Leaflet KAFTRIO 60mg / 40mg / 80mg granules

Kaftrio 60 mg/40 mg/80 mg granules in sachet

Kaftrio 75 mg/50 mg/100 mg granules in sachet

Kaftrio 60 mg/40 mg/80 mg granules in sachet

Each sachet contains 60 mg of ivacaftor, 40 mg of tezacaftor and 80 mg of elexacaftor.

Each sachet contains 188.6 mg of lactose monohydrate.

Kaftrio 75 mg/50 mg/100 mg granules in sachet

Each sachet contains 75 mg of ivacaftor, 50 mg of tezacaftor and 100 mg of elexacaftor.

Each sachet contains 235.7 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Granules in sachet (granules)

White to off-white granules approximately 2 mm in diameter.

Kaftrio granules are indicated in a combination regimen with ivacaftor for the treatment of cystic fibrosis(CF) in paediatric patients aged 2 to less than 6 years who have at least one non-Class I mutation in thecystic fibrosis transmembrane conductance regulator (CFTR) gene (see sections 4.2 and 5.1).

Kaftrio should only be prescribed by healthcare professionals with experience in the treatment of CF. Ifthe patient’s genotype is unknown, an accurate and validated genotyping method should be performed toconfirm the presence of at least one CFTR mutation that is responsive based on clinical and/or in vitro data(using a genotype assay) (see section 5.1). Kaftrio should only be used in patients diagnosed with CF. Adiagnosis of CF should be made based on diagnostic guidelines and clinical judgement.

There are a limited number of patients who harbour mutations not listed in Table 5 that may be responsiveto Kaftrio. In these cases, Kaftrio can be considered when the physician deems the potential benefitsoutweigh the potential risks and under close medical supervision. This excludes patients with two Class I(null) mutations (mutations that are known not to produce CFTR protein) as they are not expected torespond to modulator therapy (see sections 4.1, pct. 4.4, and 5.1).

Monitoring of transaminases (ALT and AST) and total bilirubin is recommended for all patients prior toinitiating treatment, every 3 months during the first year of treatment and annually thereafter. For patientswith a history of liver disease or transaminase elevations, more frequent monitoring should be considered(see section 4.4).

Paediatric patients aged 2 to less than 6 years should be dosed according to Table 1.

Table 1: Dosing recommendations for patients aged 2 to less than 6 years

Age Weight Morning dose Evening dose10 kg to One sachet of One sachet of< 14 kg ivacaftor 60 mg/tezacaftor ivacaftor 59.5 mg2 to less than 40 mg/elexacaftor 80 mg granules granules6 years One sachet of One sachet of≥ 14 kg ivacaftor 75 mg/tezacaftor ivacaftor 75 mg50 mg/elexacaftor 100 mg granules granules

The morning and evening dose should be taken approximately 12 hours apart, with fat-containing food(see Method of administration).

If 6 hours or less have passed since the missed morning or evening dose, the patient should take themissed dose as soon as possible and continue on the original schedule.

If more than 6 hours have passed since:

* the missed morning dose, the patient should take the missed dose as soon as possible and should nottake the evening dose. The next scheduled morning dose should be taken at the usual time.

OR

* the missed evening dose, the patient should not take the missed dose. The next scheduled morningdose should be taken at the usual time.

Morning and evening doses should not be taken at the same time.

When co-administered with moderate CYP3A inhibitors (e.g., fluconazole, erythromycin, verapamil) orstrong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, andclarithromycin), the dose should be reduced as in Table 2 (see sections 4.4 and 4.5).

Table 2: Dosing schedule for concomitant use with moderate and strong CYP3A inhibitors

Age Weight Moderate CYP3A Inhibitors Strong CYP3A Inhibitors2 years to 10 kg to Alternate each day: One sachet of ivacaftor 60 mg/less than < 14 kg tezacaftor 40 mg/ elexacaftor6 years * One sachet of ivacaftor 60 mg/ 80 mg granules twice a week,tezacaftor 40 mg/elexacaftor approximately 3 to 4 days apart.80 mg granules on the first day

* One sachet of ivacaftor 59.5 mg No evening sachet of ivacaftorgranules on the next day granules.

No evening sachet of ivacaftorgranules.

2 years to ≥ 14 kg Alternate each day: One sachet of ivacaftor 75 mg/less than tezacaftor 50 mg/ elexacaftor6 years * One sachet of ivacaftor 75 mg/ 100 mg granules twice a week,tezacaftor 50 mg/elexacaftor approximately 3 to 4 days apart.100 mg granules on the first day

* One sachet of ivacaftor 75 mg No evening sachet of ivacaftorgranules on the next day granules.

No evening sachet of ivacaftorgranules.

Treatment of patients aged 2 to less than 6 years with moderate hepatic impairment (Child-Pugh Class B)is not recommended. For patients aged 2 to less than 6 years with moderate hepatic impairment, the use of

Kaftrio should only be considered when there is a clear medical need, and the benefits are expected tooutweigh the risks. If used, it should be used with caution at a reduced dose (see Table 3).

Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but theexposure is expected to be higher than in patients with moderate hepatic impairment. Patients with severehepatic impairment should not be treated with Kaftrio.

No dose adjustment is recommended for patients with mild (Child-Pugh Class A) hepatic impairment (see

Table 3) (see sections 4.4, pct. 4.8, and 5.2).

Table 3: Recommendation for use in patients aged 2 to less than 6 years with hepatic impairment

Age Weight Mild Severe(Child-Pug Moderateh Class A) (Child-Pugh Class B) (Child-Pugh

Class C)

Use not recommended. Treatment of patientswith moderate hepatic impairment should onlybe considered when there is a clear medicalneed, and the benefits are expected to outweighthe risks.

If used, Kaftrio should be used with caution at areduced dose, as follows:

2 years to 10 kgless than to No doseadjustment * Days 1-3: one sachet of ivacaftor 60 mg/ Should not6 years < 14 kg tezacaftor 40 mg/elexacaftor 80 mg be usedgranules each day

* Day 4: no dose

* Days 5-6: one sachet of ivacaftor 60 mg/tezacaftor 40 mg/elexacaftor 80 mggranules each day

* Day 7: no dose

Repeat above dosing schedule each week.

The evening dose of the ivacaftor granulesshould not be taken.

Use not recommended. Treatment of patientswith moderate hepatic impairment should onlybe considered when there is a clear medicalneed, and the benefits are expected to outweighthe risks.

If used, Kaftrio should be used with caution at areduced dose, as follows:

2 years to * Days 1-3: one sachet of ivacaftor 75 mg/less than ≥ 14 kg No dose tezacaftor 50 mg/elexacaftor 100 mg Should not6 years adjustment granules each day be used

* Day 4: no dose

* Days 5-6: one sachet of ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100 mggranules each day

* Day 7: no dose

Repeat above dosing schedule each week.

The evening dose of the ivacaftor granulesshould not be taken.

No dose adjustment is recommended for patients with mild and moderate renal impairment. There is noexperience in patients with severe renal impairment or end-stage renal disease (see sections 4.4 and 5.2).

The safety and efficacy of Kaftrio in combination with ivacaftor (IVA) in children aged less than 2 yearshave not yet been established. No data are available.

For oral use. The entire contents of each sachet of granules should be mixed with one teaspoon (5 mL) ofage-appropriate soft food or liquid and the mixture completely consumed. Food or liquid should be atroom temperature or below. Each sachet is for single use only. Once mixed, the product has been shown tobe stable for one hour, and therefore should be ingested during this period. Some examples of soft food orliquids include pureed fruits or vegetables, yogurt, water, milk, or juice. A fat-containing meal or snackshould be consumed just before or after dosing.

Kaftrio should be taken with fat-containing food. Examples of meals or snacks that contain fat are thoseprepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats (see section 5.2).

Food or drink containing grapefruit should be avoided during treatment with Kaftrio (see section 4.5).

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Cases of liver failure leading to transplantation have been reported within the first 6 months of treatmentin patients with and without pre-existing advanced liver disease.

Elevated transaminases are common in patients with CF. In clinical studies, elevated transaminases weremore frequently observed in patients treated with IVA/TEZ/ELX in combination with IVA compared toplacebo. In patients taking IVA/TEZ/ELX in combination with IVA, these elevations have sometimesbeen associated with concomitant elevations in total bilirubin. Assessments of transaminases (ALT and

AST) and total bilirubin are recommended for all patients prior to initiating treatment, every 3 monthsduring the first year of treatment and annually thereafter (see section 4.2).

For patients with a history of liver disease or transaminase elevations, more frequent monitoring should beconsidered.

Interrupt treatment and promptly measure serum transaminases and total bilirubin if a patient developsclinical signs or symptoms of liver injury. Interrupt dosing in the event of ALT or AST >5 × the upperlimit of normal (ULN), or ALT or AST >3 × ULN with total bilirubin >2 × ULN. Closely monitor thelaboratory tests until the abnormalities resolve. Following resolution, consider the benefits and risks ofresuming treatment. Patients who resume treatment after interruption should be monitored closely.

In patients with pre-existing advanced liver disease, IVA/TEZ/ELX in combination with IVA should beused with caution and only if the benefits are expected to outweigh the risks (see sections 4.2, pct. 4.8, and5.2).

Treatment of patients with moderate hepatic impairment is not recommended. For patients with moderatehepatic impairment, the use of IVA/TEZ/ELX should only be considered when there is a clear medicalneed, and the benefits are expected to outweigh the risks. If used, it should be used with caution at areduced dose (see Table 3).

Patients with severe hepatic impairment should not be treated with IVA/TEZ/ELX (see sections 4.2,4.8, and 5.2).

Depression

Depression (including suicidal ideation and suicide attempt) has been reported in patients treated with

IVA/TEZ/ELX, usually occurring within three months of treatment initiation and in patients with ahistory of psychiatric disorders (see section 4.8). In some cases, symptom improvement was reported afterdose reduction or treatment discontinuation. Patients (and caregivers) should be alerted about the need tomonitor for depressed mood, suicidal thoughts, unusual changes in behaviour, anxiety, or insomnia and toseek medical advice immediately if these symptoms present.

In young children (aged 2-5 years) treated with IVA/TEZ/ELX behavioural changes have been reported,which occurred usually within the first two months of treatment initiation. In some cases, symptomimprovement was reported after treatment discontinuation.

There is no experience in patients with severe renal impairment/end-stage renal disease therefore cautionis recommended in this population (see sections 4.2 and 5.2).

Mutations unlikely to respond to modulator therapy

Patients with a genotype consisting of two CFTR mutations that are known not to produce CFTR protein(i.e., two Class I mutations) are not expected to respond to Kaftrio treatment.

Clinical studies comparing IVA/TEZ/ELX to TEZ/IVA or IVA

No clinical study has been conducted to directly compare IVA/TEZ/ELX to TEZ/IVA or IVA in patientsnot harbouring F508del variants.

IVA/TEZ/ELX in combination with IVA has not been studied in patients with CF who have undergoneorgan transplantation. Therefore, use in transplanted patients is not recommended. See section 4.5 forinteractions with commonly used immunosuppressants.

Rash events typically occur during the first month of therapy. Most events were mild to moderate inseverity and in rare cases, rash was associated with additional symptoms such as fever or facial swelling.

In the majority of cases, administration of IVA/TEZ/ELX was continued and the rash resolved withouttreatment. Children have a higher incidence rate compared to adults. The incidence of rash events was alsohigher in females compared to males, particularly in females taking hormonal contraceptives (see section4.8). A role for hormonal contraceptives in the occurrence of rash cannot be excluded. For patients takinghormonal contraceptives who develop rash, interrupting treatment with IVA/TEZ/ELX in combinationwith IVA and hormonal contraceptives should be considered. Following the resolution of rash, it should beconsidered if resuming IVA/TEZ/ELX in combination with IVA without hormonal contraceptives isappropriate. If rash does not recur, resumption of hormonal contraceptives can be considered (see section4.8).

Clinical studies of IVA/TEZ/ELX in combination with IVA did not include sufficient number of patientsaged 65 years and older to determine whether response in these patients is different from younger adults.

Dose recommendations are based on the pharmacokinetic profile and knowledge from studies withtezacaftor/ivacaftor (TEZ/IVA) in combination with IVA, and IVA monotherapy (see section 5.2).

Exposure to IVA is significantly decreased and exposures to ELX and TEZ are expected to decrease bythe concomitant use of CYP3A inducers, potentially resulting in the reduced efficacy of IVA/TEZ/ELXand IVA; therefore, co-administration with strong CYP3A inducers is not recommended (see section 4.5).

Exposures of ELX, TEZ and IVA are increased when co-administered with strong or moderate CYP3Ainhibitors. The dose of IVA/TEZ/ELX and IVA should be adjusted when used concomitantly with strongor moderate CYP3A inhibitors (see section 4.5 and Table 2 in section 4.2).

Cases of non-congenital lens opacities without impact on vision have been reported in paediatric patientstreated with IVA-containing regimens. Although other risk factors were present in some cases (such ascorticosteroid use, exposure to radiation) a possible risk attributable to treatment with IVA cannot beexcluded. Baseline and follow-up ophthalmological examinations are recommended in paediatric patientsinitiating treatment with IVA/TEZ/ELX in combination with IVA (see section 5.3).

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance,total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially‘sodium-free’.

ELX, TEZ and IVA are substrates of CYP3A (IVA is a sensitive substrate of CYP3A). Concomitant useof strong CYP3A inducers may result in reduced exposures and thus reduced IVA/TEZ/ELX efficacy.

Co-administration of IVA with rifampicin, a strong CYP3A inducer, significantly decreased IVA areaunder the curve (AUC) by 89%. ELX and TEZ exposures are also expected to decrease duringco-administration with strong CYP3A inducers; therefore, co-administration with strong CYP3A inducersis not recommended (see section 4.4).

Examples of strong CYP3A inducers include:

* rifampicin, rifabutin, phenobarbital, carbamazepine, phenytoin and St. John’s wort (Hypericumperforatum)

Co-administration with itraconazole, a strong CYP3A inhibitor, increased ELX AUC by 2.8-fold and TEZ

AUC by 4.0- to 4.5-fold. When co-administered with itraconazole and ketoconazole, IVA AUC increasedby 15.6-fold and 8.5-fold, respectively. The dose of IVA/TEZ/ELX and IVA should be reduced when co-administered with strong CYP3A inhibitors (see Table 2 in section 4.2 and section 4.4).

Examples of strong CYP3A inhibitors include:

* ketoconazole, itraconazole, posaconazole and voriconazole

* telithromycin and clarithromycin

Simulations indicated that co-administration with moderate CYP3A inhibitors fluconazole, erythromycinand verapamil, may increase ELX and TEZ AUC by approximately 1.9- to 2.3-fold. Co-administration offluconazole increased IVA AUC by 2.9-fold. The dose of IVA/TEZ/ELX and IVA should be reducedwhen co-administered with moderate CYP3A inhibitors (see Table 2 in section 4.2 and section 4.4).

Examples of moderate CYP3A inhibitors include:

* fluconazole

* erythromycin

Co-administration with grapefruit juice, which contains one or more components that moderately inhibit

CYP3A, may increase exposure of ELX, TEZ and IVA. Food or drink containing grapefruit should beavoided during treatment with IVA/TEZ/ELX and IVA (see section 4.2).

ELX/TEZ/IVA was not evaluated for concomitant use with ciprofloxacin. However, ciprofloxacin had noclinically relevant effect on the exposure of TEZ or IVA and is not expected to have a clinically relevanteffect on the exposure of ELX. Therefore, no dose adjustment is necessary during concomitantadministration of IVA/TEZ/ELX with ciprofloxacin.

In vitro studies showed that ELX is a substrate for the efflux transporters P-gp and Breast Cancer

Resistance Protein (BCRP) but is not a substrate for OATP1B1 or OATP1B3. Exposure to ELX is notexpected to be affected significantly by concomitant use of P-gp and BCRP inhibitors due to its highintrinsic permeability and low likelihood of being excreted intact.

In vitro studies showed that TEZ is a substrate for the uptake transporter OATP1B1 and efflux transporters

P-gp and BCRP. TEZ is not a substrate for OATP1B3. Exposure to TEZ is not expected to be affectedsignificantly by concomitant inhibitors of OATP1B1, P-gp, or BCRP due to its high intrinsic permeabilityand low likelihood of being excreted intact. However, exposure to M2-TEZ (TEZ metabolite) may beincreased by inhibitors of P-gp. Therefore, caution should be used when P-gp inhibitors (e.g., ciclosporin)are used with IVA/TEZ/ELX.

In vitro studies showed that IVA is not a substrate for OATP1B1, OATP1B3, or P-gp. IVA and itsmetabolites are substrates of BCRP in vitro. Due to its high intrinsic permeability and low likelihood ofbeing excreted intact, co-administration of BCRP inhibitors is not expected to alter exposure of IVA and

M1-IVA, while any potential changes in M6-IVA exposures are not expected to be clinically relevant.

IVA may inhibit CYP2C9; therefore, monitoring of the international normalised ratio (INR) duringco-administration of warfarin with IVA/TEZ/ELX and IVA is recommended. Other medicinal products forwhich exposure may be increased include glimepiride and glipizide; these medicinal products should beused with caution.

Co-administration of IVA or TEZ/IVA with digoxin, a sensitive P-gp substrate, increased digoxin AUC by1.3-fold, consistent with weak inhibition of P-gp by IVA. Administration of IVA/TEZ/ELX and IVA mayincrease systemic exposure of medicinal products that are sensitive substrates of P-gp, which may increaseor prolong their therapeutic effect and adverse reactions. When used concomitantly with digoxin or othersubstrates of P-gp with a narrow therapeutic index such as ciclosporin, everolimus, sirolimus andtacrolimus, caution and appropriate monitoring should be used.

ELX and M23-ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro. TEZ/IVA increased the AUC ofpitavastatin, an OATP1B1 substrate, by 1.2-fold. Co-administration with IVA/TEZ/ELX in combinationwith IVA may increase exposures of medicinal products that are substrates of these transporters, such asstatins, glyburide, nateglinide and repaglinide. When used concomitantly with substrates of OATP1B1 or

OATP1B3, caution and appropriate monitoring should be used. Bilirubin is an OATP1B1 and OATP1B3substrate. In study 445-102, mild increases in mean total bilirubin were observed (up to 4.0 µmol/Lchange from baseline). This finding is consistent with the in vitro inhibition of bilirubin transporters

OATP1B1 and OATP1B3 by ELX and M23-ELX.

ELX and IVA are inhibitors of BCRP. Co-administration of IVA/TEZ/ELX, and IVA may increaseexposures of medicinal products that are substrates of BCRP, such as rosuvastatin. When usedconcomitantly with substrates of BCRP, appropriate monitoring should be used.

IVA/TEZ/ELX in combination with IVA has been studied with ethinyl estradiol/levonorgestrel and wasfound to have no clinically relevant effect on the exposures of the oral contraceptive. IVA/TEZ/ELX and

IVA is not expected to have an impact on the efficacy of oral contraceptives.

Interaction studies have only been performed in adults.

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate nomalformative or feto/neonatal toxicity of ELX, TEZ, or IVA in pregnant women. Animal studies do notindicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As aprecautionary measure, it is preferable to avoid the use of IVA/TEZ/ELX during pregnancy.

Limited data show that ELX, TEZ, and IVA are excreted in human milk and have been quantified inplasma of breastfed newborns/infants of treated women. There is insufficient information on the effects of

IVA/TEZ/ELX in newborns/infants. A decision must be made whether to discontinue breast-feeding or todiscontinue/abstain from IVA/TEZ/ELX therapy taking into account the benefit of breast-feeding for thechild and the benefit of therapy for the woman.

There are no data available on the effect of ELX, TEZ and IVA on fertility in humans. TEZ had no effectson fertility and reproductive performance indices in male and female rats at clinically relevant exposures.

ELX and IVA had an effect on fertility in rats (see section 5.3).

IVA/TEZ/ELX in combination with IVA has a minor influence on the ability to drive or use machines.

Dizziness has been reported in patients receiving IVA/TEZ/ELX in combination with IVA, TEZ/IVA incombination with IVA as well as IVA (see section 4.8). Patients experiencing dizziness should be advisednot to drive or use machines until symptoms abate.

The most common adverse reactions experienced by patients aged 12 years and older who received

IVA/TEZ/ELX in combination with IVA were headache (17.3%), diarrhoea (12.9%), upper respiratorytract infection (11.9%) and aminotransferase increased (10.9%).

Serious adverse reactions of rash experienced by patients aged 12 years and older were reported in 1.5%patients treated with IVA/TEZ/ELX in combination with IVA (see section 4.4).

Table 4 reflects adverse reactions observed with IVA/TEZ/ELX in combination with IVA, TEZ/IVA incombination with IVA, and IVA monotherapy. Adverse reactions are listed by MedDRA system organclass and frequency: 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); not known (cannot be estimated from the availabledata). Within each frequency grouping, adverse reactions are presented in the order of decreasingseriousness.

Table 4: Adverse reactions

MedDRA System Organ Class Adverse Reactions Frequency

Upper respiratory tract infection*,

Infections and infestations Nasopharyngitis very common

Rhinitis*, Influenza* common

Immune system disorders Hypersensitivity not known

Metabolism and nutritiondisorders Hypoglycaemia* common

Psychiatric disorders Depression, Behavioural changes not known

Nervous system disorders Headache*, Dizziness* very common

Ear pain, Ear discomfort, Tinnitus,

Ear and labyrinth disorders Tympanic membrane hyperaemia, common

Vestibular disorder

Ear congestion uncommon

Oropharyngeal pain, Nasal congestion* very common

*

Respiratory, thoracic and Rhinorrhoea , Sinus congestion,mediastinal disorders Pharyngeal erythema, Abnormal commonbreathing*

Wheezing* uncommon

Diarrhoea*, Abdominal pain* very common

Gastrointestinal disorders Nausea, Abdominal pain upper*,

Flatulence* common

Transaminase elevations very common

Alanine aminotransferase increased* very common

Aspartate aminotransferase increased* very common

Liver injury†, Total bilirubin increase† not known

Skin and subcutaneous tissue Rash* very commondisorders Acne*, Pruritus* common

Reproductive system and breast Breast mass commondisorders Breast inflammation, Gynaecomastia,

Nipple disorder, Nipple pain uncommon

Bacteria in sputum, Blood creatine

Investigations phosphokinase increased* very common

Blood pressure increased* uncommon

*Adverse reactions observed during clinical studies with IVA/TEZ/ELX in combination with IVA.†Liver injury (ALT and AST and total bilirubin increase) reported from post-marketing data with

IVA/TEZ/ELX in combination with IVA. Frequency cannot be estimated from the available data.

Safety data from the following studies were consistent with the safety data observed in study 445-102.

* A 4-week, randomised, double-blind, active-controlled study in 107 patients aged 12 years andolder (study 445-103).

* A 192-week, open-label safety and efficacy study (study 445-105) in 506 patients who rolled overfrom studies 445-102 and 445-103.

* An 8-week, randomised, double-blind, active-controlled study in 258 patients aged 12 years andolder (study 445-104).

* A 24-week, open-label study (study 445-106) in 66 patients aged 6 to less than 12 years.

* A 24-week, randomised, placebo-controlled study (study 445-116) in 121 patients aged 6 to lessthan 12 years.

* A 192-week, two-part (part A and part B), open-label safety and efficacy study (study 445-107) in64 patients aged 6 years and older who rolled over from study 445-106.

* A 24-week, open-label study (study 445-111) in 75 patients aged 2 to less than 6 years.

* A 24-week, randomised, double-blind, placebo-controlled study (study 445-124) in 307 patientsaged 6 years and older.

In study 445-102, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 × the ULN was1.5%, 2.5% and 7.9% in IVA/TEZ/ELX-treated patients and 1.0%, 1.5% and 5.5% in placebo-treatedpatients. The incidence of adverse reactions of transaminase elevations was 10.9% in

IVA/TEZ/ELX-treated patients and 4.0% in placebo-treated patients.

During the open-label studies, some patients discontinued treatment due to elevated transaminases. Post-marketing cases of treatment discontinuation due to elevated transaminases have been reported (seesection 4.4).

Studies in IVA/TEZ/ELX-treated patients above 12 years of age showed an incidence of rash events (e.g.,rash, rash pruritic) of 10.9% (study 445-102) compared to 6.5% in placebo-treated patients. The paediatricpopulation showed a higher incidence rate (see section Paediatric population for further details). Theincidence of rash events by patient sex was 5.8% in males and 16.3% in females in IVA/TEZ/ELX-treatedpatients and 4.8% in males and 8.3% in females in placebo-treated patients. In patients treated with

IVA/TEZ/ELX, the incidence of rash events was 20.5% in females taking hormonal contraceptive and13.6% in females not taking hormonal contraceptive (see section 4.4).

Overall, rash events typically occur during the first month of therapy. Most events were mild to moderatein severity, and in rare cases, rash was associated with additional symptoms such as fever or facialswelling. In the majority of cases, administration of IVA/TEZ/ELX was continued and the rash resolvedwithout treatment.

In study 445-102, the incidence of maximum creatine phosphokinase >5 × the ULN was 10.4% in

IVA/TEZ/ELX- and 5.0% in placebo-treated patients. The observed creatine phosphokinase elevationswere generally transient and asymptomatic and many were preceded by exercise.

In study 445-102, the maximum increase from baseline in mean systolic and diastolic blood pressure was3.5 mmHg and 1.9 mmHg, respectively for IVA/TEZ/ELX-treated patients (baseline: 113 mmHg systolicand 69 mmHg diastolic) and 0.9 mmHg and 0.5 mmHg, respectively for placebo-treated patients (baseline:114 mmHg systolic and 70 mmHg diastolic).

The proportion of patients who had systolic blood pressure >140 mmHg or diastolic blood pressure>90 mmHg on at least two occasions was 5.0% and 3.0%, respectively in IVA/TEZ/ELX-treated patientscompared with 3.5% and 3.5%, respectively in placebo-treated patients.

The safety data of IVA/TEZ/ELX in combination with IVA in studies 445-102, 445-103, 445-104, 445-106, 445-111, and 445-124 and was evaluated in 272 patients between 2 to less than 18 years of age. Thesafety profile is generally consistent among paediatric and adult patients.

During study 445-106 in patients aged 6 to less than 12 years, the incidence of maximum transaminase(ALT or AST) >8, >5, and >3 × ULN were 0.0%, 1.5%, and 10.6%, respectively. No

IVA/TEZ/ELX-treated patients had transaminase elevation >3 × ULN associated with elevated totalbilirubin >2 × ULN or discontinued treatment due to transaminase elevations (see section 4.4).

During study 445-111 in patients aged 2 to less than 6 years, the incidence of maximum transaminase(ALT or AST) >8, >5, and >3 × ULN were 1.3%, 2.7%, and 8.0% respectively. No IVA/TEZ/ELX-treatedpatients had transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN ordiscontinued treatment due to transaminase elevations (see section 4.4).

While studies in patients above 12 years of age showed an incidence rate of 10.9% (study 445-102),patients between 6 and 11 years of age had an incidence rate of 24.2% (study 445-106). During study445-111 in patients aged 2 to less than 6 years, 15 (20.0%) subjects had at least 1 rash event, 4 (9.8%)females and 11 (32.4%) males.

Lenticular opacity

One patient had an adverse event of lenticular opacity.

Behavioural changes

Most cases of behavioural changes have been reported in younger children aged 2-5 years.

With the exception of sex differences in rash, the safety profile of IVA/TEZ/ELX in combination with

IVA was generally similar across all subgroups of patients, including analysis by age, baseline percentpredicted forced expiratory volume in one second (ppFEV1) and geographic regions.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

No specific antidote is available for overdose with IVA/TEZ/ELX. Treatment of overdose consists ofgeneral supportive measures including monitoring of vital signs and observation of the clinical status ofthe patient.

Pharmacotherapeutic group: Other respiratory system products, ATC code: R07AX32

ELX and TEZ are CFTR correctors that bind to different sites on the CFTR protein and have an additiveeffect in facilitating the cellular processing and trafficking of CFTR to increase the amount of CFTRprotein delivered to the cell surface compared to either molecule alone. IVA potentiates the channel openprobability (or gating) of the CFTR protein at the cell surface.

The combined effect of ELX, TEZ and IVA is increased quantity and function of CFTR at the cell surface,resulting in increased CFTR activity as measured by CFTR mediated chloride transport.

CFTR Chloride Transport Assay in Fischer Rat Thyroid (FRT) cells expressing mutant CFTR

The chloride transport response of mutant CFTR protein to IVA/TEZ/ELX was determined in Ussingchamber electrophysiology studies using a panel of FRT cell lines transfected with individual CFTRmutations. IVA/TEZ/ELX increased chloride transport in FRT cells expressing select CFTR mutations.

The in vitro CFTR chloride transport response threshold was designated as a net increase of at least 10%of normal over baseline because it is predictive or reasonably expected to predict clinical response. Forindividual mutations, the magnitude of the net change over baseline in CFTR-mediated chloride transportin vitro is not correlated with the magnitude of clinical response.

In CF, the presence of one CFTR mutation responsive to IVA/TEZ/ELX based on in vitro data in FRTcells, will likely result in a clinical response.

Table 5 lists CFTR mutations included in the indication for treatment with Kaftrio. The occurrence of

CFTR mutations listed in this table should not be used in lieu of a diagnosis of cystic fibrosis, nor as a soledeterminant for prescribing purposes.

Table 5: CFTR mutations identified to be responsive to IVA/TEZ/ELX based on clinical and/or in vitrodata293A→G E264V H939R N1088D S108F314del9 E282D H939R;H949L‡ N1195T S158N546insCTA E292K H954P N1303I S182R548insTAC E384K H1054D N1303K* S308P711+3A→G* E403D H1079P P5L† S341P1140-1151dup E474K H1085P P67L* S364P1461insGAT E527G H1085R P111L S434P1507_1515del9 E588V H1375N P140S S492F2055del9 E822K H1375P P205S S519G2183A→G E831X I86M P439S S531P2789+5G→A* E1104K I105N P499A S549I2851A/G E1104V I125T P574H S549N3007del6 E1126K I148L P750L S549R*3132T→G E1221V I148N P798S S557F3141del9 E1228K I175V P988R S589I3143del9 E1409K I331N P1013H S589N3272-26A→G*† E1433K I336K P1013L S624R3331del6 F87L I336L P1021L S686Y3410T→C F191V I444S P1021T S737F3523A→G F200I I497S P1372T S821G3601A→C F311del I502T Q30P S898R3761T→G F311L I506L Q98P S912L3791C/T F312del I506V Q98R S912L;G1244V‡3849+10kbC→T*† F433L I506V;D1168G‡ Q151K S912T3850G→A F508C;S1251 N‡ I521S Q179K S945L*†3978G→C F508del* I530N Q237E S955P

A46D F508del;R1438W‡ I556V Q237H S977F

A62P F575Y I586V Q237P S977F;R1438W‡

A107G F587I I601F Q359K;T360K‡ S1045Y

A120T F587L I618N Q359R S1118F

A141D F693L(TTG) I618T Q372H S1159F

A155P F932S I980K Q493L S1159P

A234D F1016S I1023R Q493R S1188L

A234V F1052V I1139V Q552P S1251N

A238V F1074L I1203V Q1012P S1255P

A309D F1078S I1234L Q1209P T338I

A349V F1099L I1234V Q1291H T351I

A357T F1107L I1269N Q1291R T351S

A455E*† G27E I1366N Q1313K T351S;R851L‡

A455V G27R I1366T Q1352H T388M

A457T G126D K162E R31L T465I

A462P G178E K464E R74Q T501A

A534E G178R K464N R74Q;R297Q‡ T582S

A554E G194R K522E R74Q;V201M;D1270N‡ T908N

A566D G194V K522Q R74W T990I

A872E G213E K951E R74W;D1270N‡ T1036N*

A1006E G213E;R668C‡ K1060T R74W;R1070W;D1270N‡ T1057R

A1025D G213V L15P R74W;S945L‡ T1086A

A1067P G226R L15P;L1253F‡ R74W;V201M‡ T1086I

A1067T G239R L32P R74W;V201M;D1270N‡ T1246I

A1067V G253R L88S R74W;V201M;L997F‡ T1299I

A1081V G314E L102R;F1016S‡ R75L T1299K

A1087P G314R L137P R75Q;L1065P‡ V11I

A1319E G424S L159S R75Q;N1088D‡ V93D

A1374D G437D L165S R75Q;S549N‡ V201M

A1466S G461R L167R R117C† V232A

C225R G461V L206W*† R117C;G576A;R668C‡ V232D

C491R G463V L210P R117G V317A

C590Y G480C L293P R117H* V322M

C866Y G480D L327P R117L V392Gc.1367_1369dupTTG G480S L333F R117L;L997F‡ V456A

D58H G500D L333H R117P V456F

D58V G545R L346P R248K V520I

D110E G551A L441P R258G V562I;A1006E‡

D110H G551D* L453S R297Q V562L

D110N G551R L467F R334L V591A

D192G G551S L558F R334Q V603F

D192N G576A;R668C‡ L619S R334W† V920L

D373N G576A;S1359Y‡ L633P R347H* V920M

D426N G622D L636P R347L V1008D

D443Y G622V L927P R347P V1010D

D443Y;G576A;R668C‡ G628A L967F;L1096R‡ R352Q V1153E

D529G G628R L973F R352W V1240G

D565G G85E*† L1011S R516S V1293G

D567N G930E L1065R R553Q V1293I

D579G G970D L1077P*† R555G V1415F

D614G G970S L1227S R600S W202C

D651H G970V L1324P R709Q W361R

D651N G1047D L1335P R751L W496R

D806G G1047R L1388P R792G W1098C

D924N G1061R L1480P R792Q W1282G

D979A G1069R M150K R810G W1282R

D979V G1123R M150R R851L Y89C

D985H G1173S M152L R933G Y109H

D985Y G1237V M152V R1048G Y109N

D993A G1244E M265R R1066C† Y122C

D993G G1244R M348K R1066G Y161C

D993Y G1247R M394L R1066H*† Y161D

D1152A G1249E M469V R1070P Y161S

D1152H*† G1249R M498I R1070Q Y301C

D1270N* G1265V M952I R1070W Y563N

D1270Y G1298V M952T R1162Q Y913S

D1312G G1349D M961L R1239S Y919C

D1377H G149R;G576A;R668C‡ M1101K*† R1283G Y1014C

D1445N H139L M1137R R1283M Y1032C

E56K H139R M1137V R1283S Y1032N

E60K H146R M1210K R1438W Y1073C

E92K H199Q N186K S13F Y1092H

E116K H199Y N187K S13P Y1381H

E116Q H609L N396Y S18I

E193K H620P N418S S18N

E217G H620Q N900K S50P

There are people with CF harbouring two rare, non-F508del CFTR mutations not listed in Table 5. Provided that they donot harbour two Class I (null) mutations (mutations that are known not to produce CFTR protein) (see section 4.1), theymay respond to treatment. In these cases, Kaftrio can be considered when the physician deems the potential benefitsoutweigh the potential risks and under close medical supervision.

The individual diagnosis of CF should be based on diagnostic guidelines and clinical judgement as considerable variabilityexists in phenotype for patients harbouring the same genotype.

⁎ Mutations supported by clinical data.† Mutations supported by Real-World data in ≥ 5 patients.‡ Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent ofthe presence of mutations on the other allele.

Non-annotated mutations are included based on the FRT assay in which a positive response is indicative of a clinicalresponse.

In study 445-102 (patients with an F508del mutation on one allele and a mutation on the second allele thatpredicts either no production of a CFTR protein or a CFTR protein that does not transport chloride and isnot responsive to other CFTR modulators [IVA and TEZ/IVA] in vitro), a reduction in sweat chloride wasobserved from baseline at week 4 and sustained through the 24-week treatment period. The treatmentdifference of IVA/TEZ/ELX in combination with IVA compared to placebo for mean absolute change insweat chloride from baseline through week 24 was -41.8 mmol/L (95% CI: -44.4, -39.3; P < 0.0001).

In study 445-103 (patients homozygous for the F508del mutation), the treatment difference of

IVA/TEZ/ELX in combination with IVA compared to TEZ/IVA in combination with IVA for meanabsolute change in sweat chloride from baseline at week 4 was -45.1 mmol/L (95% CI: -50.1, -40.1;

P < 0.0001).

In study 445-104 (patients heterozygous for the F508del mutation and a mutation on the second allele witha gating defect or residual CFTR activity), the mean absolute change in sweat chloride from baselinethrough week 8 for the IVA/TEZ/ELX in combination with IVA group was -22.3 mmol/L (95% CI: -24.5,

- 20.2; P < 0.0001). The treatment difference of IVA/TEZ/ELX in combination with IVA compared to thecontrol group (IVA group or TEZ/IVA in combination with IVA group) was -23.1 mmol/L(95% CI: -26.1, -20.1; P < 0.0001).

In study 445-106 (patients aged 6 to less than 12 years who are homozygous for the F508del mutation orheterozygous for the F508del mutation and a minimal function mutation), the mean absolute change insweat chloride from baseline (n=62) through week 24 (n=60) was -60.9 mmol/L (95% CI: -63.7, -58.2)*.

The mean absolute change in sweat chloride from baseline through week 12 (n=59) was -58.6 mmol/L(95% CI: -61.1, -56.1).

* Not all participants included in the analyses had data available for all follow-up visits, especially fromweek 16 onwards. The ability to collect data at week 24 was hampered by the COVID-19 pandemic. Week12 data were less impacted by the pandemic.

In study 445-116 (patients aged 6 to less than 12 years who are heterozygous for the F508del mutation anda minimal function mutation), treatment with IVA/TEZ/ELX in combination with IVA resulted inreduction in sweat chloride through week 24, as compared to placebo. The LS mean treatment differencefor the IVA/TEZ/ELX in combination with IVA group versus placebo for absolute change in sweatchloride from baseline through week 24 was -51.2 mmol/L (95% CI: -55.3, -47.1; nominal P < 0.0001).

In study 445-111 (patients aged 2 to less than 6 years who are homozygous for the F508del mutation orheterozygous for the F508del mutation and a minimal function mutation), the mean absolute change insweat chloride from baseline through week 24 was -57.9 mmol/L (95% CI: -61.3, -54.6).

In study 445-124 (patients aged 6 years and older with a qualifying non-F508del, IVA/TEZ/ELX-responsive CFTR mutation [see Table 6]), the mean absolute change in sweat chloride from baselinethrough week 24 compared to placebo was -28.3 mmol/L (95% CI: -32.1, -24.5 mmol/L; P < 0.0001).

At doses up to 2 times the maximum recommended dose of ELX and 3 times the maximum recommendeddose of TEZ and IVA, the QT/QTc interval in healthy subjects was not prolonged to any clinicallyrelevant extent.

In study 445-102, mean decreases in heart rate of 3.7 to 5.8 beats per minute (bpm) from baseline(76 bpm) were observed in IVA/TEZ/ELX-treated patients.

The efficacy of IVA/TEZ/ELX in combination with IVA in patients with CF was demonstrated in sevenphase 3 studies. Patients enrolled in these studies were homozygous for the F508del mutation orheterozygous for the F508del mutation and a mutation with minimal function (MF), a gating defect, orresidual CFTR activity on the second allele. Study 445-124 enrolled patients who had at least onequalifying non-F508del, IVA/TEZ/ELX-responsive CFTR mutation (see Table 6).

Study 445-102 was a 24-week, randomised, double-blind, placebo-controlled study in patients who had an

F508del mutation on one allele and an MF mutation on the second allele. CF patients eligible for thisstudy were required to either have Class I mutations that predicted no CFTR protein being produced(including nonsense mutations, canonical splice mutations and insertion/deletion frameshift mutationsboth small (≤3 nucleotide) and non-small (>3 nucleotide)), or missense mutations which results in CFTRprotein that does not transport chloride and is not responsive to IVA and TEZ/IVA in vitro. The mostfrequent alleles with minimal function assessed in the study were G542X, W1282X, R553X, and R1162X;621+1G→T, 1717-1G→A, and 1898+1G→A; 3659delC, and 394delTT; CFTRdele2,3; and N1303K,

I507del, G85E, R347P, and R560T. A total of 403 patients aged 12 years and older (mean age 26.2 years)were randomised and dosed to receive placebo or IVA/TEZ/ELX in combination with IVA. Patients had appFEV1 at screening between 40-90%. The mean ppFEV1 at baseline was 61.4% (range: 32.3%, 97.1%).

Study 445-103 was a 4-week, randomised, double-blind, active-controlled study in patients who werehomozygous for the F508del mutation. A total of 107 patients aged 12 years and older (mean age28.4 years) received TEZ/IVA in combination with IVA during a 4-week open-label run-in period andwere then randomised and dosed to receive either IVA/TEZ/ELX in combination with IVA or TEZ/IVA incombination with IVA during a 4-week double-blind treatment period. Patients had a ppFEV1 at screeningbetween 40-90%. The mean ppFEV1 at baseline, following the run-in period was 60.9% (range: 35.0%,89.0%).

Study 445-104 was an 8-week, randomised, double-blind, active-controlled study in patients who wereheterozygous for the F508del mutation and a mutation on the second allele with a gating defect (Gating)or residual CFTR activity (RF). A total of 258 patients aged 12 years and older (mean age 37.7 years)received either IVA (F/Gating) or TEZ/IVA in combination with IVA (F/RF) during a 4-week open-labelrun-in period and patients with the F/R117H genotype received IVA during the run-in period. Patientswere then randomised and dosed to receive either IVA/TEZ/ELX in combination with IVA or remained onthe CFTR modulator therapy received during the run-in period. Patients had a ppFEV1 at screeningbetween 40-90%. The mean ppFEV1 at baseline, following the run-in period, was 67.6% (range: 29.7%,113.5%).

Study 445-106 was a 24-week open-label study in patients who were homozygous for the F508delmutation or heterozygous for the F508del mutation and a minimal function mutation. A total of 66 patientsaged 6 to less than 12 years (mean age at baseline 9.3 years) were dosed according to weight. Patientsweighing <30 kg at baseline were administered two IVA 37.5 mg/TEZ 25 mg/ELX 50 mg tablets in themorning and one IVA 75 mg tablet in the evening. Patients weighing ≥30 kg at baseline were administeredtwo IVA 75 mg/TEZ 50 mg/ELX 100 mg tablets in the morning and one IVA 150 mg tablet in theevening. Patients had a ppFEV1 ≥40% and weighed ≥15 kg at screening. The mean ppFEV1 at baselinewas 88.8% (range: 39.0%, 127.1%).

Study 445-116 was a 24-week, randomised, double-blind, placebo-controlled study in patients aged 6 toless than 12 years (mean age at baseline 9.2 years) who were heterozygous for the F508del mutation and aminimal function mutation. A total of 121 patients were randomised to receive either placebo or

IVA/TEZ/ELX in combination with IVA. Patients who received IVA/TEZ/ELX in combination with IVAweighing <30 kg at baseline were administered two IVA 37.5 mg/TEZ 25 mg/ELX 50 mg tablets in themorning and one IVA 75 mg tablet in the evening. Patients weighing ≥30 kg at baseline were administeredtwo IVA 75 mg/TEZ 50 mg/ELX 100 mg tablets in the morning and one IVA 150 mg tablet in theevening. At screening, patients had a ppFEV1 ≥70% [mean ppFEV1 at baseline of 89.3% (range: 44.6%,121.8%)], LCI2.5 result ≥7.5 [mean LCI2.5 at baseline of 10.01 (range: 6.91, 18.36)], and weighed ≥15 kg.

Study 445-111 was a 24-week open-label study in patients aged 2 to less than 6 years (mean age atbaseline 4.1 years). A total of 75 patients who are homozygous for the F508del mutation or heterozygousfor the F508del mutation and a minimal function mutation were enrolled and dosed according to weight.

Patients weighing 10 kg to <14 kg at baseline were administered IVA 60 mg/TEZ 40 mg/ELX 80 mg onceevery morning and IVA 59.5 mg once every evening. Patients weighing ≥14 kg at baseline wereadministered IVA 75 mg every 12 hours/TEZ 50 mg qd/ELX 100 mg qd.

Study 445-124 was a 24-week, randomised, placebo-controlled, double-blind, parallel group study inpatients aged 6 years and older. Patients who had at least one qualifying non-F508del, IVA/TEZ/ELX-responsive CFTR mutation (see Table 6) and did not have an exclusionary (other IVA/TEZ/ELX-responsive) mutation were eligible for the study.

Table 6: Eligible IVA/TEZ/ELX-responsive CFTR mutations2789+5G>A D1152H L997F R117C T338I3272-26A>G G85E M1101K R347H V232D3849+10kbC>T L1077P P5L R347P

A455E L206W R1066H S945L

A total of 307 patients were enrolled and dosed according to age and weight. Patients ≥6 to <12 yearsweighing <30 kg at baseline (n=31) were administered ELX 100 mg qd/TEZ 50 mg qd/IVA 75 mg q12h.

Patients ≥6 to <12 years weighing ≥30 kg at baseline were administered ELX 200 mg qd/TEZ100 mg qd/IVA 150 mg q12h. Patients ≥12 years at baseline were administered ELX 200 mg qd/TEZ100 mg qd/IVA 150 mg q12h. Patients had a ppFEV1 ≥40% and ≤100% and aged 6 years or older atscreening. The mean ppFEV1 at baseline was 67.7% (range: 34.0%, 108.7%).

Patients in these studies continued on their CF therapies (e.g., bronchodilators, inhaled antibiotics, dornasealfa and hypertonic saline), but discontinued any previous CFTR modulator therapies, except for studymedicinal products. Patients had a confirmed diagnosis of CF.

Study CFD-016 was an observational, retrospective study evaluating Real-World clinical outcomes inpatients aged 6 years and older. Patients had at least one IVA/TEZ/ELX-responsive mutation and did nothave an F508del mutation. A total of 422 patients were evaluated with a total of 82 IVA/TEZ/ELX-responsive non-F508del mutations represented. The mean ppFEV1 at baseline was 74.15%.

In studies 445-102, 445-103, 445-104, 445-106, 445-111, and 445-124 patients continued their CFtherapies, but discontinued any previous CFTR modulator therapies, except for study medicinal products.

Patients who had lung infection with organisms associated with a more rapid decline in pulmonary status,including but not limited to Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacteriumabscessus, or who had an abnormal liver function test at screening (ALT, AST, ALP, or GGT ≥3 × ULN,or total bilirubin ≥2 × ULN), were excluded. In study 445-111, patients who had ALT or AST ≥2 × ULNwere also excluded.

Patients in studies 445-102 and 445-103 were eligible to roll over into a 192-week open-label extensionstudy (study 445-105). Patients in studies 445-104, 445-106, 445-116, 445-111, and 445-124 were eligibleto roll over into separate open-label extension studies.

In study 445-102 the primary endpoint was mean absolute change in ppFEV1 from baseline throughweek 24. Treatment with IVA/TEZ/ELX in combination with IVA compared to placebo resulted instatistically significant improvement in ppFEV1 of 14.3 percentage points (95% CI: 12.7, 15.8;

P < 0.0001) (see Table 7). Mean improvement in ppFEV1 was observed at the first assessment on day 15and sustained through the 24-week treatment period. Improvements in ppFEV1 were observed regardlessof age, baseline ppFEV1, sex, and geographic region.

A total of 18 patients receiving IVA/TEZ/ELX in combination with IVA had ppFEV1 <40 percentagepoints at baseline. The safety and efficacy in this subgroup were consistent to those observed in the overallpopulation. The mean treatment difference of IVA/TEZ/ELX in combination with IVA- compared toplacebo-treated patients for absolute change in ppFEV1 through week 24 in this subgroup was18.4 percentage points (95% CI: 11.5, 25.3).

See Table 7 for a summary of primary and key secondary outcomes.

Table 7: Primary and key secondary efficacy analyses, full analysis set (study 445-102)

IVA/TEZ/ELX in

Analysis Statistic Placebo combination with

N=203 IVA

N=200

Primary

Baseline ppFEV1 Mean (SD) 61.3 (15.5) 61.6 (15.0)

Absolute change in ppFEV1 Treatment difference (95% CI) NA 14.3 (12.7, 15.8)from baseline through week 24 P value NA P < 0.0001(percentage points) Within-group change (SE) -0.4 (0.5) 13.9 (0.6)

Key secondary

Absolute change in Treatment difference (95% CI) NA 13.7 (12.0, 15.3)ppFEV1 from baseline at week 4 P value NA P < 0.0001(percentage points) Within-group change (SE) -0.2 (0.6) 13.5 (0.6)

Number of pulmonary Number of events (event rate 113 (0.98) 41 (0.37)†exacerbations from baseline per year )through week 24* Rate ratio (95% CI) NA 0.37 (0.25, 0.55)

P value NA P < 0.0001

Baseline sweat chloride(mmol/L) Mean (SD) 102.9 (9.8) 102.3 (11.9)

Absolute change in sweat Treatment difference (95% CI) NA -41.8 (-44.4, -39.3)chloride from baseline through P value NA P < 0.0001week 24 (mmol/L) Within-group change (SE) -0.4 (0.9) -42.2 (0.9)

Absolute change in sweat Treatment difference (95% CI) NA -41.2 (-44.0, -38.5)chloride from baseline at P value NA P < 0.0001week 4 (mmol/L) Within-group change (SE) 0.1 (1.0) -41.2 (1.0)

Baseline CFQ-R respiratorydomain score (points) Mean (SD) 70.0 (17.8) 68.3 (16.9)

Absolute change in CFQ-Rrespiratory domain score from Treatment difference (95% CI) NA 20.2 (17.5, 23.0)baseline through week 24 P value NA P < 0.0001(points) Within-group change (SE) -2.7 (1.0) 17.5 (1.0)

Absolute change in CFQ-R Treatment difference (95% CI) NA 20.1 (16.9, 23.2)respiratory domain score from P value NA P < 0.0001baseline at week 4 (points) Within-group change (SE) -1.9 (1.1) 18.1 (1.1)

Baseline BMI (kg/m2) Mean (SD) 21.31 21.49 (3.07)(3.14)

Absolute change in BMI from Treatment difference (95% CI) NA 1.04 (0.85, 1.23)baseline at week 24 (kg/m2) P value NA P < 0.0001

Within-group change (SE) 0.09 (0.07) 1.13 (0.07)ppFEV1: percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; SD:

Standard Deviation; SE: Standard Error; NA: Not Applicable; CFQ-R: Cystic Fibrosis Questionnaire-

Revised; BMI: Body Mass Index

* A pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as aresult of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms.† Estimated event rate per year was calculated based on 48 weeks per year.

In study 445-103 the primary endpoint was mean absolute change in ppFEV1 from baseline at week 4 ofthe double-blind treatment period. Treatment with IVA/TEZ/ELX in combination with IVA compared to

TEZ/IVA in combination with IVA resulted in a statistically significant improvement in ppFEV1 of10.0 percentage points (95% CI: 7.4, 12.6; P < 0.0001) (see Table 8). Improvements in ppFEV1 wereobserved regardless of age, sex, baseline ppFEV1, and geographic region.

See Table 8 for a summary of primary and key secondary outcomes in the overall trial population.

In a post-hoc analysis of patients with (N=66) and without (N=41) recent CFTR modulator use, animprovement in ppFEV1 of 7.8 percentage points (95% CI: 4.8, 10.8) and 13.2 percentage points (95% CI:8.5, 17.9), respectively was observed.

Table 8: Primary and key secondary efficacy analyses, full analysis set (study 445-103)

TEZ/IVA in IVA/TEZ/ELX

Analysis* Statistic combination in combinationwith IVA with IVA

N=52 N=55

Primary

Baseline ppFEV1 Mean (SD) 60.2 (14.4) 61.6 (15.4)

Absolute change in ppFEV1 Treatment difference (95% CI) NA 10.0 (7.4, 12.6)from baseline at week 4 P value NA P < 0.0001(percentage points) Within-group change (SE) 0.4 (0.9) 10.4 (0.9)

Key secondary

Baseline sweat chloride(mmol/L) Mean (SD) 90.0 (12.3) 91.4 (11.0)

Absolute change in sweat Treatment difference (95% CI) NA -45.1chloride from baseline at (-50.1, -40.1)week 4 (mmol/L) P value NA P < 0.0001

Within-group change (SE) 1.7 (1.8) -43.4 (1.7)

Baseline CFQ-R respiratorydomain score (points) Mean (SD) 72.6 (17.9) 70.6 (16.2)

Absolute change in CFQ-Rrespiratory domain score Treatment difference (95% CI) NA 17.4 (11.8, 23.0)from baseline at week 4 P value NA P < 0.0001(points) Within-group change (SE) -1.4 (2.0) 16.0 (2.0)ppFEV1: percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; SD:

Standard Deviation; SE: Standard Error; NA: Not Applicable; CFQ-R: Cystic Fibrosis

Questionnaire-Revised

* Baseline for primary and key secondary endpoints is defined as the end of the 4-week run-in periodof TEZ/IVA in combination with IVA.

In study 445-104 the primary endpoint was within-group mean absolute change in ppFEV1 from baselinethrough week 8 for the IVA/TEZ/ELX in combination with IVA group. Treatment with IVA/TEZ/ELX incombination with IVA resulted in statistically significant improvement in ppFEV1 from baseline of3.7 percentage points (95% CI: 2.8, pct. 4.6; P < 0.0001) (see Table 9). Overall improvements in ppFEV1 wereobserved regardless of age, sex, baseline ppFEV1, geographic region, and genotype groups (F/Gating or

F/RF).

See Table 9 for a summary of primary and secondary outcomes in the overall trial population.

In a subgroup analysis of patients with an F/Gating genotype, the treatment difference of IVA/TEZ/ELXin combination with IVA (N=50) compared with IVA (N=45) for mean absolute change in ppFEV1 was5.8 percentage points (95% CI: 3.5, 8.0). In a subgroup analysis of patients with an F/RF genotype, thetreatment difference of IVA/TEZ/ELX in combination with IVA (N=82) compared with TEZ/IVA incombination with IVA (N=81) for mean absolute change in ppFEV1 was 2.0 percentage points (95% CI:0.5, 3.4). The results of the F/Gating and the F/RF genotype subgroups for improvement in sweat chlorideand CFQ-R respiratory domain score were consistent with the overall results.

Table 9: Primary and secondary efficacy analyses, full analysis set (study 445-104)

Control IVA/TEZ/ELX in

Analysis* Statistic group† combination with

N=126 IVA

N=132

Primary

Baseline ppFEV1 Mean (SD) 68.1 (16.4) 67.1 (15.7)

Absolute change in ppFEV1 from Within-group change 0.2 (-0.7, 1.1) 3.7 (2.8, pct. 4.6)baseline through week 8 (percentage (95% CI)points) P value NA P < 0.0001

Key and other secondary

Absolute change in ppFEV1 from Treatment difference NA 3.5 (2.2, 4.7)baseline through week 8 compared to (95% CI)the control group (percentage points) P value NA P < 0.0001

Baseline sweat chloride (mmol/L) Mean (SD) 56.4 (25.5) 59.5 (27.0)

Absolute change in sweat chloride Within-group change 0.7 (-1.4, 2.8) -22.3 (-24.5, -20.2)from baseline through week 8 (95% CI) P < 0.0001(mmol/L) P value NA

Absolute change in sweat chloride Treatment difference NA -23.1 (-26.1, -20.1)from baseline through week 8 (95% CI) P < 0.0001compared to the control group P value NA(mmol/L)

Baseline CFQ-R respiratory domainscore (points) Mean (SD) 77.3 (15.8) 76.5 (16.6)

Absolute change in CFQ-Rrespiratory domain score from Within-group change 1.6 (-0.8, 4.1) 10.3 (8.0, 12.7)baseline through week 8 (points) (95% CI)

Absolute change in CFQ-Rrespiratory domain score from Treatment differencebaseline through week 8 (points) (95% CI) NA 8.7 (5.3, 12.1)compared to the control groupppFEV1: percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; SD:

Standard Deviation; NA: Not Applicable; CFQ-R: Cystic Fibrosis Questionnaire-Revised

* Baseline for primary and secondary endpoints is defined as the end of the 4-week run-in period of IVAor TEZ/IVA in combination with IVA.† IVA group or TEZ/IVA in combination with IVA group.

Study 445-105 was a 192-week open-label extension study to evaluate the safety and efficacy of long-termtreatment with IVA/TEZ/ELX in combination with IVA. Patients who rolled over from studies 445-102(N=399) and 445-103 (N=107) received IVA/TEZ/ELX in combination with IVA.

In study 445-105, patients from the control arms in the parent studies showed improvements in efficacyendpoints consistent with those observed in subjects who received IVA/TEZ/ELX in combination with

IVA in the parent studies. Patients from the control arms as well as patients who received IVA/TEZ/ELXin combination with IVA in the parent studies, showed sustained improvements. Secondary efficacyendpoints are summarised in Table 10.

Table 10: Study 445-105 secondary efficacy analysis, full analysis set (F/MF and F/F subjects)

Study 445-105 week 192

Placebo in IVA/TEZ/ELX TEZ/IVA in IVA/TEZ/E445-102 in 445-102 445-103 LX in

N=203 N=196 N=52 445-103

Analysis Statistic N=55

Absolute change n 136 133 32 36from baseline* in LS mean 15.3 13.8 10.9 10.7ppFEV1 95% CI (13.7, 16.8) (12.3, 15.4) (8.2, 13.6) (8.1, 13.3)(percentage points)

Absolute change n 133 128 31 38from baseline* in LS mean -47.0 -45.3 -48.2 -48.2

SwCl (mmol/L) 95% CI (-50.1, -43.9) (-48.5, -42.2) (-55.8, -40.7) (-55.1, -41.3)

Number of PEx Number ofduring the events 385 71

Cumulative Triple Estimated

Combination (TC) event rate per 0.21 (0.17, 0.25) 0.18 (0.12, 0.25)

Efficacy Period† year (95% CI)

Absolute change n 144 139 32 42from baseline* in LS mean 1.81 1.74 1.72 1.85

BMI (kg/m2) 95% CI (1.50, 2.12) (1.43, 2.05) (1.25, 2.19) (1.41, 2.28)

Absolute change n 144 139 32 42from baseline* in LS mean 6.6 6.0 6.1 6.3body weight (kg) 95% CI (5.5, 7.6) (4.9, 7.0) (4.6, 7.6) (4.9, 7.6)

Absolute change n 148 147 33 42from baseline* in LS mean 15.3 18.3 14.8 17.6

CFQ-R RD score 95% CI (12.3, 18.3) (15.3, 21.3) (9.7, 20.0) (12.8, 22.4)(points)ppFEV1 = percent predicted Forced Expiratory Volume in 1 second; SwCl = Sweat Chloride; PEx = Pulmonary

Exacerbation; BMI = Body Mass Index; CFQ-R RD = Cystic Fibrosis Questionnaire - Revised Respiratory Domain;

LS = Least Squares; CI = Confidence Interval; n = size of subsample

* Baseline = parent study baseline† For subjects who were randomised to the IVA/TEZ/ELX group, the Cumulative TC Efficacy Period includes datafrom the parent studies through 192 weeks of treatments in study 445-105 (N=255, including 4 patients that did notrollover into study 445-105). For subjects who were randomised to the Placebo or TEZ/IVA group, the Cumulative

TC Efficacy Period includes data from 192 weeks of treatments in study 445-105 only (N=255).

Study 445-124

The safety and efficacy of IVA/TEZ/ELX in 307 patients with CF aged 6 years and older without an

F508del mutation but with a qualifying IVA/TEZ/ELX-responsive CFTR mutation were evaluated (study445-124).

In study 445-124 the primary endpoint of efficacy was mean absolute change in ppFEV1 from baselinethrough week 24. Secondary endpoints were absolute change in sweat chloride, CFQ-R respiratory domainscore, growth parameters (BMI, weight), and number of PEx. See Table 11 for a summary of primary andsecondary efficacy outcomes.

Table 11: Primary and secondary efficacy analyses, full analysis set (study 445-124)

Analysis Statistic Placebo IVA/TEZ/ELX

N=102 N=205

Primary

Absolute change in ppFEV1 Treatment difference (95% CI) NA 9.2 (7.2, 11.3)from baseline through P value NA P < 0.0001week 24 (percentage points) Within-group change (SE) -0.4 (0.8) 8.9 (0.6)

Secondary

Absolute change in sweat Treatment difference (95% CI) NA -28.3 (-32.1, -24.5)chloride from baseline P value NA P < 0.0001through week 24 (mmol/L) Within-group change (SE) 0.5 (1.6) -27.8 (1.1)

Absolute change in CFQ-Rrespiratory domain score Treatment difference (95% CI) NA 19.5 (15.5, 23.5)from baseline through P value NA P < 0.0001week 24 (points) Within-group change (SE) -2.0 (1.6) 17.5 (1.2)

Absolute change from Treatment difference (95% CI) NA 0.47 (0.24, 0.69)baseline in BMI at week 24 P value NA P < 0.0001(kg/m2) Within-group change (SE) 0.35 (0.09) 0.81 (0.07)

Absolute change from Treatment difference (95% CI) NA 1.3 (0.6, 1.9)baseline in weight at P value NA P < 0.0001week 24 (kg) Within-group change (SE) 1.2 (0.3) 2.4 (0.2)

Number of PEx through Rate ratio (95% CI) NA 0.28 (0.15, 0.51)week 24 P value NA P < 0.0001

Number of events 40 21

Estimated event rate per year 0.63 0.17

BMI: Body Mass Index; CFQ-R RD: Cystic Fibrosis Questionnaire-Revised Respiratory Domain; CI:

Confidence Interval; IV: intravenous; IVA: ivacaftor; LS: Least Squares;; N: total sample size;

P: probability; PEx: Pulmonary Exacerbation; ppFEV1: percent predicted Forced Expiratory Volume in1 second; SE: Standard Error; SwCl: Sweat Chloride; TEZ: tezacaftor

Study CFD-016

Study CFD-016 included 422 homozygotic non-F508del CF patients harbouring at least one

IVA/TEZ/ELX-responsive CFTR mutation based on in vitro FRT data. After a median follow-up of 1.31year, the mean change in ppFEV1 was 4.53% (95% CI: 3.5, 5.56). Almost all subgroups according to

CFTR mutation that included ≥5 patients showed an improvement in ppFEV1 over that time, except for thesubgroup with R74W.

Paediatric patients aged 2 to <12 years

In study 445-106, the primary endpoint of safety and tolerability was evaluated through 24 weeks inpatients aged 6 to less than 12 years. Secondary endpoints were evaluation of pharmacokinetics andefficacy.

See Table 12 for a summary of secondary efficacy outcomes.

Table 12: Secondary efficacy analyses, full analysis set (N=66) (study 445-106)

Absolute change Absolute change

Analysis Baseline through week 12 through week 24

Mean (SD) Within-group change Within-group change(95% CI) (95% CI)*ppFEV (percentage points) n=62 n=59 n=591 88.8 (17.7) 9.6 (7.3, 11.9) 10.2 (7.9, 12.6)

CFQ-R respiratory domain n=65 n=65 n=65score (points) 80.3 (15.2) 5.6 (2.9, 8.2) 7.0 (4.7, 9.2)

BMI-for-age z-score n=66 n=58 n=33

- 0.16 (0.74) 0.22 (0.13, 0.30) † 0.37 (0.26, 0.48) ‡

Weight-for-age z-score n=66 n=58 n=33

- 0.22 (0.76) 0.13 (0.07, 0.18) † 0.25 (0.16, 0.33) ‡

Height-for-age z-score n=66 n=58 n=33

- 0.11 (0.98) -0.03 (-0.06, 0.00) † -0.05 (-0.12, 0.01) ‡

Number of pulmonary n=66exacerbations†† N/A N/A4 (0.12) §

LCI n=53 n=48 n=502.5 9.77 (2.68) -1.83 (-2.18, -1.49) -1.71 (-2.11, -1.30)

SD: Standard Deviation; CI: Confidence Interval; ppFEV1: percent predicted Forced Expiratory Volumein 1 second; CFQ-R: Cystic Fibrosis Questionnaire-Revised; BMI: Body Mass Index; N/A: Not

Applicable; LCI: Lung Clearance Index; n: size of subsample

* Not all participants included in the analyses had data available for all follow-up visits, especially fromweek 16 onwards. The ability to collect data at week 24 was hampered by the COVID-19 pandemic.

Week 12 data were less impacted by the pandemic.† At week 12 assessment.‡ At week 24 assessment.†† A pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as aresult of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms.§ Number of events and estimated event rate per year based on 48 weeks per year.

Study 445-107

Study 445-107 is a 192-week, two-part (part A and part B), open-label extension study to evaluate thesafety and efficacy of long-term treatment with IVA/TEZ/ELX in patients who completed study 445-106.

Efficacy endpoints were included as secondary endpoints. The final analysis of this study was conductedin 64 paediatric patients aged 6 years and older. With 192 additional weeks of treatment, sustainedimprovements in ppFEV1, SwCl, CFQ-R RD score, and LCI2.5 were shown, consistent with the resultsobserved in the study 445-106.

In study 445-116 treatment with IVA/TEZ/ELX in combination with IVA in patients aged 6 to less than12 years resulted in statistically significant improvement through 24 weeks in the primary endpoint(LCI2.5). The LS mean treatment difference for the IVA/TEZ/ELX in combination with IVA group versusplacebo for the absolute change in LCI2.5 from baseline through week 24 was -2.26 (95% CI: -2.71, -1.81;

P < 0.0001).

Study 445-111

In study 445-111 the primary endpoint of safety and tolerability was evaluated through 24 weeks.

Secondary endpoints included an evaluation of pharmacokinetics, and efficacy endpoints includingabsolute change in sweat chloride (see Pharmacodynamic effects) and LCI2.5 from baseline through week24. See Table 13 for a summary of secondary efficacy outcomes.

Table 13: Secondary efficacy analyses, full analysis set (study 445-111)

Within-group change (95% CI)

Analysis for IVA/TEZ/ELX incombination with IVA

Absolute change in sweat chloride from baseline through N=75week 24 (mmol/L) -57.9 (-61.3, -54.6)

*

Absolute change in LCI from baseline through week 24 N=632.5 -0.83 (-1.01, -0.66)

CI: Confidence Interval; LCI: Lung Clearance Index

* LCI assessed only on patients aged 3 years and older at screening.

Study 445-124

In study 445-124, the safety and efficacy of IVA/TEZ/ELX in patients with CF aged 6 years and olderwithout an F508del mutation were evaluated. A post-hoc efficacy analysis was conducted in 31 patientsaged 6-12 years, of whom 23 patients received IVA/TEZ/ELX. The mean change (SD) from baseline was10.2% (16.2) for ppFEV1 and -37.7 (18.8) mmol/L for sweat chloride.

The European Medicines Agency has deferred the obligation to submit the results of studies with

IVA/TEZ/ELX in combination with IVA in one or more subset of the paediatric population in cysticfibrosis (see section 4.2 for information on paediatric use).

The pharmacokinetics of ELX, TEZ and IVA are similar between healthy adult subjects and patients with

CF. Following initiation of once-daily dosing of ELX and TEZ and twice-daily dosing of IVA, plasmaconcentrations of ELX, TEZ and IVA reach steady state within approximately 7 days for ELX, within8 days for TEZ, and within 3-5 days for IVA. Upon dosing IVA/TEZ/ELX to steady state, theaccumulation ratio is approximately 3.6 for ELX, 2.8 for TEZ and 4.7 for IVA. Key pharmacokineticparameters for ELX, TEZ and IVA at steady state in patients with CF aged 12 years and older are shownin Table 14.

Table 14: Mean (SD) pharmacokinetic parameters of ELX, TEZ and IVA at steady state inpatients with CF aged 12 years and older

Dose Active Substance C (μg/mL) AUC0-24h, ss or AUC0-12h,ssmax (μg∙h/mL)*

IVA 150 mg every ELX 9.15 (2.09) 162 (47.5)12 hours/TEZ 100 mg and TEZ 7.67 (1.68) 89.3 (23.2)

ELX 200 mg once daily IVA 1.24 (0.34) 11.7 (4.01)

SD: Standard Deviation; Cmax: maximum observed concentration; AUCss: Area Under the Concentrationversus time curve at steady state

* AUC0-24h for ELX and TEZ and AUC0-12h for IVA.

The absolute bioavailability of ELX when administered orally in the fed state is approximately 80%. ELXis absorbed with a median (range) time to maximum concentration (tmax) of approximately 6 hours (4 to12 hours) while the median (range) tmax of TEZ and IVA is approximately 3 hours (2 to 4 hours) and 4hours (3 to 6 hours), respectively. ELX exposure (AUC) increases approximately 1.9- to 2.5-fold whenadministered with a moderate-fat meal relative to fasted conditions. IVA exposure increasesapproximately 2.5- to 4.0-fold when administered with fat-containing meals relative to fasted conditions,while food has no effect on the exposure of TEZ (see section 4.2).

As exposures of ELX were approximately 20% lower after administration of the IVA/TEZ/ELX granulesrelative to the reference IVA/TEZ/ELX tablet, the formulations are not considered interchangeable.

ELX is >99% bound to plasma proteins and TEZ is approximately 99% bound to plasma proteins, in bothcases primarily to albumin. IVA is approximately 99% bound to plasma proteins, primarily to albumin,and also to alpha 1-acid glycoprotein and human gamma-globulin. After oral administration of

IVA/TEZ/ELX in combination with IVA, the mean (±SD) apparent volume of distribution of ELX, TEZand IVA was 53.7 L (17.7), 82.0 L (22.3) and 293 L (89.8), respectively. ELX, TEZ and IVA do notpartition preferentially into human red blood cells.

ELX is metabolised extensively in humans, mainly by CYP3A4/5. Following oral administration of asingle dose of 200 mg 14C-ELX to healthy male subjects, M23-ELX was the only major circulatingmetabolite. M23-ELX has similar potency to ELX and is considered pharmacologically active.

TEZ is metabolised extensively in humans, mainly by CYP3A4/5. Following oral administration of asingle dose of 100 mg 14C-TEZ to healthy male subjects, M1-TEZ, M2-TEZ and M5-TEZ were the threemajor circulating metabolites of TEZ in humans. M1-TEZ has similar potency to that of TEZ and isconsidered pharmacologically active. M2-TEZ is much less pharmacologically active than TEZ or

M1-TEZ and M5-TEZ is not considered pharmacologically active. Another minor circulating metabolite,

M3-TEZ, is formed by direct glucuronidation of TEZ.

IVA is also metabolised extensively in humans. In vitro and in vivo data indicate that IVA is metabolisedprimarily by CYP3A4/5. M1-IVA and M6-IVA are the two major metabolites of IVA in humans. M1-IVAhas approximately one-sixth the potency of IVA and is considered pharmacologically active. M6-IVA isnot considered pharmacologically active.

The effect of the CYP3A4*22 heterozygous genotype on TEZ, IVA and ELX exposure is consistent withthe effect of co-administration of a weak CYP3A4 inhibitor, which is not clinically relevant. No dose-adjustment of TEZ, IVA or ELX is considered necessary. The effect in CYP3A4*22 homozygousgenotype patients is expected to be stronger. However, no data are available for such patients.

Following multiple dosing in the fed state, the mean (±SD) apparent clearance values of ELX, TEZ and

IVA at steady state were 1.18 (0.29) L/h, 0.79 (0.10) L/h and 10.2 (3.13) L/h, respectively. The mean (SD)terminal half-lives of ELX, TEZ and IVA following administration of the IVA/TEZ/ELX fixed-dosecombination tablets are approximately 24.7 (4.87) hours, 60.3 (15.7) hours and 13.1 (2.98) hours,respectively. The mean (SD) effective half-life of TEZ following administration of the IVA/TEZ/ELXfixed-dose combination tablets is 11.9 (3.79) hours.

Following oral administration of 14C-ELX alone, the majority of ELX (87.3%) was eliminated in thefaeces, primarily as metabolites.

Following oral administration of 14C-TEZ alone, the majority of the dose (72%) was excreted in the faeces(unchanged or as the M2-TEZ) and about 14% was recovered in urine (mostly as M2-TEZ), resulting in amean overall recovery of 86% up to 26 days after the dose.

Following oral administration of 14C-IVA alone, the majority of IVA (87.8%) was eliminated in the faecesafter metabolic conversion.

For ELX, TEZ and IVA there was negligible urinary excretion of unchanged medicine.

ELX alone or in combination with TEZ and IVA has not been studied in subjects with severe hepaticimpairment (Child-Pugh Class C, score 10-15). Following multiple doses of ELX, TEZ and IVA for10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) had anapproximately 25% higher AUC and a 12% higher Cmax for ELX, 73% higher AUC and a 70% higher Cmaxfor M23-ELX, 20% higher AUC but similar Cmax for TEZ, 22% lower AUC and a 20% lower Cmax for

M1-TEZ, and a 1.5-fold higher AUC and a 10% higher Cmax for IVA compared with healthy subjectsmatched for demographics. The effect of moderately impaired hepatic function on total exposure (basedon summed values of ELX and its M23-ELX metabolite) was 36% higher AUC and a 24% higher Cmaxcompared with healthy subjects matched for demographics (see sections 4.2, pct. 4.4, and 4.8).

Following multiple doses of TEZ and IVA for 10 days, subjects with moderately impaired hepaticfunction had an approximately 36% higher AUC and a 10% higher Cmax for TEZ, and a 1.5-fold higher

AUC but similar Cmax for IVA compared with healthy subjects matched for demographics.

In a study with IVA alone, subjects with moderately impaired hepatic function had similar IVA Cmax, butan approximately 2.0-fold higher IVA AUC0-∞ compared with healthy subjects matched for demographics.

ELX alone or in combination with TEZ and IVA has not been studied in patients with severe renalimpairment [estimated glomerular filtration rate (eGFR) less than 30 mL/min] or in patients with end-stage renal disease.

In human pharmacokinetic studies of ELX, TEZ and IVA, there was minimal elimination of ELX, TEZand IVA in urine (only 0.23%, 13.7% [0.79% as unchanged medicine] and 6.6% of total radioactivity,respectively).

Based on population pharmacokinetic (PK) analysis, exposure of ELX was similar in patients with mildrenal impairment (N=75; eGFR 60 to less than 90 mL/min) relative to those with normal renal function(N=341; eGFR 90 mL/min or greater).

In population PK analysis conducted in 817 patients administered TEZ alone or in combination with IVAin phase 2 or phase 3 studies indicated that mild renal impairment (N=172; eGFR 60 to less than90 mL/min) and moderate renal impairment (N=8; eGFR 30 to less than 60 mL/min) did not affect theclearance of TEZ significantly (see sections 4.2 and 4.4).

The pharmacokinetic parameters of ELX (244 males compared to 174 females), TEZ and IVA are similarin males and females.

Race had no clinically meaningful effect on ELX exposure based on population PK analysis in whites(N=373) and non-whites (N=45). The non-white races consisted of 30 Blacks or African Americans, 1with multiple racial background and 14 with other ethnic background (no Asians).

Very limited PK data indicate comparable exposure of TEZ in whites (N=652) and non-whites (N=8). Thenon-white races consisted of 5 Blacks or African Americans and 3 Native Hawaiians or other Pacific

Islanders.

Race had no clinically meaningful effect on the PK of IVA in whites (N=379) and non-whites (N=29)based on a population PK analysis. The non-white races consisted of 27 African Americans and 2 Asians.

Clinical trials of IVA/TEZ/ELX in combination with IVA did not include sufficient number of patientsaged 65 years and older to determine whether response in these patients is different from younger adults(see section 4.4).

ELX, TEZ and IVA exposures observed in phase 3 studies as determined using population PK analysis arepresented by age group in Table 15. Exposures of ELX, TEZ and IVA in patients aged 2 to less than18 years are within the range observed in patients aged 18 years and older.

Table 15: Mean (SD) ELX, M23-ELX, TEZ, M1-TEZ and IVA exposures observed at steady state byage group and dose administered

Age/Weight ELX M23-ELX TEZ M1-TEZ IVAgroup Dose AUC0-24h, ss AUC0-24h, ss AUC0-24h, ss AUC0-24h, ss AUC0-12h, ss(μg∙h/mL) (μg∙h/mL) (μg∙h/mL) (μg∙h/mL) (μg∙h/mL)

IVA 60 mg

Patients aged 2 qAM/to <6 years, TEZ 40 mg qd/10 kg to <14 kg ELX 80 mg qd 128 (24.8) 56.5 (29.4) 87.3 (17.3) 194 (24.8) 11.9 (3.86)(N=16) and IVA 59.5 mgqPM

Patients aged 2 IVA 75 mgto <6 years, q12h/≥14 kg TEZ 50 mg qd/ 138 (47.0) 59.0 (32.7) 90.2 (27.9) 197 (43.2) 13.0 (6.11)(N=59) ELX 100 mg qd

Patients aged 6 IVA 75 mgto <12 years, q12h/<30 kg TEZ 50 mg qd/ 116 (39.4) 45.4 (25.2) 67.0 (22.3) 153 (36.5) 9.78 (4.50)(N=36) ELX 100 mg qd

Patients aged 6 IVA 150 mgto <12 years, q12h/TEZ≥30 kg 100 mg qd/ 195 (59.4) 104 (52.0) 103 (23.7) 220 (37.5) 17.5 (4.97)(N=30) ELX 200 mg qd

Adolescent IVA 150 mgpatients q12h/(12 to <18 TEZ 100 mg qd/ 147 (36.8) 58.5 (25.6) 88.8 (21.8) 148 (33.3) 10.6 (3.35)years) (N=72) ELX 200 mg qd

Adult patients IVA 150 mg(≥18 years) q12h/(N=179) TEZ 100 mg qd/ 168 (49.9) 64.6 (28.9) 89.5 (23.7) 128 (33.7) 12.1 (4.17)

ELX 200 mg qd

SD: Standard Deviation; AUCss: Area Under the Concentration versus time curve at steady state; qd: oncedaily; qAM: once each morning; qPM: once each evening; q12h: once every 12 hours

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.

The No Observed Adverse Effect Level (NOAEL) for fertility findings was 55 mg/kg/day (2 times themaximum recommended human dose (MRHD) based on summed AUCs of ELX and its metabolite) inmale rats and 25 mg/kg/day (4 times the MRHD based on summed AUCs of ELX and its metabolite) infemale rats. In rat, at doses exceeding the maximum tolerated dose (MTD), degeneration and atrophy ofseminiferous tubules are correlated to oligo-/aspermia and cellular debris in epididymides. In dog testes,minimal or mild, bilateral degeneration/atrophy of the seminiferous tubules was present in malesadministered 14 mg/kg/day ELX (15 times the MRHD based on summed AUCs of ELX and itsmetabolite) that did not resolve during the recovery period, however without further sequelae. The humanrelevance of these findings is unknown.

ELX was not teratogenic in rats at 40 mg/kg/day and at 125 mg/kg/day in rabbits (approximately 9 and4 times, respectively, the MRHD based on summed AUCs of ELX and its metabolite [for rat] and AUC of

ELX [for rabbit]) with developmental findings being limited to lower mean foetal body weight at≥25 mg/kg/day.

Placental transfer of ELX was observed in pregnant rats.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproductionand development. Placental transfer of TEZ was observed in pregnant rats.

Juvenile toxicity studies in rats exposed during postnatal day 7 to 35 (PND 7-35) showed mortality andmoribundity, even at low doses. Findings were dose related and generally more severe when dosing withtezacaftor was initiated earlier in the postnatal period. Exposure in rats from PND 21-49 did not showtoxicity at the highest dose which was approximately two times the intended human exposure. Tezacaftorand its metabolite, M1-TEZ, are substrates for P-glycoprotein. Lower brain levels of P-glycoproteinactivity in younger rats resulted in higher brain levels of tezacaftor and M1-TEZ. These findings are likelynot relevant for the indicated paediatric population of 2 years of age and older, for whom P-glycoproteinexpression levels are equivalent to levels observed in adults.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.

The NOAEL for fertility findings was 100 mg/kg/day (5 times the MRHD based on summed AUCs of

IVA and its metabolites) in male rats and 100 mg/kg/day (3 times the MRHD based on summed AUCs of

IVA and its metabolites) in female rats.

In the pre- and post-natal study IVA decreased survival and lactation indices and caused a reduction in pupbody weights. The NOAEL for viability and growth in the offspring provides an exposure level ofapproximately 3 times the systemic exposure of IVA and its metabolites in adult humans at the MRHD.

Placental transfer of IVA was observed in pregnant rats and rabbits.

Findings of cataracts were observed in juvenile rats dosed from postnatal day 7 through day 35 at IVAexposure levels of 0.21 time the MRHD based on systemic exposure of IVA and its metabolites. Thisfinding has not been observed in foetuses derived from rat dams treated with IVA on gestation days 7 today 17, in rat pups exposed to IVA through milk ingestion up to postnatal day 20, in 7-week-old rats, norin 3.5- to 5-month-old dogs treated with IVA. The potential relevance of these findings in humans isunknown (see section 4.4).

Combination repeat-dose toxicity studies in rats and dogs involving the co-administration of ELX, TEZand IVA to assess the potential for additive and/or synergistic toxicity did not produce any unexpectedtoxicities or interactions. The potential for synergistic toxicity on male reproduction has not been assessed.

Silica, colloidal anhydrous (E551)

Croscarmellose sodium (E468)

Hypromellose (E464)

Hypromellose acetate succinate

Lactose monohydrate

Magnesium stearate (E470b)

Mannitol (E421)

Sodium laurilsulfate (E487)

Sucralose (E955)

Not applicable.

4 years

Once mixed, the mixture has been shown to be stable for one hour.

This medicinal product does not require any special storage conditions.

Biaxially-oriented polyethylene terephthalate/polyethylene/foil/polyethylene (BOPET/PE/Foil/PE) printedfoil laminate sachet.

Pack size of 28 sachets (4 weekly wallets, each with 7 sachets).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Vertex Pharmaceuticals (Ireland) Limited

Unit 49, Block 5, Northwood Court, Northwood Crescent,

Dublin 9, D09 T665,

Ireland

EU/1/20/1468/003

EU/1/20/1468/004

Date of first authorisation: 21 August 2020

Date of latest renewal: 22 May 2025

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.