KAFTRIO 37.5mg / 25mg / 50mg tablets medication leaflet

Each film-coated tablet contains 37.5 mg of ivacaftor, 25 mg of tezacaftor and 50 mg of elexacaftor.

Each film-coated tablet contains 75 mg of ivacaftor, 50 mg of tezacaftor and 100 mg of elexacaftor.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Light orange, capsule-shaped tablet debossed with “T50” on one side and plain on the other(dimensions 6.4 mm x 12.2 mm).

Orange, capsule-shaped tablet debossed with “T100” on one side and plain on the other (dimensions7.9 mm x 15.5 mm).

Kaftrio tablets are indicated in a combination regimen with ivacaftor for the treatment of cysticfibrosis (CF) in patients aged 6 years and older who have at least one F508del mutation in the cysticfibrosis transmembrane conductance regulator (CFTR) gene (see section 5.1).

Kaftrio should only be prescribed by healthcare professionals with experience in the treatment of CF.

If the patient’s genotype is unknown, an accurate and validated genotyping method should beperformed to confirm the presence of at least one F508del mutation using a genotyping assay (seesection 5.1).

Monitoring of transaminases (ALT and AST) and total bilirubin is recommended for all patients priorto initiating treatment, every 3 months during the first year of treatment and annually thereafter. Forpatients with a history of liver disease or transaminase elevations, more frequent monitoring should beconsidered (see section 4.4).

Adults and paediatric patients aged 6 years and older should be dosed according to Table 1.

Table 1: Dosing recommendations for patients aged 6 years and older

Age Weight Morning dose Evening dose6 to < 12 years < 30 kg Two ivacaftor 37.5 mg/tezacaftor25 mg/elexacaftor 50 mg tablets One ivacaftor 75 mg tablet6 to < 12 years ≥ 30 kg Two ivacaftor 75 mg/tezacaftor50 mg/elexacaftor 100 mg tablets One ivacaftor 150 mg tablet12 years and older - Two ivacaftor 75 mg/tezacaftor50 mg/elexacaftor 100 mg tablets One ivacaftor 150 mg tablet

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 shouldnot take the evening dose. The next scheduled morning dose should be taken at the usual time.

* the missed evening dose, the patient should not take the missed dose. The next scheduledmorning dose 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)or strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole,telithromycin, and clarithromycin), 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 Inhibitors

Alternate each day: Two IVA 37.5 mg/TEZ 25mg/ELX 50 mg tablets

* Two ivacaftor 37.5 mg/tezacaftor 25 twice a week,6 to < 12 mg/elexacaftor 50 mg (IVA/TEZ/ELX) approximately 3 to 4 daysyears < 30 kg tablets on the first day apart.

* One ivacaftor 75 mg (IVA) tablet onthe next day No evening IVA tabletdose.

No evening IVA tablet dose.

Alternate each day: Two IVA 75 mg/TEZ 50mg/ELX 100 mg tablets

* Two ivacaftor 75 mg/tezacaftor 50 twice a week,6 to < 12 mg/elexacaftor 100 mg approximately 3 to 4 daysyears ≥ 30 kg (IVA/TEZ/ELX) tablets on the first day apart.

* One ivacaftor 150 mg (IVA) tablet onthe next day No evening IVA tabletdose.

No evening IVA tablet dose.

12 years Alternate each day: Two IVA 75 mg/TEZ 50and older - mg/ELX 100 mg tabletstwice a week,

* Two ivacaftor 75 mg/tezacaftor 50 approximately 3 to 4 daysmg/elexacaftor 100 mg apart.(IVA/TEZ/ELX) tablets on the first day

* One ivacaftor 150 mg (IVA) tablet on No evening IVA tabletthe next day dose.

No evening IVA tablet dose.

No dose adjustment is recommended for the elderly patient population (see sections 4.4 and 5.2).

Treatment of patients with moderate hepatic impairment (Child-Pugh Class B) is not recommended.

For patients with moderate hepatic impairment, the use of Kaftrio should only be considered whenthere is a clear medical need, and the benefits are expected to outweigh the risks. If used, it should beused with caution at a reduced dose (see Table 3).

Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), butthe exposure is expected to be higher than in patients with moderate hepatic impairment. Patients withsevere hepatic 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 6 years and older with hepatic impairment

Age Weight Mild Severe(Child-Pugh Moderate

Class A) (Child-Pugh Class B) (Child-Pugh

Class C)6 to <30 kg Use not recommended. Treatment of< 12 patients with moderate hepaticyears impairment should only be consideredwhen there is a clear medical need andthe benefits are expected to outweighthe risks.

If used, Kaftrio should be used withcaution at a reduced dose, as follows:

No dose * Day 1: two IVA 37.5 mg/TEZ Should notadjustment 25 mg/ELX 50 mg tablets in the be usedmorning

* Day 2: one IVA 37.5 mg/TEZ25 mg/ELX 50 mg tablet in themorning

Continue alternating Day 1 and Day 2dosing thereafter.

The evening dose of the IVA tabletshould not be taken.

6 to ≥30 kg Use not recommended. Treatment of< 12 patients with moderate hepaticyears impairment should only be consideredwhen there is a clear medical need andthe benefits are expected to outweighthe risks.

If used, Kaftrio should be used withcaution at a reduced dose, as follows:

No dose * Day 1: two IVA 75 mg/TEZ 50 Should notadjustment mg/ELX 100 mg tablets in the be usedmorning

* Day 2: one IVA 75 mg/TEZ 50mg/ELX 100 mg tablet in themorning

Continue alternating Day 1 and Day 2dosing thereafter.

The evening dose of the IVA tabletshould not be taken.

12 years - Use not recommended. Treatment ofand patients with moderate hepaticolder impairment should only be consideredwhen there is a clear medical need andthe benefits are expected to outweighthe risks.

If used, Kaftrio should be used withcaution at a reduced dose, as follows:

No dose * Day 1: two IVA 75 mg/TEZ 50 Should notadjustment mg/ELX 100 mg tablets in the be usedmorning

* Day 2: one IVA 75 mg/TEZ 50mg/ELX 100 mg tablet in themorning

Continue alternating Day 1 and Day 2dosing thereafter.

The evening dose of the IVA tabletshould not be taken.

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

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

For oral use. Patients should be instructed to swallow the tablets whole. The tablets should not bechewed, crushed, or broken before swallowing because there are no clinical data currently available tosupport other methods of administration; chewing or crushing the tablet is not recommended.

Kaftrio should be taken with fat-containing food. Examples of meals or snacks that contain fat arethose prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats (seesection 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.

In a patient with cirrhosis and portal hypertension liver failure leading to transplantation has beenreported while receiving IVA/TEZ/ELX in combination with ivacaftor. IVA/TEZ/ELX in combinationwith IVA should be used with caution in patients with pre-existing advanced liver disease (e.g.,cirrhosis, portal hypertension) and only if the benefits are expected to outweigh the risks. If used inthese patients, they should be closely monitored after the initiation of treatment (see sections 4.2, pct. 4.8,and 5.2).

Elevated transaminases are common in patients with CF. In clinical studies, elevated transaminaseswere more frequently observed in patients treated with IVA/TEZ/ELX in combination with IVAcompared to placebo. In patients taking IVA/TEZ/ELX in combination with IVA, these elevationshave sometimes been associated with concomitant elevations in total bilirubin. Assessments oftransaminases (ALT and AST) and total bilirubin are recommended for all patients prior to initiatingtreatment, every 3 months during 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 monitoringshould be considered. In the event of ALT or AST >5 x the upper limit of normal (ULN), or ALT or

AST >3 x ULN with bilirubin >2 x ULN, dosing should be interrupted, and laboratory tests closelyfollowed until the abnormalities resolve. Following the resolution of transaminase elevations, thebenefits and risks of resuming treatment should be considered (see sections 4.2, pct. 4.8, and 5.2).

Treatment of patients with moderate hepatic impairment is not recommended. For patients withmoderate hepatic impairment, the use of IVA/TEZ/ELX should only be considered when there is aclear medical need, and the benefits are expected to outweigh the risks. If used, it should be used withcaution at a reduced 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. In some cases, symptom improvement was reported after dosereduction or treatment discontinuation. Patients (and caregivers) should be alerted about the need tomonitor for depressed mood, suicidal thoughts, or unusual changes in behaviour and to seek medicaladvice immediately if these symptoms present.

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

IVA/TEZ/ELX in combination with IVA has not been studied in patients with CF who haveundergone organ transplantation. Therefore, use in transplanted patients is not recommended. Seesection 4.5 for interactions with commonly used immunosuppressants.

The incidence of rash events was higher in females than in males, particularly in females takinghormonal contraceptives. A role for hormonal contraceptives in the occurrence of rash cannot beexcluded. For patients taking hormonal contraceptives who develop rash, interrupting treatment with

IVA/TEZ/ELX in combination with IVA and hormonal contraceptives should be considered.

Following the resolution of rash, it should be considered if resuming IVA/TEZ/ELX in combinationwith IVA without hormonal contraceptives is appropriate. If rash does not recur, resumption ofhormonal contraceptives can be considered (see section 4.8).

Clinical studies of IVA/TEZ/ELX in combination with IVA did not include sufficient number ofpatients aged 65 years and older to determine whether response in these patients is different fromyounger adults. Dose recommendations are based on the pharmacokinetic profile and knowledge fromstudies with tezacaftor/ivacaftor (TEZ/IVA) in combination with ivacaftor (IVA), and ivacaftor (IVA)monotherapy (see sections 4.2 and 5.2).

Exposure to IVA is significantly decreased and exposures to ELX and TEZ are expected to decreaseby the concomitant use of CYP3A inducers, potentially resulting in the reduced efficacy of

IVA/TEZ/ELX and IVA; therefore, co-administration with strong CYP3A inducers is notrecommended (see section 4.5).

Exposures of ELX, TEZ and IVA are increased when co-administered with strong or moderate

CYP3A inhibitors. The dose of IVA/TEZ/ELX and IVA should be adjusted when used concomitantlywith strong or 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 paediatricpatients treated with IVA-containing regimens. Although other risk factors were present in some cases(such as corticosteroid use, exposure to radiation) a possible risk attributable to treatment with IVAcannot be excluded. Baseline and follow-up ophthalmological examinations are recommended inpaediatric patients initiating treatment with IVA/TEZ/ELX in combination with IVA (see section 5.3).

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

ELX, TEZ and IVA are substrates of CYP3A (IVA is a sensitive substrate of CYP3A). Concomitantuse of strong CYP3A inducers may result in reduced exposures and thus reduced IVA/TEZ/ELXefficacy. Co-administration of IVA with rifampicin, a strong CYP3A inducer, significantly decreased

IVA area under the curve (AUC) by 89%. ELX and TEZ exposures are also expected to decreaseduring co-administration with strong CYP3A inducers; therefore, co-administration with strong

CYP3A inducers is 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 AUCincreased by 15.6-fold and 8.5-fold, respectively. The dose of IVA/TEZ/ELX and IVA should bereduced when co-administered with strong CYP3A inhibitors (see Table 2 in section 4.2 andsection 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,erythromycin and verapamil, may increase ELX and TEZ AUC by approximately 1.9- to 2.3-fold. Co-administration of fluconazole increased IVA AUC by 2.9-fold. The dose of IVA/TEZ/ELX and IVAshould be reduced when co-administered with moderate CYP3A inhibitors (see Table 2 in section 4.2and section 4.4).

Examples of moderate CYP3A inhibitors include:

* fluconazole

* erythromycin

Co-administration with grapefruit juice, which contains one or more components that moderatelyinhibit CYP3A, may increase exposure of ELX, TEZ and IVA. Food or drink containing grapefruitshould be avoided during treatment with IVA/TEZ/ELX and IVA (see section 4.2).

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 effluxtransporters P-gp and BCRP. TEZ is not a substrate for OATP1B3. Exposure to TEZ is not expectedto be affected significantly by concomitant inhibitors of OATP1B1, P-gp, or BCRP due to its highintrinsic permeability and low likelihood of being excreted intact. However, exposure to M2-TEZ(TEZ metabolite) may be increased 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 likelihoodof being excreted intact, co-administration of BCRP inhibitors is not expected to alter exposure of IVAand M1-IVA, while any potential changes in M6-IVA exposures are not expected to be clinicallyrelevant.

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 medicinalproducts for which exposure may be increased include glimepiride and glipizide; these medicinalproducts should be used with caution.

Co-administration of IVA or TEZ/IVA with digoxin, a sensitive P-gp substrate, increased digoxin

AUC by 1.3-fold, consistent with weak inhibition of P-gp by IVA. Administration of IVA/TEZ/ELXand IVA may increase systemic exposure of medicinal products that are sensitive substrates of P-gp,which may increase or prolong their therapeutic effect and adverse reactions. When usedconcomitantly with digoxin or other substrates of P-gp with a narrow therapeutic index such asciclosporin, everolimus, sirolimus and tacrolimus, caution and appropriate monitoring should be used.

ELX and M23-ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro. TEZ/IVA increased the

AUC of pitavastatin, an OATP1B1 substrate, by 1.2-fold. Co-administration with IVA/TEZ/ELX incombination with IVA may increase exposures of medicinal products that are substrates of thesetransporters, such as statins, glyburide, nateglinide and repaglinide. When used concomitantly withsubstrates of OATP1B1 or OATP1B3, caution and appropriate monitoring should be used. Bilirubin isan OATP1B1 and OATP1B3 substrate. In study 445-102, mild increases in mean total bilirubin wereobserved (up to 4.0 µmol/L change from baseline). This finding is consistent with the in vitroinhibition 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 andwas found 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.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of ELX, TEZor IVA in pregnant women. Animal studies do not indicate direct or indirect harmful effects withrespect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoidthe use of IVA/TEZ/ELX during pregnancy.

Limited data show that ELX, TEZ, and IVA are excreted in human milk. A risk to thenewborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feedingor to discontinue/abstain from IVA/TEZ/ELX therapy taking into account the benefit of breast-feedingfor the child 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 noeffects on fertility and reproductive performance indices in male and female rats at clinically relevantexposures. 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/IVAin combination with IVA as well as IVA (see section 4.8). Patients experiencing dizziness should beadvised not 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%), upperrespiratory tract infection (11.9%) and aminotransferase increased (10.9%).

Serious adverse reactions of rash experienced by patients aged 12 years and older were reported in1.5% 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/IVAin combination with IVA, and IVA monotherapy. Adverse reactions are listed by MedDRA systemorgan class and frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated fromthe available data). Within each frequency grouping, adverse reactions are presented in the order ofdecreasing seriousness.

Table 4: Adverse reactions

MedDRA System Organ Class Adverse Reactions Frequency

Upper respiratory tract infection*,

Infections and infestations Nasopharyngitis very common

Rhinitis*, Influenza* common

Metabolism and nutritiondisorders Hypoglycaemia* common

Psychiatric disorders Depression 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

Hepatobiliary disorders Aspartate aminotransferase increased* very common

Liver injury† not known

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 very common

Investigations Blood creatine phosphokinaseincreased* 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. This also included liver failure leading to transplantationin a patient with pre-existing cirrhosis and portal hypertension. Frequency cannot be estimated fromthe 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 rolledover from 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)in 64 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.

In study 445-102, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 x the ULNwas 1.5%, 2.5% and 7.9% in IVA/TEZ/ELX-treated patients and 1.0%, 1.5% and 5.5% inplacebo-treated patients. 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(see section 4.4).

In study 445-102, the incidence of rash events (e.g., rash, rash pruritic) was 10.9% in

IVA/TEZ/ELX- and 6.5% in placebo-treated patients. The rash events were generally mild tomoderate in severity. The incidence of rash events by patient sex was 5.8% in males and 16.3% infemales in IVA/TEZ/ELX-treated patients and 4.8% in males and 8.3% in females in placebo-treatedpatients. In patients treated with IVA/TEZ/ELX, the incidence of rash events was 20.5% in femalestaking hormonal contraceptive and 13.6% in females not taking hormonal contraceptive (seesection 4.4).

In study 445-102, the incidence of maximum creatine phosphokinase >5 x 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. No

IVA/TEZ/ELX-treated patients discontinued treatment for increased creatine phosphokinase.

In study 445-102, the maximum increase from baseline in mean systolic and diastolic blood pressurewas 3.5 mmHg and 1.9 mmHg, respectively for IVA/TEZ/ELX-treated patients (baseline: 113 mmHgsystolic and 69 mmHg diastolic) and 0.9 mmHg and 0.5 mmHg, respectively for placebo-treatedpatients (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-treatedpatients compared with 3.5% and 3.5%, respectively in placebo-treated patients.

The safety data of IVA/TEZ/ELX in combination with IVA in studies 102, 103, 104,106 and 111 wasevaluated in 228 patients between 2 to less than 18 years of age. The safety profile is generallyconsistent 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 x ULN were 0.0%, 1.5%, and 10.6%, respectively. No

IVA/TEZ/ELX-treated patients had transaminase elevation >3 x ULN associated with elevated totalbilirubin >2 x 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 x ULN were 1.3%, 2.7%, and 8.0% respectively. No IVA/TEZ/ELX-treated patients had transaminase elevation >3 x ULN associated with elevated total bilirubin>2 x 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, 15 (20.0%) subjects had at least 1 rashevent, 4 (9.8%) females and 11 (32.4%) males.

Lenticular opacity

One patient had an adverse event of lenticular opacity.

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. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted 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 statusof the 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 anadditive effect in facilitating the cellular processing and trafficking of F508del-CFTR to increase theamount of CFTR protein delivered to the cell surface compared to either molecule alone. IVApotentiates the channel open probability (or gating) of the CFTR protein at the cell surface.

The combined effect of ELX, TEZ and IVA is increased quantity and function of F508del-CFTR atthe cell surface, resulting in increased CFTR activity as measured by CFTR mediated chloridetransport. With regard to non-F508del CFTR variants on the second allele, it is not clear whether andto what extent the combination of ELX, TEZ and IVA also increases the amount of these mutated

CFTR variants on the cell surface and potentiates its channel open probability (or gating).

In study 445-102 (patients with an F508del mutation on one allele and a mutation on the second allelethat predicts either no production of a CFTR protein or a CFTR protein that does not transport chlorideand is not responsive to other CFTR modulators [IVA and TEZ/IVA] in vitro), a reduction in sweatchloride was observed from baseline at week 4 and sustained through the 24-week treatment period.

The treatment difference of IVA/TEZ/ELX in combination with IVA compared to placebo for meanabsolute change in sweat 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 allelewith a gating defect or residual CFTR activity), the mean absolute change in sweat chloride frombaseline through 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 the control 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 mutationor heterozygous for the F508del mutation and a minimal function mutation), the mean absolute changein sweat 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, especiallyfrom week 16 onwards. The ability to collect data at week 24 was hampered by the COVID-19pandemic. Week 12 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 mutationand a 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 treatmentdifference for the IVA/TEZ/ELX in combination with IVA group versus placebo for absolute changein sweat chloride from baseline through week 24 was -51.2 mmol/L (95% CI: -55.3, -47.1; nominal

P<0.0001).

At doses up to 2 times the maximum recommended dose of ELX and 3 times the maximumrecommended dose of TEZ and IVA, the QT/QTc interval in healthy subjects was not prolonged toany clinically relevant 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 six

Phase 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. Not all F508del heterozygotes have been clinicallyevaluated with IVA/TEZ/ELX in combination with IVA.

Study 445-102 was a 24-week, randomised, double-blind, placebo-controlled study in patients whohad an F508del mutation on one allele and an MF mutation on the second allele. CF patients eligiblefor this study were required to either have Class I mutations that predicted no CFTR protein beingproduced (including nonsense mutations, canonical splice mutations and insertion/deletion frameshiftmutations both small (≤3 nucleotide) and non-small (>3 nucleotide)), or missense mutations whichresults in CFTR protein that does not transport chloride and is not responsive to IVA and TEZ/IVAin vitro. The most frequent 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 yearsand older (mean age 26.2 years) were randomised and dosed to receive placebo or IVA/TEZ/ELX incombination with IVA. Patients had a ppFEV1 at screening between 40-90%. The mean ppFEV1 atbaseline 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 in combination with IVA during a 4-week double-blind treatment period. Patients had appFEV1 at screening between 40-90%. The mean ppFEV1 at baseline, following the run-in period was60.9% (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 age37.7 years) received either IVA (F/Gating) or TEZ/IVA in combination with IVA (F/RF) during a4-week open-label run-in period and were dosed during the treatment period and patients with the

F/R117H genotype received IVA during the run-in period. Patients were then randomised and dosed toreceive either IVA/TEZ/ELX in combination with IVA or remained on the CFTR modulator therapyreceived during the run-in period. Patients had a ppFEV1 at screening between 40-90%. The meanppFEV1 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 66patients aged 6 to less than 12 years (mean age at baseline 9.3 years) were dosed according to weight.

Patients weighing <30 kg at baseline were administered two IVA 37.5 mg/TEZ 25 mg/ELX 50 mgtablets in the morning and one IVA 75 mg tablet in the evening. Patients weighing ≥30 kg at baselinewere administered two IVA 75 mg/TEZ 50 mg/ELX 100 mg tablets in the morning and one IVA150 mg tablet in the evening. Patients had a ppFEV1 ≥40% and weighed ≥15 kg at screening. Themean ppFEV1 at baseline was 88.8% (range: 39.0%, 127.1%).

Study 445-116 was a 24-week, randomised, double-blind, placebo-controlled study in patients aged 6to less than 12 years (mean age at baseline 9.2 years) who were heterozygous for the F508del mutationand a minimal 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

IVA weighing <30 kg at baseline were administered two IVA 37.5 mg/TEZ 25 mg/ELX 50 mg tabletsin the morning and one IVA 75 mg tablet in the evening. Patients weighing ≥30 kg at baseline wereadministered two IVA 75 mg/TEZ 50 mg/ELX 100 mg tablets in the morning and one IVA 150 mgtablet in the evening. 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.

Patients in these studies continued on their CF therapies (e.g., bronchodilators, inhaled antibiotics,dornase alfa and hypertonic saline), but discontinued any previous CFTR modulator therapies, exceptfor study medicinal products. Patients had a confirmed diagnosis of CF.

In studies 445-102, 445-103, 445-104, and 445-106, patients who had lung infection with organismsassociated with a more rapid decline in pulmonary status, including but not limited to Burkholderiacenocepacia, Burkholderia dolosa, or Mycobacterium abscessus, or who had an abnormal liverfunction test at screening (ALT, AST, ALP, or GGT ≥3 x ULN, or total bilirubin ≥2 x ULN), wereexcluded. Patients in studies 445-102 and 445-103 were eligible to roll over into a 192-weekopen-label extension study (study 445-105).

Patients in studies 445-104, 445-106, and 445-116 were eligible to roll over into separate open-labelextension 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 5). Mean improvement in ppFEV1 was observed at the first assessment onday 15 and sustained through the 24-week treatment period. Improvements in ppFEV1 were observedregardless of 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 theoverall population. The mean treatment difference of IVA/TEZ/ELX in combination with

IVA- compared to placebo-treated patients for absolute change in ppFEV1 through week 24 in thissubgroup was 18.4 percentage points (95% CI: 11.5, 25.3).

See Table 5 for a summary of primary and key secondary outcomes.

Table 5: 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 P value NA P < 0.0001week 4 (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)

Table 5: 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

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 4of the double-blind treatment period. Treatment with IVA/TEZ/ELX in combination with IVAcompared to TEZ/IVA in combination with IVA resulted in a statistically significant improvement inppFEV1 of 10.0 percentage points (95% CI: 7.4, 12.6; P < 0.0001) (see Table 6). Improvements inppFEV1 were observed regardless of age, sex, baseline ppFEV1 geographic region.

See Table 6 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 6: 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 Treatment difference (95% CI) NA 10.0 (7.4, 12.6)ppFEV1 from baseline at P value NA P < 0.0001week 4 (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-Rrespiratory domain score Mean (SD) 72.6 (17.9) 70.6 (16.2)(points)

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)

Table 6: 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 = 55ppFEV1: 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-inperiod of TEZ/IVA in combination with IVA.

In study 445-104 the primary endpoint was within-group mean absolute change in ppFEV1 frombaseline through week 8 for the IVA/TEZ/ELX in combination with IVA group. Treatment with

IVA/TEZ/ELX in combination with IVA resulted in statistically significant improvement in ppFEV1from baseline of 3.7 percentage points (95% CI: 2.8, pct. 4.6; P < 0.0001) (see Table 7). Overallimprovements in ppFEV1 were observed regardless of age, sex, baseline ppFEV1 geographic region,and genotype groups (F/Gating or F/RF).

See Table 7 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/ELX in combination with IVA (N = 50) compared with IVA (N = 45) for mean absolutechange in ppFEV1 was 5.8 percentage points (95% CI: 3.5, 8.0). In a subgroup analysis of patientswith an F/RF genotype, the treatment difference of IVA/TEZ/ELX in combination with IVA (N = 82)compared with TEZ/IVA in combination with IVA (N = 81) for mean absolute change in ppFEV1 was2.0 percentage points (95% CI: 0.5, 3.4). The results of the F/Gating and the F/RF genotype subgroupsfor improvement in sweat chloride and CFQ-R respiratory domain score were consistent with theoverall results.

Table 7: Primary and secondary efficacy analyses, full analysis set (study 445-104)

Control IVA/TEZ/ELX

Analysis* Statistic group† in combination

N = 126 with 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 (95% CI)(percentage 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 (95% CI)to the control group (percentage P value NA P < 0.0001points)

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) -22.3from baseline through week 8 (95% CI) (-24.5, -20.2)(mmol/L) P value NA P < 0.0001

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

Baseline CFQ-R respiratorydomain score (points) Mean (SD) 77.3 (15.8) 76.5 (16.6)

Table 7: Primary and secondary efficacy analyses, full analysis set (study 445-104)

Control IVA/TEZ/ELX

Analysis* Statistic group† in combination

N = 126 with IVA

N = 132

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 periodof IVA or 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 oflong-term treatment with IVA/TEZ/ELX in combination with IVA.Patients who rolled over fromstudies 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 inefficacy endpoints consistent with those observed in subjects who received IVA/TEZ/ELX incombination with IVA in the parent studies. Patients from the control arms as well as patients whoreceived IVA/TEZ/ELX in combination with IVA in the parent studies, showed sustainedimprovements. Secondary efficacy endpoints are summarized in Table 8.

Table 8: 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/EL445-102 in 445-102 445-103 X in 445-103

Analysis Statistic N = 203 N = 196 N = 52 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)(percentagepoints)

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 score95% 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

* Baseline = parent study baseline† For subjects who were randomized 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 445-105). For subjects who were randomized 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).

Paediatric patients aged 6 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 9 for a summary of secondary efficacy outcomes.

Table 9: 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(95% CI) change (95% CI)*ppFEV1 (percentage points) n=62 n=59 n=5988.8 (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)n=58

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

- 0.16 (0.74) 0.22 (0.13, 0.30) † 0.37 (0.26, 0.48) ‡n=58

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

- 0.22 (0.76) 0.13 (0.07, 0.18) † 0.25 (0.16, 0.33) ‡n=58

Height-for-age z-score n=66 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/A 4 (0.12) §n=53 n=48

LCI 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.

* 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 wasconducted in 64 paediatric patients aged 6 years and older. With 192 additional weeks of treatment,sustained improvements in ppFEV1, SwCl, CFQ-R RD score, and LCI2.5 were shown, consistent withthe results observed in the study 445-106.

In study 445-116, treatment with IVA/TEZ/ELX in combination with IVA in patients aged 6 to lessthan 12 years resulted in statistically significant improvement through 24 weeks in the primaryendpoint (LCI2.5). The LS mean treatment difference for the IVA/TEZ/ELX in combination with IVAgroup versus placebo for the absolute change in LCI2.5 from baseline through week 24 was -2.26(95% CI: -2.71, -1.81; P<0.0001).

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 patientswith CF. Following initiation of once-daily dosing of ELX and TEZ and twice-daily dosing of IVA,plasma concentrations of ELX, TEZ and IVA reach steady state within approximately 7 days for ELX,within 8 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 areshown in Table 10.

Table 10: Mean (SD) pharmacokinetic parameters of ELX, TEZ and IVA at steady state inpatients with CF aged 12 years and older

Active AUC0-24h, ss or

Dose Substance Cmax (μg/mL) AUC0-12h, ss(μg∙h/mL)*

IVA 150 mg every ELX 9.15 (2.09) 162 (47.5)12 hours/TEZ 100 mgand ELX 200 mg once TEZ 7.67 (1.68) 89.3 (23.2)daily IVA 1.24 (0.34) 11.7 (4.01)

SD: Standard Deviation; Cmax: maximum observed concentration; AUCss: Area Under the

Concentration versus 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%.

ELX is absorbed with a median (range) time to maximum concentration (tmax) of approximately6 hours (4 to 12 hours) while the median (range) tmax of TEZ and IVA is approximately 3 hours (2 to4 hours) and 4 hours (3 to 6 hours), respectively. ELX exposure (AUC) increases approximately 1.9-to 2.5-fold when administered with a moderate-fat meal relative to fasted conditions. IVA exposureincreases approximately 2.5- to 4-fold when administered with fat-containing meals relative to fastedconditions, 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/ELXgranules relative to the reference IVA/TEZ/ELX tablet, the formulations are not consideredinterchangeable.

ELX is >99% bound to plasma proteins and TEZ is approximately 99% bound to plasma proteins, inboth cases primarily to albumin. IVA is approximately 99% bound to plasma proteins, primarily toalbumin, and also to alpha 1-acid glycoprotein and human gamma-globulin. After oral administrationof IVA/TEZ/ELX in combination with IVA, the mean (±SD) apparent volume of distribution of ELX,

TEZ and IVA was 53.7 L (17.7), 82.0 L (22.3) and 293 L (89.8), respectively. ELX, TEZ and IVA donot partition preferentially into human red blood cells.

ELX is metabolized 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 metabolized 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 thethree major circulating metabolites of TEZ in humans. M1-TEZ has similar potency to that of TEZand is considered pharmacologically active. M2-TEZ is much less pharmacologically active than TEZor M1-TEZ and M5-TEZ is not considered pharmacologically active. Another minor circulatingmetabolite, M3-TEZ, is formed by direct glucuronidation of TEZ.

IVA is also metabolized extensively in humans. In vitro and in vivo data indicate that IVA ismetabolized primarily by CYP3A4/5. M1-IVA and M6-IVA are the two major metabolites of IVA inhumans. M1-IVA has approximately one-sixth the potency of IVA and is consideredpharmacologically active. M6-IVA is not considered pharmacologically active.

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

Following multiple dosing in the fed state, the mean (±SD) apparent clearance values of ELX, TEZand 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. Themean (SD) terminal half-lives of ELX, TEZ and IVA following administration of the IVA/TEZ/ELXfixed-dose combination 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/ELX fixed-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 thefaeces (unchanged or as the M2-TEZ) and about 14% was recovered in urine (mostly as M2-TEZ),resulting in a mean 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 thefaeces after 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

Cmax for 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 healthysubjects matched for demographics. The effect of moderately impaired hepatic function on totalexposure (based on summed values of ELX and its M23-ELX metabolite) was 36% higher AUC and a24% higher Cmax compared with healthy subjects matched for demographics (see sections 4.2, pct. 4.4, and4.8).

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,but an approximately 2.0-fold higher IVA AUC0-∞ compared with healthy subjects matched fordemographics.

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,

TEZ and IVA in urine (only 0.23%, 13.7% [0.79% as unchanged medicine] and 6.6% of totalradioactivity, respectively).

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

In population PK analysis conducted in 817 patients administered TEZ alone or in combination with

IVA in 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 affectthe clearance of TEZ significantly (see sections 4.2 and 4.4).

The pharmacokinetic parameters of ELX (244 males compared to 174 females), TEZ and IVA aresimilar in 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,1 with 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). The non-white races consisted of 5 Blacks or African Americans and 3 Native Hawaiians orother 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 Americansand 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 youngeradults (see sections 4.2 and 4.4).

ELX, TEZ and IVA exposures observed in phase 3 studies as determined using population PK analysisare presented by age group in Table 11. Exposures of ELX, TEZ and IVA in patients aged 2 to lessthan 18 years are within the range observed in patients aged 18 years and older.

Table 11. Mean (SD) ELX, M23-ELX, TEZ, M1-TEZ and IVA exposures observed at steady state by agegroup 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)

Patients aged 2 IVA 60 mg 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 2to < 6 years, IVA 75 mg 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 6to < 12 years IVA 75 mg q12h/weighing TEZ 50 mg qd/ 116 (39.4) 45.4 (25.2) 67.0 (22.3) 153 (36.5) 9.78 (4.50)< 30 kg ELX 100 mg qd(N = 36)

Patients aged 6to < 12 years IVA 150 mgweighing q12h/ TEZ100 mg qd/ 195 (59.4) 104 (52) 103 (23.7) 220 (37.5) 17.5 (4.97)≥ 30 kg(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/

TEZ 100 mg qd/ 168 (49.9) 64.6 (28.9) 89.5 (23.7) 128 (33.7) 12.1 (4.17)(N = 179) 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)in female rats. In rat, at doses exceeding the maximum tolerated dose (MTD), degeneration andatrophy of seminiferous 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 presentin males administered 14 mg/kg/day ELX (15 times the MRHD based on summed AUCs of ELX andits metabolite) that did not resolve during the recovery period, however without further sequelae. Thehuman relevance 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 bodyweight 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 toreproduction and 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 mortalityand moribundity, even at low doses. Findings were dose related and generally more severe whendosing with tezacaftor was initiated earlier in the postnatal period. Exposure in rats from PND 21-49did not show toxicity at the highest dose which was approximately two times the intended humanexposure. Tezacaftor and its metabolite, M1-TEZ, are substrates for P-glycoprotein. Lower brainlevels of P-glycoprotein activity in younger rats resulted in higher brain levels of tezacaftor and

M1-TEZ. These findings are likely not relevant for the indicated paediatric population of 2 years ofage and older, for whom P-glycoprotein expression 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 AUCsof IVA and its metabolites) in female rats.

In the pre- and post-natal study IVA decreased survival and lactation indices and caused a reduction inpup body 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 7to day 17, in rat pups exposed to IVA through milk ingestion up to postnatal day 20, in 7-week-oldrats, nor in 3.5- to 5-month-old dogs treated with IVA. The potential relevance of these findings inhumans is unknown (see section 4.4).

Combination repeat-dose toxicity studies in rats and dogs involving the co-administration of ELX,

TEZ and IVA to assess the potential for additive and/or synergistic toxicity did not produce anyunexpected toxicities or interactions. The potential for synergistic toxicity on male reproduction hasnot been assessed.

Hypromellose (E464)

Hypromellose acetate succinate

Sodium laurilsulfate (E487)

Croscarmellose sodium (E468)

Microcrystalline cellulose (E460(i))

Magnesium stearate (E470b)

Hypromellose (E464)

Hydroxypropyl cellulose (E463)

Titanium dioxide (E171)

Talc (E553b)

Iron oxide yellow (E172)

Iron oxide red (E172)

Not applicable.

Kaftrio 37.5 mg/25 mg/50 mg film-coated tablets4 years

Kaftrio 75 mg/50 mg/100 mg film-coated tablets4 years

This medicinal product does not require any special storage conditions.

Blister consisting of PCTFE (polychlorotrifluoroethylene) film laminated to PVC (polyvinyl chloride)film and sealed with blister foil lidding.

Pack size of 56 tablets (4 blister cards, each with 14 tablets).

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/1/20/1468/001

EU/1/20/1468/002

Date of first authorisation: 21 August 2020

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

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