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 F508del mutation in the cystic fibrosis 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 be performed to confirm the presence of at least one F508del mutation using a genotyping assay (see section 5.1).

Posology

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

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

Missed dose

If 6 hours or less have passed since the missed morning or evening dose, the patient should take the missed 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 not 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 scheduled morning dose should be taken at the usual time.

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

Concomitant use of CYP3A inhibitors

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).

Special populations

Hepatic impairment

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 to outweigh 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 the exposure is expected to be higher than in patients with moderate hepatic impairment. Patients with severe 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, 4.8, and 5.2).

Renal impairment

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

Paediatric population

The safety and efficacy of Kaftrio in combination with ivacaftor in children aged less than 2 years have not yet been established.

No data are available (see section 5.1).

Method of administration

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

Kaftrio should be taken with fat-containing food. Examples of meals or snacks that contain fat are those prepared 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.

Elevated transaminases and hepatic injury

In a patient with cirrhosis and portal hypertension liver failure leading to transplantation has been reported while receiving IVA/TEZ/ELX in combination with ivacaftor. IVA/TEZ/ELX in combination with 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 in these patients, they should be closely monitored after the initiation of treatment (see sections 4.2, 4.8, and 5.2).

Elevated transaminases are common in patients with CF and have been observed in some patients treated with IVA/TEZ/ELX in combination with IVA. In patients taking IVA/TEZ/ELX in combination with IVA, these elevations have sometimes been 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 months during the first year of treatment and annually thereafter. For patients with a history of liver disease or transaminase elevations, more frequent monitoring should 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 closely followed until the abnormalities resolve. Following the resolution of transaminase elevations, the benefits and risks of resuming treatment should be considered (see sections 4.2, 4.8, and 5.2).

Hepatic impairment

Treatment of patients with moderate hepatic impairment is not recommended. For patients with moderate hepatic impairment, the use of IVA/TEZ/ELX should only be considered when there is a clear medical need, and the benefits are expected to outweigh the risks. If used, it should be used with caution 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).

Renal impairment

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

Patients after organ transplantation

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

Rash events

The incidence of rash events was higher in females than in males, particularly in females taking hormonal contraceptives. A role for hormonal contraceptives in the occurrence of rash cannot be excluded. 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 combination with IVA without hormonal contraceptives is appropriate. If rash does not recur, resumption of hormonal contraceptives can be considered (see section 4.8).

Elderly population

Clinical studies of IVA/TEZ/ELX in combination with IVA did not include sufficient number of patients aged 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 with tezacaftor/ivacaftor in combination with ivacaftor, and ivacaftor monotherapy (see sections 4.2 and 5.2).

Interactions with medicinal products

CYP3A inducers

Exposure to IVA is significantly decreased and exposures to ELX and TEZ are expected to decrease by 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 not recommended (see section 4.5).

CYP3A inhibitors

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 concomitantly with strong or moderate CYP3A inhibitors (see section 4.5 and Table 2 in section 4.2).

Cataracts

Cases of non-congenital lens opacities without impact on vision have been reported in paediatric patients 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 IVA cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in paediatric patients initiating treatment with IVA/TEZ/ELX in combination with IVA (see section 5.3).

Lactose content

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

Sodium content

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

Medicinal products affecting the pharmacokinetics of ELX, TEZ and/or IVA

CYP3A inducers

ELX, TEZ and IVA are substrates of CYP3A (IVA is a sensitive substrate of CYP3A). Concomitant use of 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 area under the curve (AUC) by 89%. ELX and TEZ exposures are also expected to decrease during 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 (Hypericum perforatum)

CYP3A inhibitors

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 increased by 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, 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 IVA should be reduced when 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 be avoided during treatment with IVA/TEZ/ELX and IVA (see section 4.2).

Potential for interaction with transporters

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 not expected to be affected significantly by concomitant use of P-gp and BCRP inhibitors due to its high intrinsic 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 affected significantly by concomitant inhibitors of OATP1B1, P-gp, or BCRP due to its high intrinsic 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 its metabolites are substrates of BCRP in vitro. Due to its high intrinsic permeability and low likelihood of being 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.

Medicinal products affected by ELX, TEZ and/or IVA

CYP2C9 substrates

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

Potential for interaction with transporters

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/ELX and 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 used concomitantly with digoxin or other substrates of P-gp with a narrow therapeutic index such as ciclosporin, 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 in combination with IVA may increase exposures of medicinal products that are substrates of these transporters, such as statins, 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 OATP1B3 substrate. In study 445-102, mild increases in mean total bilirubin were observed (up to 4.0 µ mol/L change 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 increase exposures of medicinal products that are substrates of BCRP, such as rosuvastatin. When used concomitantly with substrates of BCRP, appropriate monitoring should be used.

Hormonal contraceptives

IVA/TEZ/ELX in combination with IVA has been studied with ethinyl estradiol/levonorgestrel and was 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.

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

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

Breast-feeding

It is unknown whether ELX, TEZ, IVA, or their metabolites are excreted in human milk. Available pharmacokinetic/toxicological data in animals have shown excretion of ELX, TEZ and IVA into the milk of lactating female rats (see section 5.3). A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from IVA/TEZ/ELX therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data available on the effect of ELX, TEZ and IVA on fertility in humans. TEZ had no effects on 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 in combination with IVA as well as IVA (see section 4.8). Patients experiencing dizziness should be advised not to drive or use machines until symptoms abate.

Summary of the safety profile

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%) and upper respiratory tract infection (11.9%).

Serious adverse reactions of rash were reported in 3 (1.5%) patients treated with IVA/TEZ/ELX in combination with IVA compared to 1 (0.5%) in placebo.

Tabulated list of adverse reactions

Table 4 reflects adverse reactions observed with IVA/TEZ/ELX in combination with IVA, TEZ/IVA in combination with IVA, and IVA monotherapy. Adverse reactions are listed by MedDRA system organ class 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 available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

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 (study 445-103).

• A 96-week, open-label safety and efficacy study (study 445-105) for patients rolled over from studies 445-102 and 445-103, with interim analysis performed on 510 patients including 271 patients with ≥ 48 weeks of cumulative treatment with IVA/TEZ/ELX in combination with IVA.

• An 8-week, randomised, double-blind, active-controlled study in 258 patients (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, open-label study (study 445-111) in 75 patients aged 2 to less than 6 years.

Description of selected adverse reactions

Transaminase elevations

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

Post-marketing cases of treatment discontinuation due to elevated transaminases have been reported (see section 4.4).

Rash events

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 to moderate in severity. The incidence of rash events by patient sex was 5.8% in males and 16.3% in females in IVA/TEZ/ELX-treated patients 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 and 13.6% in females not taking hormonal contraceptive (see section 4.4).

Increased creatine phosphokinase

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 elevations were generally transient and asymptomatic and many were preceded by exercise. No IVA/TEZ/ELX-treated patients discontinued treatment for increased creatine phosphokinase.

Increased blood pressure

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

Paediatric population

The safety data of IVA/TEZ/ELX in combination with IVA in studies 102, 103, 104 and 106 was evaluated in 153 patients between 6 to less than 18 years of age. The safety profile is generally consistent among adolescents 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%, 1.5%, and 10.6%, 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, 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).

Other special populations

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 percent predicted forced expiratory volume in one second (ppFEV₁), and geographic regions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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

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

Mechanism of action

ELX and TEZ are CFTR correctors that bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of F508del-CFTR to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. IVA potentiates 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 at the cell surface, resulting in increased CFTR activity as measured by CFTR mediated chloride transport. With regard to non-F508del CFTR variants on the second allele, it is not clear whether and to 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).

Pharmacodynamic effects

Effects on sweat chloride

In study 445-102 (patients with an F508del mutation on one allele and a mutation on the second allele that predicts either no production of a CFTR protein or a CFTR protein that does not transport chloride and is not responsive to other CFTR modulators [IVA and TEZ/IVA] in vitro), a reduction in sweat chloride 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 mean absolute 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 mean absolute 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 with a gating defect or residual CFTR activity), the mean absolute change in sweat chloride from baseline 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 mutation or heterozygous for the F508del mutation and a minimal function mutation), the mean absolute change in 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).

* The through week 24 endpoint is analyzed using mixed model with repeated measures (MMRM) including data from week 4, week 12 and week 24.

‡ The through week 12 endpoint is analyzed using MMRM including data from week 4 and week 12.

≠ Not all participants included in the analyses had data available for all follow-up visits, especially from week 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.

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

Cardiovascular effects

Effect on QT interval

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

Heart rate

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.

Clinical efficacy and safety

The efficacy of IVA/TEZ/ELX in combination with IVA in patients with CF was demonstrated in five Phase 3 studies. Patients enrolled in these studies were homozygous for the F508del mutation or heterozygous for the F508del mutation and a mutation with minimal function (MF), a gating defect, or residual CFTR activity on the second allele. Not all F508del heterozygotes have been clinically evaluated with IVA/TEZ/ELX in combination with IVA.

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 this study 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 mutations both small (≤ 3 nucleotide) and non-small (>3 nucleotide)), or missense mutations which results in CFTR protein that does not transport chloride and is not responsive to IVA and TEZ/IVA in 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 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 a ppFEV₁ 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 were homozygous for the F508del mutation. A total of 107 patients aged 12 years and older (mean age 28.4 years) received TEZ/IVA in combination with IVA during a 4-week open-label run-in period and were 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 a ppFEV₁ at screening between 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 were heterozygous 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-label run-in period and were dosed during the treatment period. Patients with the F/R117H genotype received IVA during the run-in period. Patients were then randomised and dosed to receive either IVA/TEZ/ELX in combination with IVA or remained on the CFTR modulator therapy received during the run-in period. Patients had a ppFEV₁ at screening between 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 F508del mutation or heterozygous for the F508del mutation and a minimal function mutation. A total of 66 patients 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 mg tablets in the morning and one IVA 75 mg tablet in the evening. Patients weighing ≥ 30 kg at baseline were administered two IVA 75 mg/TEZ 50 mg/ELX 100 mg tablets in the morning and one IVA 150 mg tablet in the evening. Patients had a ppFEV₁ ≥ 40% and weighed ≥ 15 kg at screening. The mean ppFEV₁ at baseline was 88.8% (range: 39.0%, 127.1%).

Study 445-111 was a 24-week open-label study in patients aged 2 to less than 6 years (mean age at baseline 4.1 years). Patients who had at least one F508del mutation or a mutation known to be responsive to ELX/TEZ/IVA were eligible for the study. A total of 75 patients who are homozygous for the F508del mutation or heterozygous for 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 once every morning/TEZ 40 mg once daily (qd)/ELX 80 mg qd and IVA 59.5 mg once every evening. Patients weighing ≥ 14 kg at baseline were administered IVA 75 every 12 hours/TEZ 50 mg qd/ELX 100 mg qd.

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, except for study drugs. Patients had a confirmed diagnosis of CF.

In studies 445-102, 445-103, 445-104, 445-106, and 445-111 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 Mycobacterium abscessus, or who had an abnormal liver function test at screening (ALT, AST, ALP, or GGT ≥ 3 x ULN, or total bilirubin ≥ 2 x ULN), were excluded. In study 445-111, patients who had ALT or AST ≥ 2 x ULN were also excluded.

Patients in studies 445-102 and 445-103 were eligible to roll over into the 96-week open-label extension study (Study 445-105). Patients in studies 445-104, 445-106, and 445-111 were eligible to roll over into separate open-label extension studies.

Study 445-102

In study 445-102 the primary endpoint was mean absolute change in ppFEV₁ from baseline through week 24. Treatment with IVA/TEZ/ELX in combination with IVA compared to placebo resulted in statistically 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 on Day 15 and sustained through the 24-week treatment period. Improvements in ppFEV₁ were observed regardless of age, baseline ppFEV₁, sex, and geographic region.

A total of 18 patients receiving IVA/TEZ/ELX in combination with IVA had ppFEV₁ <40 percentage points at baseline. The safety and efficacy in this subgroup were consistent to those observed in the overall 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 this subgroup was 18.4 percentage points (95% CI: 11.5, 25.3).

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

Study 445-103

In study 445-103 the primary endpoint was mean absolute change in ppFEV₁ from baseline at week 4 of the 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 of 10.0 percentage points (95% CI: 7.4, 12.6; P<0.0001) (Table 6). Improvements in ppFEV₁ 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, an improvement 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.

Study 445-104

In study 445-104 the primary endpoint was within-group mean absolute change in ppFEV₁ from baseline 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 ppFEV₁ from baseline of 3.7 percentage points (95% CI: 2.8, 4.6; P<0.0001) (See Table 7). Overall improvements 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 absolute change in ppFEV₁ was 5.8 percentage points (95% CI: 3.5, 8.0). In a subgroup analysis of patients with 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 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 chloride and CFQ-R respiratory domain score were consistent with the overall results.

Study 445-105

An ongoing, 96-week open-label extension study to evaluate the safety and efficacy of long-term treatment with IVA/TEZ/ELX in combination with IVA is being conducted in patients who rolled over from studies 445-102 and 445-103. In this open-label extension study all patients received IVA/TEZ/ELX in combination with IVA. For patients who rolled over from studies 445-102 (N=400) and 445-103 (N=107), an interim efficacy analysis was conducted when they completed the week 24 visit of study 445-105.

Patients homozygous for the F508del mutation who received IVA/TEZ/ELX in combination with IVA in study 445-103, and continued on the same treatment in study 445-105, showed sustained improvements in ppFEV₁, CFQ-R respiratory domain score, and sweat chloride, through 28 weeks of cumulative treatment (i.e., through week 24 in study 445-105). The outcomes of annualised pulmonary exacerbation event rate through 28 weeks of cumulative treatment (i.e., through week 24 in study 445-105), and BMI and BMI-z score at 28 weeks of cumulative treatment (at week 24 in study 445-105), were consistent with those seen in patients with the genotypes studied in study 445-102.

Paediatric population

Study 445-106

The pharmacokinetic profile, safety, and efficacy of IVA/TEZ/ELX in combination with IVA in patients with CF aged 6 to less than 12 years are supported by evidence from studies in patients aged 12 years and older (studies 445-102 and 445-103), with additional data from a 24-week, open-label, phase 3 study in 66 patients aged 6 to less than 12 years (study 445-106).

In study 445-106 the primary endpoint of safety and tolerability was evaluated through 24 weeks. Secondary endpoints were evaluation of pharmacokinetics, and efficacy including absolute change in ppFEV₁, sweat chloride (also see pharmacodynamics section), and LCI_2.5 from baseline through Week 24; and measure of growth parameters (weight-for-age z-score, height-for-age z-score) from baseline at Week 24. See Table 8 for a summary of secondary efficacy outcomes.

Study 445-111

The pharmacokinetic profile, safety, and efficacy of IVA/TEZ/ELX in combination with IVA in patients with CF aged 2 to less than 6 years are supported by evidence from studies of IVA/TEZ/ELX in combination with IVA in patients aged 12 years and older (studies 445-102, 445-103 and 445-104), with additional data from a 24-week, open-label, phase 3 study in 75 patients aged 2 to less than 6 years (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 including absolute change in sweat chloride (see Pharmacodynamic effects) and LCI_2.5 from baseline through week 24. See Table 9 for a summary of secondary efficacy outcomes.

The Medicines and Healthcare products Regulatory Agency (MHRA) 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 cystic fibrosis (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, 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, the accumulation ratio is approximately 3.6 for ELX, 2.8 for TEZ and 4.7 for IVA. Key pharmacokinetic parameters for ELX, TEZ and IVA at steady state in patients with CF aged 12 years and older are shown in Table 10.

Absorption

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 (t_max) of approximately 6 hours (4 to 12 hours) while the median (range) t_max of TEZ and IVA is approximately 3 hours (2 to 4 hours) and 4 (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 exposure increases approximately 2.5- to 4-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).

Distribution

ELX is >99% bound to plasma proteins and TEZ is approximately 99% bound to plasma proteins, in both cases 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, TEZ and IVA was 53.7 L (17.7), 82.0 L (22.3) and 293 L (89.8), respectively. ELX, TEZ and IVA do not partition preferentially into human red blood cells.

Biotransformation

ELX is metabolized extensively in humans, mainly by CYP3A4/5. Following oral administration of a single dose of 200 mg ¹⁴C-ELX to healthy male subjects, M23-ELX was the only major circulating metabolite. 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 a single dose of 100 mg ¹⁴C-TEZ to healthy male subjects, M1-TEZ, M2-TEZ, and M5-TEZ were the 3 major circulating metabolites of TEZ in humans. M1-TEZ has similar potency to that of TEZ and is considered 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 metabolized extensively in humans. In vitro and in vivo data indicate that IVA is metabolized primarily by CYP3A4/5. M1-IVA and M6-IVA are the two major metabolites of IVA in humans. M1-IVA has approximately one-sixth the potency of IVA and is considered pharmacologically active. M6-IVA is not considered pharmacologically active.

The effect of the CYP3A4*22 heterozygous genotype on TEZ, IVA and ELX exposure is consistent with the 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 homozygous genotype patients is expected to be stronger. However, no data are available for such patients.

Elimination

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-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 the faeces, 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 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 the faeces after metabolic conversion.

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

Hepatic impairment

ELX alone or in combination with TEZ and IVA has not been studied in subjects with severe hepatic impairment (Child-Pugh Class C, score 10-15). Following multiple doses of ELX, TEZ and IVA for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) had an approximately 25% higher AUC and a 12% higher C_max for ELX, 73% higher AUC and a 70% higher C_max for M23-ELX, 20% higher AUC but similar C_max for TEZ, 22% lower AUC and a 20% lower C_max for M1-TEZ, and a 1.5-fold higher AUC and a 10% higher C_max for IVA compared with healthy subjects matched for demographics. The effect of moderately impaired hepatic function on total exposure (based on summed values of ELX and its M23-ELX metabolite) was 36% higher AUC and a 24% higher C_max compared with healthy subjects matched for demographics (see sections 4.2, 4.4, and 4.8).

Tezacaftor and ivacaftor

Following multiple doses of TEZ and IVA for 10 days, subjects with moderately impaired hepatic function had an approximately 36% higher AUC and a 10% higher C_max for TEZ, and a 1.5-fold higher AUC but similar C_max for IVA compared with healthy subjects matched for demographics.

Ivacaftor

In a study with IVA alone, subjects with moderately impaired hepatic function had similar IVA C_max, but an approximately 2.0-fold higher IVA AUC_0-∞ compared with healthy subjects matched for demographics.

Renal impairment

ELX alone or in combination with TEZ and IVA has not been studied in patients with severe renal impairment (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 total radioactivity, respectively).

Based on population pharmacokinetic (PK) analysis, exposure of ELX was similar in patients with mild renal 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 IVA in phase 2 or phase 3 studies indicated that mild renal impairment (N=172; eGFR 60 to less than 90 mL/min) and moderate renal impairment (N=8; eGFR 30 to less than 60 mL/min) did not affect the clearance of TEZ significantly (see sections 4.2 and 4.4).

Gender

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

Race

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 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.

Elderly

Clinical trials of IVA/TEZ/ELX in combination with IVA did not include sufficient number of patients aged 65 years and older to determine whether response in these patients is different from younger adults (see sections 4.2 and 4.4).

Paediatric population

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

Elexacaftor

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

Fertility and pregnancy

The No Observed Adverse Effect Level (NOAEL) for fertility findings was 55 mg/kg/day (2 times the maximum recommended human dose (MRHD) based on summed AUCs of ELX and its metabolite) in male 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 and atrophy 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 present in males administered 14 mg/kg/day ELX (14 times the MRHD based on summed AUCs of ELX and its metabolite) that did not resolve during the recovery period, however without further sequelae. The human 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 and 4 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.

Tezacaftor

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction 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 mortality and moribundity, even at low doses. Findings were dose related and generally more severe when dosing with tezacaftor was initiated earlier in the postnatal period. Exposure in rats from PND 21-49 did not show toxicity at the highest dose which was approximately two times the intended human exposure. Tezacaftor and its metabolite, M1-TEZ, are substrates for P-glycoprotein. Lower brain levels of P-glycoprotein activity in younger rats resulted in higher brain levels of tezacaftor and M1-TEZ. These findings are not relevant for the indicated paediatric population 6 to 11 years of age, for whom levels of P-glycoprotein activity are equivalent to levels observed in adults.

Ivacaftor

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

Fertility and pregnancy

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 pup body weights. The NOAEL for viability and growth in the offspring provides an exposure level of approximately 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.

Juvenile animals

Findings of cataracts were observed in juvenile rats dosed from postnatal day 7 through day 35 at IVA exposure levels of 0.21 times the MRHD based on systemic exposure of IVA and its metabolites. This finding has not been observed in foetuses derived from rat dams treated with IVA on gestation days 7 to day 17, in rat pups exposed to IVA through milk ingestion up to postnatal day 20, in 7-week-old rats, nor in 3.5- to 5-month-old dogs treated with IVA. The potential relevance of these findings in humans is unknown (see section 4.4).

Ivacaftor/tezacaftor/elexacaftor

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 any unexpected toxicities or interactions. The potential for synergistic toxicity on male reproduction has not been assessed.

Colloidal silicon dioxide

Croscarmellose sodium

Hypromellose

Hypromellose acetate succinate

Lactose monohydrate

Magnesium stearate

Mannitol

Sodium lauryl sulfate

Sucralose

Not applicable.

2 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) printed foil 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 local requirements.