmacodynamic effects section

Changes in sweat chloride in response to lumacaftor/ivacaftor were evaluated as part of a 24-week, placebo-controlled, Phase 3 clinical study (Trial 7) in 204 patients (103 received lumacaftor 200 mg/ivacaftor 250 mg every 12 hours and 101 received placebo) with CF aged 6 to 11 years old who were homozygous for the F508del mutation in the CFTR gene. Treatment with lumacaftor/ivacaftor demonstrated a statistically significant decrease in sweat chloride compared to placebo and sustained through 24 weeks of treatment. The treatment difference (LS mean) in sweat chloride for the average absolute change at Day 15 and at Week 4 as compared to placebo was -20.8 mmol/L (95% CI:  23.4,  18.2; P<0.0001). The treatment difference (LS mean) in sweat chloride for the absolute change at Week 24 as compared to placebo was  24.9 mmol/L (P<0.0001).

Wording updated:

Changes in FEV1:

Changes in ppFEV1 in response to lumacaftor alone or in combination with ivacaftor were also evaluated in this the double blind, placebo controlled, Phase 2 trial in patients with CF age 18 years and older.

Wording updated with new trial data:

Clinical efficacy and safety

Trials in patients with CF aged 12 years and above

New data regarding Trial 7 added:

Trials in patients with CF aged 6 to 11 years old who are homozygous for the F508del mutation in the CFTR gene

Trial 7 was a 24-week, placebo-controlled, Phase 3 clinical study in 204 patients with CF aged 6 to 11 years old (mean age 8.8 years). Trial 7 evaluated subjects with lung clearance index (LCI2.5) ≥7.5 at the initial screening visit (mean LCI2.5 10.28 at baseline [range: 6.55 to 16.38]) and ppFEV1 ≥70 at screening (mean ppFEV1 89.8 at baseline [range: 48.6 to 119.6]). Patients received either lumacaftor 200 mg/ivacaftor 250 mg every 12 hours (n=103) or placebo (n=101) in addition to their prescribed CF therapies. Patients who had 2 or more abnormal liver function tests (ALT, AST, AP, GGT ≥3 times the ULN), or ALT or AST >5 times ULN, or total bilirubin >2 times ULN were excluded.

The primary efficacy endpoint was absolute change in LCI2.5 from baseline through Week 24. Key secondary endpoints included average absolute change from baseline in sweat chloride at Day 15 and Week 4 and at Week 24 (see Pharmacodynamic effects), absolute change from baseline in BMI at Week 24, absolute change from baseline in CFQ R Respiratory Domain through Week 24. These results are presented in Table 6 below:

Addition of Table 6: Summary of primary and key secondary outcomes in Trial 7

Percent predicted FEV1 was also evaluated as a clinically meaningful other secondary endpoint. In the lumacaftor/ivacaftor patients, the treatment difference for absolute change in ppFEV1 from baseline through Week 24 was 2.4 (P=0.0182).

Section 5.2 Addition of data regarding Paediatric population and Table 7

The exposures are similar between adults and the paediatric population based on population (PK) analyses as presented in Table 7 below:

Updated wording regarding Long term safety and efficacy rollover trial

Trial 3 was a Phase 3, parallel group, multicentre, rollover extension study in patients with CF that includesd patients aged 12 years and older from Trial 1 and Trial 2. This extension trial was designed to evaluate the safety and efficacy of long-term treatment of lumacaftor/ivacaftor. Of the 1108 patients who received any treatment in Trial 1 or Trial 2, 1029 (93%) were enrolled dosed and received active treatment (lumacaftor 600 mg q12h/ivacaftor 250 mg q12h or lumacaftor 400 mg q12h/ivacaftor 250 mg q12h) in Trial 3 for up to an additional 96 weeks (i.e. up to a total of 120 weeks). The primary efficacy analysis of this extension study included data up to Week 72 of Trial 3 with a sensitivity analysis that included data up to Week 96 of Trial 3. This 96 week trial is designed to evaluate the safety and efficacy of long term treatment of lumacaftor/ivacaftor and is ongoing.

Patients treated with lumacaftor/ivacaftor in Trial 1 or Trial 2 showed an effect that was maintained with respect to baseline after an additional 96 weeks through Trial 3. For patients who transitioned from placebo to active treatment similar changes as those observed in patients treated with lumacaftor/ivacaftor in Trial 1 or Trial 2 were seen (see Table 53). Results from Trial 3 are presented in Figure 1 and Table 64.

Figure 1. Absolute change from baseline in percent predicted FEV1 at each visit updated

Addition of Table 64: Long-term effect of Lumacaftor/Ivacaftor in Trial 3

Section 6.3

Information on shelf life updated to include new formulation:

Orkambi 100 mg/125 mg film-coated tablets

3 years

Orkambi 200 mg/125 mg film-coated tablets

2 years

Section 6.5 wording updated to include new formulation:

Blister consisting of PolyChloroTriFluoroEthylene (PCTFE (polychlorotrifluoroethylene)/PolyVinyl Chloride (PVC (polyvinyl chloride) with a paper backed aluminium foil lidding.

Orkambi 100 mg/125 mg film-coated tablets

Pack containing 112 film-coated tablets (4 packs of 28 film-coated tablets).

Orkambi 200 mg/125 mg film-coated tablets

Orkambi is available in the following pack sizes:

Pack containingsize of 28 film-coated tablets.

Multipacks containing 56 film-coated tablets (2 packs of 28 film-coated tablets).

Multipacks containing 112 film-coated tablets (4 packs of 28 film-coated tablets).

112 tablets (4 packs of 28 tablets each).

Pack size of 56 tablets (2 packs of 28 tablets each).

Pack size of 28 tablets

Section 8: New MARKETING AUTHORISATION NUMBER added: EU/1/15/1059/005

During a 24-week, open label, Phase 3b clinical study (Trial 4) in 46 patients aged 12 years and older with advanced lung disease (ppFEV₁ <40) [mean ppFEV₁ 29.1 at baseline (range: 18.3 to 42.0)], the incidence of respiratory events was 65.2%. In the subgroup of 28 patients who were initiated at the full dose of lumacaftor/ivacaftor (2 tablets every 12 hours), the incidence was 71.4%, and in the 18 patients who were initiated at a reduced dose of lumacaftor/ivacaftor (1 tablet every 12 hours for up to 2 weeks, and subsequently increased to the full dose), the incidence was 55.6%. Of the patients who were initiated lumacaftor/ivacaftor at the full dose, one patient had a serious respiratory event, three patients subsequently had their dose reduced, and three patients discontinued treatment. No serious respiratory events, dose reductions or discontinuations were seen in patients who were initiated at the half dose (see section 4.4).

Section 4.4: Respiratory adverse events: updated information as follows - Serious respiratory events were seen more frequently in patients with percent predicted FEV1 (ppFEV1) <40, and may lead to drug discontinuation.

​​Section 4.4: Patients with advanced liver disease : updates to describe the risk of potential fatal decompensation in patients who have cirrhosis with portal hypertension

Section 4.4: Cataracts : to report that cataracts were observed with lumacaftor/Ivacaftor and Ivacaftor alone

Section 4.8: Post-Marketing experience, update to existing Selected Adverse Reaction subsection Hepatobiliary events to add information related to a fatal outcome seen in a post-marketing setting.

Pregnancy and Fertility

Ivacaftor was not teratogenic when dosed orally to pregnant rats and rabbits during the organogenesis stage of foetal development at doses approximately 7 times (ivacaftor and metabolite exposure) and 46 times the ivacaftor exposure in humans at the therapeutic lumacaftor/ivacaftor dose, respectively. At maternally toxic doses in rats, ivacaftor produced reductions in foetal body weight; an increase in the incidence of variations in cervical ribs, hypoplastic ribs, and wavy ribs; and sternal irregularities, including fusions. The significance of these findings for humans is unknown.

Ivacaftor impaired fertility and reproductive performance indices in male and female rats at 200 mg/kg/day (yielding exposures approximately 11 and 7 times, respectively, those obtained with the maximum recommended human dose of the ivacaftor component of Orkambi based on summed AUCs of ivacaftor and its metabolites extrapolated from Day 90 exposures at 150 mg/kg/day in the 6‑month repeat‑dose toxicity study and gestation Day 17 exposures in the pilot embryofetal development study in this species) when dams were dosed prior to and during early pregnancy. No effects on male or female fertility and reproductive performance indices were observed at ≤100 mg/kg/day (yielding exposures approximately 8 and 5 times, respectively, those obtained with the maximum recommended human dose of the ivacaftor component of Orkambi based on summed AUCs of ivacaftor and its metabolites extrapolated from Day 90 exposures at 100 mg/kg/day in the 6‑month repeat‑dose toxicity study and gestation Day 17 exposures in the embryofetal development study in this species).

• Section 4.5: Additional text reflect new in-vitro transporters data: The following text below has been added     

  Potential for lumacaftor/ivacaftor  to interact with transporters

   

  In vitro experiments show that lumacaftor is a substrate for Breast Cancer Resistance Protein (BCRP). Co-administration of Orkambi with medicinal products that inhibit BCRP may increase plasma lumacaftor concentration. Lumacaftor inhibits the organic anion transporter (OAT) 1 and 3. Lumacaftor and ivacaftor are inhibitors of BCRP. Co-administration of Orkambi with medicinal products that are substrates for OAT1/3 and BCRP transport may increase plasma concentrations of such medicinal products. Lumacaftor and ivacaftor are not inhibitors of OATP1B1, OATP1B3, and organic cation transporter (OCT) 1 and 2. Ivacaftor is not an inhibitor of OAT1 and OAT3. 

   

   

   

•    Section 5.2: Additional text added in the section on distribution as follows: In vitro studies indicate that lumacaftor is a substrate of Breast Cancer Resistance Protein (BCRP).

Section 4.4 Special warnings and precautions for use

                Addition of a paragraph on the effect on blood pressure

Section 4.8 Undesirable Effects

Update to Adverse reactions table (table 2): addition of hypertension as uncommon AR and blood pressure increased as uncommon AR

Addition of a new section about increase blood pressure and results from pivotal Phase 3 studies.

Additional sub-headings in Section 5.1 Pharmacodynamic properties: “effects on sweat chloride”, “Decrease in Heart Rate”

Additional paragraph in Section 5.1:

Decrease in heart rate