SYMKEVI 100mg / 150mg tablets medication leaflet

Symkevi 50 mg/75 mg film-coated tablets

Symkevi 100 mg/150 mg film-coated tablets

Symkevi 50 mg/75 mg film-coated tablets

Each tablet contains 50 mg of tezacaftor and 75 mg of ivacaftor.

Symkevi 100 mg/150 mg film-coated tablets

Each tablet contains 100 mg of tezacaftor and 150 mg of ivacaftor.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Symkevi 50 mg/75 mg film-coated tablets

White, capsule-shaped tablet debossed with “V50” on one side and plain on the other (dimensions12.70 mm x 6.78 mm).

Symkevi 100 mg/150 mg film-coated tablets

Yellow, capsule-shaped tablet debossed with “V100” on one side and plain on the other (dimensions15.9 mm x 8.5 mm).

Symkevi is indicated in a combination regimen with ivacaftor tablets for the treatment of patients withcystic fibrosis (CF) aged 6 years and older who are homozygous for the F508del mutation or who areheterozygous for the F508del mutation and have one of the following mutations in the cystic fibrosistransmembrane conductance regulator (CFTR) gene: P67L, R117C, L206W, R352Q, A455E, D579G,711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G, and 3849+10kbC→T.

Symkevi should only be prescribed by physicians with experience in the treatment of CF. If thepatient’s genotype is unknown, an accurate and validated genotyping method should be performed toconfirm the presence of an indicated mutation using a genotyping assay.

Adults, adolescents and children 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 Evening(1 tablet) (1 tablet)6 to < 12 years weighing < 30 kg tezacaftor 50 mg/ivacaftor 75 mg ivacaftor 75 mg6 to < 12 years weighing ≥ 30 kg tezacaftor 100 mg/ivacaftor 150 mg ivacaftor 150 mg≥ 12 years tezacaftor 100 mg/ivacaftor 150 mg ivacaftor 150 mg

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 or evening dose, the patient should nottake the missed dose. The next scheduled dose can be taken at the usual time.

More than one dose of either tablet should not be taken at the same time.

The dose of Symkevi and ivacaftor should be adjusted when co-administered with moderate andstrong 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 according to Table 2 (see sections 4.4and 4.5).

Table 2: Dosing recommendations for concomitant use with moderate or strong CYP3Ainhibitors

Age/Weight Moderate CYP3A inhibitors Strong CYP3A inhibitors6 years to < 12 years, Alternate each morning: One morning tablet of< 30 kg - one tablet of tezacaftor tezacaftor 50 mg/ivacaftor50 mg/ivacaftor 75 mg 75 mg twice a week,once daily on the first day approximately 3 to 4 days

- one tablet of ivacaftor apart.75 mg on the next day.

Continue alternating tablets No evening dose.each day.

No evening dose.

6 years to < 12 years, Alternate each morning: One morning tablet of≥ 30 kg - one tablet of tezacaftor tezacaftor 100 mg/ivacaftor100 mg/ivacaftor 150 mg 150 mg twice a week,once daily on the first day approximately 3 to 4 days

- one tablet of ivacaftor apart.150 mg on the next day.

Continue alternating tablets No evening dose.each day.

No evening dose.

Table 2: Dosing recommendations for concomitant use with moderate or strong CYP3Ainhibitors

Age/Weight Moderate CYP3A inhibitors Strong CYP3A inhibitors12 years and older Alternate each morning: One morning tablet of

- one tablet of tezacaftor tezacaftor 100 mg/ivacaftor100 mg/ivacaftor 150 mg 150 mg twice a week,once daily on the first day approximately 3 to 4 days

- one tablet of ivacaftor apart.150 mg on the next day.

Continue alternating tablets No evening dose.each day.

No evening dose.

Elderly people

The safety, efficacy and pharmacokinetics of Symkevi have been examined in a limited number ofelderly patients. No dose adjustment specific to this patient population is required (see section 5.2).

No dose adjustment is recommended for patients with mild or moderate renal impairment. Caution isrecommended in patients with severe renal impairment or end-stage renal disease (see sections 4.4 and5.2).

For dose adjustment for patients with hepatic impairment, (see Table 3). There is no experience of theuse of Symkevi in patients with severe hepatic impairment (Child-Pugh Class C); therefore, its use isnot recommended unless the benefits outweigh the risks. In such cases, Symkevi should be used at areduced dose (see sections 4.4 and 5.2). No dose adjustment is necessary for Symkevi in patients withmild hepatic impairment (Child-Pugh Class A).

Table 3: Dosing recommendations for use in patients with hepatic impairment

Age/Weight Moderate (Child-Pugh Class B) Severe (Child-Pugh Class C)6 years to < 12 years, One morning tablet of tezacaftor One morning tablet of< 30 kg 50 mg/ivacaftor 75 mg once tezacaftor 50 mg/ivacaftordaily. 75 mg once daily or lessfrequently.

No evening dose.

Dosing intervals should bemodified according to clinicalresponse and tolerability.

No evening dose.

6 years to < 12 years, One morning tablet of tezacaftor One morning tablet of≥ 30 kg 100 mg/ivacaftor 150 mg once tezacaftor 100 mg/ivacaftordaily. 150 mg once daily or lessfrequently.

No evening dose.

Dosing intervals should bemodified according to clinicalresponse and tolerability.

Table 3: Dosing recommendations for use in patients with hepatic impairment

Age/Weight Moderate (Child-Pugh Class B) Severe (Child-Pugh Class C)

No evening dose.12 years and older One morning tablet of tezacaftor One morning tablet of100 mg/ivacaftor 150 mg once tezacaftor 100 mg/ivacaftordaily. 150 mg once daily or lessfrequently.

No evening dose.

Dosing intervals should bemodified according to clinicalresponse and tolerability.

No evening dose.

The safety and efficacy of Symkevi in children aged less than 6 years has not yet been established. Nodata are available (see sections 4.8 and 5.1).

For oral use.

Patients should be instructed to swallow the tablets whole. The tablets should not be chewed, crushed,or broken before swallowing because there are no clinical data currently available to support othermethods of administration.

Both Symkevi and ivacaftor tablets should be taken with fat-containing food, such as foodrecommended in standard nutritional guidelines (see section 5.2).

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

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Symkevi should not be prescribed in patients with CF who are heterozygous for the F508del mutationand have a second CFTR mutation not listed in section 4.1.

Elevated transaminase and hepatic injury

Liver function decompensation, including liver failure leading to transplantation and death has beenreported in CF patients with pre-existing cirrhosis and portal hypertension whilst receiving treatmentwith other CFTR modulator regimens. TEZ/IVA in combination with IVA should be used with cautionin patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If

TEZ/IVA is used in these 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 and have been observed in some patientstreated with Symkevi in combination with ivacaftor, as well as with ivacaftor monotherapy. Therefore,liver function tests are recommended for all patients prior to initiating treatment, every three monthsduring the first year of treatment, and annually thereafter. For patients with a history of transaminaseelevations, more frequent monitoring of liver function tests should be considered. In the event ofsignificant elevations of transaminases (e.g., patients with 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 andlaboratory tests closely followed until the abnormalities resolve. Following resolution of transaminaseelevations, the benefits and risks of resuming treatment should be considered (see section 4.8).

The use of Symkevi is not recommended in patients with severe hepatic impairment unless thebenefits are expected to outweigh the risks (see sections 4.2 and 5.2).

Depression

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

IVA/TEZ, usually occurring within three months of treatment initiation and in patients with a historyof psychiatric disorders. In some cases, symptom improvement was reported after dose reduction ortreatment discontinuation. Patients (and caregivers) should be alerted about the need to monitor fordepressed mood, suicidal thoughts, or unusual changes in behaviour and to seek medical adviceimmediately if these symptoms present.

Caution is recommended in patients with severe renal impairment or end-stage renal disease (seesections 4.2 and 5.2).

Symkevi in combination with ivacaftor has not been studied in patients with CF who have undergoneorgan transplantation. Therefore, use in transplanted patients is not recommended. See section 4.5 forinteractions with ciclosporin or tacrolimus.

Exposure to tezacaftor and ivacaftor may be reduced by the concomitant use of CYP3A inducers,potentially resulting in reduced efficacy of Symkevi and ivacaftor. Therefore, co-administration withstrong CYP3A inducers is not recommended (see section 4.5).

The dose of Symkevi and ivacaftor should be adjusted when used concomitantly with strong ormoderate 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 ivacaftor-containing regimens. Although other risk factors were present in somecases (such as corticosteroid use and exposure to radiation), a possible risk attributable to treatmentcannot be excluded. Baseline and follow-up ophthalmological examinations are recommended inpaediatric patients initiating treatment with Symkevi in combination with ivacaftor (see section 5.3).

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

Medicinal products affecting the pharmacokinetics of tezacaftor and ivacaftor

Tezacaftor and ivacaftor are substrates of CYP3A (ivacaftor is a sensitive substrate of CYP3A).

Concomitant use of CYP3A inducers may result in reduced exposures and thus reduced efficacy of

Symkevi and ivacaftor. Co-administration of ivacaftor with rifampicin, a strong CYP3A inducer,significantly decreased ivacaftor exposure [area under the curve (AUC)] by 89%. Tezacaftorexposures can also be expected to decrease significantly during co-administration with strong CYP3Ainducers; therefore, co-administration with strong CYP3A inducers is not recommended.

Examples of strong CYP3A inducers include rifampicin, rifabutin, phenobarbital, carbamazepine,phenytoin, and St. John’s wort (Hypericum perforatum).

Co-administration with itraconazole, a strong CYP3A inhibitor, increased tezacaftor exposure(measured as AUC) by 4-fold and increased ivacaftor AUC by 15.6-fold. The dose of Symkevi shouldbe adjusted when co-administered with strong CYP3A inhibitors (see Table 2 in section 4.2).

Examples of strong CYP3A inhibitors include ketoconazole, itraconazole, posaconazole, andvoriconazole, telithromycin and clarithromycin.

Physiologically based pharmacokinetic modeling suggested co-administration with fluconazole, amoderate CYP3A inhibitor, may increase tezacaftor exposure (AUC) by approximately 2-fold.

Co-administration of fluconazole increased ivacaftor AUC by 3-fold. The dose of Symkevi andivacaftor should be adjusted when co-administered with moderate CYP3A inhibitors (see Table 2 insection 4.2).

Examples of moderate CYP3A inhibitors include fluconazole, erythromycin and verapamil.

Co-administration with grapefruit juice, which contains one or more components that moderatelyinhibit CYP3A, may increase exposure of ivacaftor and tezacaftor; therefore, food or drink containinggrapefruit should be avoided during treatment (see section 4.2).

Potential for tezacaftor/ivacaftor to interact with transporters

In vitro studies showed that tezacaftor is a substrate for the uptake transporter OATP1B1, and effluxtransporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Tezacaftor is not asubstrate for OATP1B3. Exposure to tezacaftor is not expected to be affected significantly byconcomitant inhibitors of OATP1B1, P-gp, or BCRP due to its high intrinsic permeability and lowlikelihood of being excreted intact. However, exposure to M2-TEZ (tezacaftor metabolite) may beincreased by inhibitors of P-gp. Therefore, caution should be used when P-gp inhibitors are used with

Symkevi.

In vitro studies showed that ivacaftor is not a substrate for OATP1B1, OATP1B3, or P-gp. Ivacaftorand its metabolites are substrates of BCRP in vitro. Due to its high intrinsic permeability and lowlikelihood of being excreted intact, co-administration of BCRP inhibitors is not expected to alterexposure of ivacaftor and M1-IVA, while any potential changes in M6-IVA exposures are notexpected to be clinically relevant.

Co-administration of ciprofloxacin did not affect the exposure of ivacaftor or tezacaftor. No doseadjustment is required when Symkevi is co-administered with ciprofloxacin.

Medicinal products affected by tezacaftor and ivacaftor

Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) isrecommended during co-administration of warfarin with Symkevi given in combination with ivacaftor.

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

CYP3A, digoxin and other P-gp substrates

Co-administration with (oral) midazolam, a sensitive CYP3A substrate, did not affect midazolamexposure. No dose adjustment of CYP3A substrates is required when co-administered with Symkevi incombination with ivacaftor.

Co-administration with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold,consistent with weak inhibition of P-gp by ivacaftor. Administration of Symkevi in combination withivacaftor 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.

Symkevi in combination with ivacaftor has been studied with an estrogen/progesterone oralcontraceptive and was found to have no significant effect on the exposures of the hormonalcontraceptive. Symkevi and ivacaftor are not expected to modify the efficacy of hormonalcontraceptives.

OATP1B1 substrates

Symkevi in combination with ivacaftor has been studied with pitavastatin, an OATP1B1 substrate, andwas found to have no clinically relevant effect on the exposure of pitavastatin (1.24-fold increasedexposure based on AUC). No dose adjustment of OATP1B1 substrates is required whenco-administered with Symkevi.

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 tezacaftoror ivacaftor 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 therapy during pregnancy.

Limited data show that tezacaftor and ivacaftor are excreted into human milk. A risk to thenewborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feedingor to discontinue/abstain from therapy taking into account the benefit of breast-feeding for the childand the benefit of therapy for the woman.

There are no data available on the effect of tezacaftor on fertility in humans. Tezacaftor had no effectson fertility and reproductive performance indices in male and female rats at doses up to100 mg/kg/day.

There are no data available on the effect of ivacaftor on fertility in humans. Ivacaftor had an effect onfertility in rats (see section 5.3).

Symkevi in combination with ivacaftor has minor influence on the ability to drive and use machines.

Dizziness has been reported in patients receiving Symkevi in combination with ivacaftor, as well asivacaftor monotherapy (see section 4.8). Patients experiencing dizziness should be advised not to driveor use machines until symptoms abate.

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

Symkevi in combination with ivacaftor in phase 3 clinical studies were headache (14% versus 11% onplacebo) and nasopharyngitis (12% versus 10% on placebo).

Table 4 reflects adverse reactions observed with Symkevi in combination with ivacaftor and withivacaftor monotherapy in clinical studies. Adverse reactions are listed by MedDRA system organ classand 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 fromthe available data).

Table 4: Adverse reactions

MedDRA System Organ Adverse reactions Frequency

Class

Upper respiratory tract infection,

Infections and infestations Nasopharyngitis* very common

Rhinitis common

Psychiatric disorders Depression not known

Nervous system disorders Headache*, Dizziness* very common

Table 4: Adverse reactions

MedDRA System Organ Adverse reactions Frequency

Class

Ear pain, Ear discomfort,

Tinnitus, Tympanic membrane common

Ear and labyrinth disorders hyperaemia, Vestibular disorder

Ear congestion uncommon

Oropharyngeal pain, Nasal

Respiratory, thoracic and congestion very commonmediastinal disorders Sinus congestion*, Pharyngealerythema common

Abdominal pain, Diarrhoea very common

Gastrointestinal disorders Nausea* common

Hepatobiliary disorders Transaminase elevations very common

Skin and subcutaneous tissuedisorders Rash very common

Breast mass common

Reproductive system and breast Breast inflammation,disorders Gynaecomastia, Nipple disorder, uncommon

Nipple pain

Investigations Bacteria in sputum very common

*Adverse reactions observed during clinical studies with IVA/TEZ in combination with ivacaftor.

The safety data from 1042 adults and 130 children aged 6 to less than 12 years old, treated with

Symkevi in combination with ivacaftor for up to an additional 96 weeks in two long-term safety andefficacy rollover studies (study 661-110 and study 661-116 part A, respectively) were consistent withthe safety data from the placebo-controlled phase 3 studies.

During the adult placebo-controlled phase 3 studies (up to 24 weeks), the incidence of maximumtransaminase (ALT or AST) >8, >5, or >3 x ULN were similar between Symkevi- and placebo-treatedpatients; 0.2%, 1.0%, and 3.4% in Symkevi-treated patients, and 0.4%, 1.0%, and 3.4% inplacebo-treated patients. One patient (0.2%) on therapy and two patients (0.4%) on placebopermanently discontinued treatment for elevated transaminases. No patients treated with Symkeviexperienced a transaminase elevation >3 x ULN associated with elevated total bilirubin >2 x ULN.

The safety of Symkevi in combination with ivacaftor was evaluated in 124 patients between 6 to lessthan 12 years of age. The tezacaftor 100 mg/ivacaftor 150 mg and ivacaftor 150 mg dose has not beeninvestigated in clinical studies in children aged 6 to less than 12 years weighing 30 to < 40 kg.

The safety profile is generally consistent among children and adolescents, and is also consistent withadult patients.

During the 24-week, open-label phase 3 study in patients aged 6 to less than 12 years (study 661-113part B, n=70), the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 x ULN were1.4%, pct. 4.3%, and 10.0%, respectively. No Symkevi-treated patients experienced a transaminaseelevation >3 x ULN associated with elevated total bilirubin >2 x ULN or discontinued Symkevitreatment due to transaminase elevations. One patient interrupted treatment due to elevatedtransaminases, and subsequently resumed Symkevi treatment successfully (see section 4.4 formanagement of elevated transaminases).

The safety profile of Symkevi in combination with ivacaftor, including respiratory events (e.g., chestdiscomfort, dyspnea, and respiration abnormal), was generally similar across all subgroups of patients,including analysis by age, gender, and baseline percent predicted FEV1 (ppFEV1).

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.

There are no known risks due to overdose with Symkevi and there is no specific antidote available inthe event of overdose. Treatment of overdose consists of general supportive measures includingmonitoring of vital signs and observation of the clinical status of the patient.

Pharmacotherapeutic group: Other respiratory system products, ATC code: R07AX31

Tezacaftor is a selective CFTR corrector that binds to the first Membrane Spanning Domain (MSD-1)of CFTR. Tezacaftor facilitates the cellular processing and trafficking of normal or multiple mutantforms of CFTR (including F508del-CFTR) to increase the amount of CFTR protein delivered to thecell surface, resulting in increased chloride transport in vitro.

Ivacaftor is a CFTR potentiator that potentiates the channel-open probability (or gating) of CFTR atthe cell surface to increase chloride transport. For ivacaftor to function CFTR protein must be presentat the cell surface. Ivacaftor can potentiate the CFTR protein delivered to the cell surface bytezacaftor, leading to a further enhancement of chloride transport than either active substance alone.

The combination targets the abnormal CFTR protein by increasing the quantity and function of CFTRat the cell surface and subsequently increasing airway surface liquid height, and ciliary beat frequencyin vitro in human bronchial epithelial (HBE) cells from homozygous F508del CF patients. The exactmechanisms by which tezacaftor improves cellular processing and trafficking of F508del-CFTR andivacaftor potentiates F508del-CFTR are not known.

In study 661-106 (patients homozygous for the F508del mutation), the treatment difference between

Symkevi in combination with ivacaftor and placebo in mean absolute change from baseline in sweatchloride through week 24 was -10.1 mmol/L (95% CI: -11.4, -8.8; nominal P<0.0001*).

In study 661-108 (patients heterozygous for the F508del mutation and a second mutation associatedwith residual CFTR activity), the treatment difference in mean absolute change from baseline in sweatchloride through week 8 was -9.5 mmol/L (95% CI: -11.7, -7.3; nominal P<0.0001*) between

Symkevi in combination with ivacaftor and placebo, and -4.5 mmol/L (95% CI: -6.7, -2.3; nominal

P<0.0001*) between ivacaftor and placebo.

In study 661-115 (patients aged 6 to less than 12 years who were homozygous or heterozygous for the

F508del mutation and a second mutation associated with residual CFTR activity), the within treatmentmean absolute change in sweat chloride from baseline at week 8 was -12.3 mmol/L(95% CI: -15.3, -9.3; nominal P<0.0001). In subgroup analyses the mean absolute changewas -12.9 mmol/L (95% CI: -16.0, -9.9) for patients with F/F and for patients with F/RF the meanabsolute change was -10.9 mmol/L (95% CI: -20.8, -0.9).

*Nominal p-value, based on hierarchical testing procedure.

In study 661-116 part A, patients (aged 6 years and older) rolled over from studies 661-113 part B and661-115. The changes observed in sweat chloride in studies 661-113 part B and 661-115 weremaintained over 96 weeks of treatment with Symkevi in combination with ivacaftor. At week 96, the

LS mean absolute change from parent baseline in sweat chloride for patients from study 661-113 part

B was -16.2 mmol/L (95% CI: -21.9, -10.5), and for patients from study 661-115 was -13.8 mmol/L(95% CI: -17.7, -9.9).

ECG evaluation

Neither tezacaftor nor ivacaftor prolong the QTcF interval in healthy subjects at 3 times thetherapeutic dose.

The efficacy of Symkevi in combination with ivacaftor 150 mg tablet in adult and adolescent patientswith CF was demonstrated in two phase 3, double-blind, controlled studies (study 661-106 andstudy 661-108), and one phase 3, open-label extension study (study 661-110).

Study 661-106 was a 24-week, randomised, double-blind, placebo-controlled study. A total of504 patients aged 12 years and older (mean age 26.3 years) who were homozygous for the F508delmutation in the CFTR gene were randomised (1:1 randomization: 248 Symkevi in combination withivacaftor, 256 placebo). Patients had a percent predicted forced expiratory volume in one second(ppFEV1) at screening between 40 to 90%. The mean ppFEV1 at baseline was 60.0% (range: 27.8% to96.2%).

Study 661-108 was a randomised, double-blind, placebo-controlled, 2-period, 3-treatment, 8-weekcrossover study. A total of 244 patients aged 12 years and older (mean age 34.8 years) who wereheterozygous for the F508del mutation and a second mutation associated with residual CFTR activitywere randomised to and received sequences of treatment that included Symkevi in combination withivacaftor, ivacaftor, and placebo. Patients had a ppFEV1 at screening between 40 to 90%. The meanppFEV1 at baseline was 62.3% (range: 34.6% to 93.5%).

Patients in studies 661-106 and 661-108 continued on their standard-of-care CF therapies during thestudies (e.g., bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline), and wereeligible to rollover into a 96-week open-label extension study (study 661-110). Patients had aconfirmed genotype of a protocol-specified CFTR mutation, and a confirmed diagnosis of CF.

Patients with a history of colonization with organisms associated with a more rapid decline inpulmonary status such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacteriumabscessus, or who had two or more abnormal liver function tests at screening (ALT, AST, AP, GGT≥3 x ULN or total bilirubin ≥2 x ULN) or AST or ALT ≥5 x ULN, were excluded from both studies.

Study 661-106

In study 661-106, treatment with Symkevi in combination with ivacaftor resulted in a statisticallysignificant improvement in ppFEV1 (see Table 5). The treatment difference between Symkevi (incombination with ivacaftor) and placebo for the primary endpoint of mean absolute change (95% CI)in ppFEV1 from baseline through week 24 was 4.0 percentage points (95% CI: 3.1, pct. 4.8; P<0.0001).

Mean improvement in ppFEV1 was observed at the first assessment on day 15 and sustainedthroughout the 24-week treatment period. Improvements in ppFEV1 were observed regardless of age,sex, baseline ppFEV1, colonization with Pseudomonas, concomitant use of standard-of-care therapiesfor CF, and geographic region. See Table 5 for a summary of primary and key secondary outcomes.

Table 5: Primary and key secondary efficacy analyses, full analysis set (study 661-106)

Symkevi in

Analysis Statistic Placebo combination

N=256 with ivacaftor

N=248

PrimaryppFEV1

Baseline value n/N 256/256 247/248

Mean (SD) 60.4 (15.7) 59.6 (14.7)n/N 256/256 245/248

Within-group change -0.6 (-1.3, 0.0) 3.4 (2.7, 4.0)

LS mean (95% CI)

Average absolute change Treatment difference 4.0 (3.1, pct. 4.8)from baseline through LS mean (95% CI)week 24 (percentage P value P<0.0001*points)**

Key secondaryppFEV1

Baseline value n/N 256/256 247/248

Mean (SD) 60.4 (15.7) 59.6 (14.7)n/N 256/256 245/248

Within-group change -0.5 (-1.7, 0.6) 6.3 (5.1, 7.4)

LS mean (95% CI)

Relative change from Treatment difference 6.8 (5.3, 8.3)baseline through week 24 LS mean (95% CI)(%)** P value P<0.0001*

Pulmonary exacerbations Number of subjects with 88/256 62/248events (n)/N

Number of events (estimated 122 (0.99) 78 (0.64)event rate per year†)

Number of pulmonary Rate ratio (RR) (95% CI) 0.65 (0.48, 0.88)exacerbations from P value P=0.0054*baseline through week 24

BMI

Baseline value n/N 256/256 248/248

Mean (SD) 21.12 (2.88) 20.96 (2.95)n/N 245/256 237/248

Within-group change 0.12 (0.03, 0.18 (0.08,

LS mean (95% CI) 0.22) 0.28)

Absolute change from Treatment difference 0.06 (-0.08, 0.19)baseline at week 24 LS mean (95% CI)(kg/m2)** P value P=0.4127#

Table 5: Primary and key secondary efficacy analyses, full analysis set (study 661-106)

Symkevi in

Analysis Statistic Placebo combination

N=256 with ivacaftor

N=248

CFQ-R respiratory domainscore

Baseline value n/N 256/256 248/248

Mean (SD) 69.9 (16.6) 70.1 (16.8)n/N 256/256 246/248

Within-group change -0.1 (-1.6, 1.4) 5.0 (3.5, 6.5)

LS mean (95% CI)

Absolute change from Treatment difference 5.1 (3.2, 7.0)baseline through week 24 LS mean (95% CI)(points)** P value nominal P<0.0001±ppFEV1: percent predicted Forced Expiratory Volume in 1 second; SD: Standard Deviation; LSmean: Least Squares mean; CI: Confidence Interval; BMI: Body Mass Index; CFQ-R: Cystic

Fibrosis Questionnaire-Revised.

**Mixed Effect model for repeated measures with treatment, visit, treatment-by-visit interaction,sex, age group (<18, ≥18 years) at screening, baseline value, and baseline value-by-visitinteraction as fixed effect.

*Indicates statistical significance confirmed in the hierarchical testing procedure.†Estimated event rate per year calculated using 48 weeks per year.#P value not statistically significant.±Nominal p value, based on hierarchical testing procedure.

Symkevi in combination with ivacaftor was associated with a lower event rate per year of severepulmonary exacerbations requiring hospitalization or intravenous antibiotic therapy (0.29) comparedto placebo (0.54). The rate ratio versus placebo was 0.53 (95% CI: 0.34, 0.82; nominal P=0.0042).

Pulmonary exacerbations requiring intravenous antibiotic therapy were lower in the treatment groupcompared to placebo (RR: 0.53 [95% CI: 0.34, 0.82]; nominal P=0.0042). Pulmonary exacerbationsrequiring hospitalizations were similar between treatment groups (RR: 0.78 [95% CI: 0.44, 1.36];

P=0.3801).

BMI increased in both treatment groups (Symkevi in combination with ivacaftor: 0.18 kg/m2, placebo:0.12 kg/m2). The treatment difference of 0.06 kg/m2 for mean change in BMI from baseline toweek 24 (95% CI: -0.08, 0.19) was not statistically significant (P=0.4127).

For CFQ-R respiratory domain score (a measure of respiratory symptoms relevant to patients with CFincluding cough, sputum production, and difficulty breathing) the percentage of subjects with at least a4 point-increase from baseline (minimal clinically important difference) was 51.1% for Symkevi and35.7% for placebo at week 24.

Study 661-108

Of the 244 patients enrolled in study 661-108 the following indicated mutations associated withresidual CFTR activity were represented: P67L, R117C, L206W, R352Q, A455E, D579G,711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G, and 3849+10kbC→T.

In study 661-108, treatment with Symkevi in combination with ivacaftor resulted in a statisticallysignificant improvement in ppFEV1 (see Table 6). The treatment difference between Symkevi incombination with ivacaftor- and placebo-treated patients for the primary endpoint of mean absolutechange in ppFEV1 from study baseline to the average of week 4 and week 8 was 6.8 percentage points(95% CI: 5.7, 7.8; P<0.0001). The treatment difference between ivacaftor alone- and placebo-treatedpatients was 4.7 percentage points (95% CI: 3.7, 5.8; P<0.0001) and 2.1 percentage points (95% CI:1.2, 2.9) between Symkevi in combination with ivacaftor- and ivacaftor alone-treated patients. Meanimprovement in ppFEV1 was observed at the first assessment on day 15 and sustained throughout the8-week treatment period. Improvements in ppFEV1 were observed regardless of age, disease severity,sex, mutation class, colonization with Pseudomonas, concomitant use of standard-of-care therapies for

CF, and geographic region. See Table 6 for a summary of primary and key secondary outcomes.

Table 6: Primary and key secondary efficacy analyses, full analysis set (study 661-108)

Symkevi in

Placebo Ivacaftor combination

Analysis Statistic N=161 N=156 withivacaftor

N=161ppFEV

Baseline value n/N 161/161 156/156 161/161

Mean (SD) 62.2 (14.3) 62.1 (14.6) 62.1 (14.7)n/N 160/161 156/156 159/161

Within-group change -0.3 (-1.2, pct. 4.4 (3.5, 5.3) 6.5 (5.6, 7.3)

LS mean (95% CI) 0.6)

Absolute change Treatment difference NA 4.7 (3.7, 5.8) 6.8 (5.7, 7.8)from baseline to versus placebo LS meanthe average of (95% CI) NA P<0.0001* P<0.0001*week 4 and week 8 P value(percentage Treatment difference NA NA 2.1 (1.2, 2.9)points)** versus IVA LS mean(95% CI)

CFQ-R respiratorydomain score n/N 161/161 156/156 161/161

Baseline value Mean (SD) 68.7 (18.3) 67.9 (16.9) 68.2 (17.5)n/N 160/161 156/156 161/161

Within-group change -1.0 (-2.9, 8.7 (6.8, 10.1 (8.2,

LS mean (95% CI) 1.0) 10.7) 12.1)

Treatment difference NA 9.7 (7.2, 11.1 (8.7,

Absolute change versus placebo LS mean 12.2) 13.6)from baseline to (95% CI) NA P<0.0001* P<0.0001*the average of P valueweek 4 and week 8 Treatment difference NA NA 1.4 (-1.0, 3.9)(points)** versus IVA LS mean(95% CI)ppFEV1: percent predicted Forced Expiratory Volume in 1 second; SD: Standard Deviation; LSmean: Least Squares mean; CI: Confidence Interval; NA: Not Applicable; IVA: ivacaftor;

CFQ-R: Cystic Fibrosis Questionnaire-Revised.

**Linear Mixed Effects model with treatment, period, and study baseline ppFEV1 as fixed effectsand subject as a random effect.

*Indicates statistical significance confirmed in the hierarchical testing procedure.

Subgroup analysis of patients with severe lung dysfunction (ppFEV1 <40)

Study 661-106 and study 661-108 included a total of 39 patients treated with Symkevi in combinationwith ivacaftor with ppFEV1 <40. There were 23 patients with ppFEV1 <40 at baseline receiving

Symkevi and 24 patients receiving placebo in study 661-106. The mean treatment difference between

Symkevi and placebo-treated patients for absolute change in ppFEV1 through week 24 in thissubgroup was 3.5 percentage points (95% CI: 1.0, 6.1). There were 16 patients with ppFEV1 <40 atbaseline receiving Symkevi, 13 receiving ivacaftor and 15 receiving placebo in study 661-108.

The mean treatment difference between Symkevi and placebo-treated patients for absolute change inppFEV1 through the average of week 4 and week 8 was 4.4 percentage points (95% CI: 1.1, 7.8). Themean treatment difference between ivacaftor and placebo-treated patients was 4.4 percentage points(95% CI: 0.9, 7.9).

Study 661-110

Study 661-110 was a phase 3, open-label, multicenter, rollover study to evaluate the safety andefficacy of long-term treatment with Symkevi in combination with ivacaftor in patients aged 12 yearsand older with cystic fibrosis, homozygous or heterozygous for the F508del-CFTR mutation. Study661-110 consisted of 3 parts, part A with a treatment period of approximately 96 weeks, part B with atreatment period of approximately 96 weeks, and part C with a treatment period of approximately 192weeks. Patients enrolled from 8 different parent studies with different background therapies anddifferent treatment periods before entering the study. Efficacy was a secondary objective forstudy 661-110 and the efficacy endpoints were not adjusted for multiplicity.

In part A, patients who received placebo in both study 661-106 and study 661-108 demonstratedimprovements in ppFEV1 when treated with Symkevi in combination with ivacaftor in study 661-110[study 661-106: within-group change=2.1 (95% CI: 0.8, 3.3) percentage points, study 661-108:within-group change=4.1 (95% CI: 2.2, 6.0) percentage points]. Patients who received Symkevi incombination with ivacaftor in the parent studies and continued on treatment, showed a slightattenuation in ppFEV1 in the extension study, however the overall treatment effect was still positive,i.e., an improvement from baseline, through 120 weeks and 104 weeks for study 661-106 and study661-108, respectively. Similar trends were observed for CFQ-R respiratory domain score, pulmonaryexacerbation rate and BMI.

Generally similar results are observed in part B. Part C collected only safety assessments.

Adolescents aged 12 years and older

Adolescents were included together with adults in the studies.

Adolescent patients with CF who were homozygous for the F508del mutation in the CFTR gene (study661-106)

The mean absolute change (SE) from baseline in ppFEV1 was 3.5 (0.6) percentage points in the

Symkevi in combination with ivacaftor group and -0.4 (0.6) percentage points in the placebo group instudy 661-106. Patients who received Symkevi in combination with ivacaftor in study 661-106 andcontinued on treatment showed sustained improvements in ppFEV1 through 96 weeks in study661-110 [within-group change=1.5 (1.6) percentage points]. Patients who were previously treated withplacebo and received Symkevi in combination with ivacaftor in study 661-110 showed an increase of0.9 (1.7) percentage points.

The mean absolute change (SE) from baseline in BMI z-value was -0.01 (0.05) kg/m2 in the Symkeviin combination with ivacaftor group and 0.00 (0.05) kg/m2 in the placebo group in study 661-106. Instudy 661-110, the change in BMI z-value in the Symkevi in combination with ivacaftor group wasmaintained and patients previously treated with placebo showed an increase of 0.12 (0.07) kg/m2.

Adolescent patients with CF who were heterozygous for the F508del mutation and a second mutationassociated with residual CFTR activity (study 661-108)

The mean absolute change (SE) from baseline in ppFEV1 was 11.7 (1.2) percentage points in the

Symkevi in combination with ivacaftor group, 7.6 (1.2) percentage points in the ivacaftor groupand -0.4 (1.2) percentage points in the placebo group in study 661-108. Patients who received

Symkevi in combination with ivacaftor in study 661-108 and continued on treatment showed sustainedimprovements in ppFEV1 through 96 weeks in study 661-110 [within-group change=16.9 (4.0)percentage points]. Patients who were previously treated with ivacaftor or placebo and received

Symkevi in combination with ivacaftor in study 661-110 showed an increase of 4.1 (4.5) percentagepoints and 6.0 (3.5) percentage points, respectively.

The mean absolute change (SE) from baseline in BMI z-value was 0.24 (0.07) kg/m2 in the Symkevi incombination with ivacaftor group, 0.20 (0.07) kg/m2 in the ivacaftor group and 0.04 (0.07) kg/m2 in theplacebo group in study 661-108. In study 661-110, the change in BMI z-value were maintained in the

Symkevi in combination with ivacaftor group 0.29 (0.22) kg/m2, in the ivacaftor group 0.23(0.27) kg/m2, and in the placebo group 0.23 (0.19) kg/m2.

Paediatric patients aged 6 to <12 years

Study 661-115

Study 661-115 was an 8-week, double-blind, phase 3 trial in 67 patients aged 6 to less than 12 years(mean age 8.6 years) who were randomised 4:1 to either Symkevi or a blinding group. The Symkevigroup included patients who were homozygous for the F508del mutation (F/F) (n=42) or heterozygousfor the F508del mutation and a second mutation associated with residual CFTR activity (F/RF)(n=12). Blinding groups were placebo if homozygous F/F (n=10), or ivacaftor if heterozygous F/RF(n=3). Fifty-four patients received either tezacaftor 50 mg/ivacaftor 75 mg and ivacaftor 75 mg(patients weighing < 40 kg at baseline) or tezacaftor 100 mg/ivacaftor 150 mg and ivacaftor 150 mg(patients weighing ≥ 40 kg at baseline), 12 hours apart. Patients receiving tezacaftor/ivacaftor had ascreening ppFEV1 ≥ 70% [mean baseline ppFEV1 of 86.5% (range: 57.9, 124.1%)], baseline LCI2.5 of9.56 (range: 6.95, 15.52), and weight ≥ 15 kg. Patients with abnormal hepatic or renal function wereexcluded from the study. Abnormal hepatic impairment was defined as any two or more of ≥ 3 x ULN

AST, ALT, GGT, ALP; ≥ 2 x ULN total bilirubin; or ≥ 5 x ULN ALT or AST. Abnormal renalfunction was defined as GFR ≤ 45 mL/min/1.73 m2 calculated by the Counahan-Barratt equation.

In study 661-115, treatment with Symkevi in combination with ivacaftor resulted in a statisticallysignificant within-group reduction from baseline in LCI2.5 through week 8. Reduction in LCI2.5 wasobserved at week 2 and was sustained through week 8. See Table 7 for a summary of primary and keysecondary endpoints. Growth parameters, which were exploratory endpoints, remained stable over 8weeks of Symkevi treatment.

Table 7: Effect of Symkevi on efficacy parameters (study 661-115)

Parameter Baseline Absolute change throughmean (SD) week 8*

N=54 mean (95% CI)

N=54

Primary endpoint

LCI2.5 9.56 (2.06) -0.51 (-0.74, -0.29)

P<0.0001

Secondary and other key endpoints

CFQ-R respiratory domain scores (points) 84.6 (11.4) 2.3 (-0.1, pct. 4.6)ppFEV1 86.5 (12.9) 2.8 (1.0, pct. 4.6)

SD: Standard Deviation; CI: Confidence Interval; CFQ-R: Cystic Fibrosis Questionnaire-Revised;

FEV1: Forced Expiratory Volume in 1 second

*within-group change

In subgroup analyses of F/F and F/RF patients, the within-group mean absolute change in LCI2.5was -0.39 (95% CI: -0.67, -0.10) and -0.92 (95% CI: -1.65, -0.20), respectively. The within-groupmean change in CFQ-R respiratory domain scores in F/F and F/RF patients was 1.4 points(95% CI: -1.9, 4.7) and 5.6 points (95% CI: -2.8, 13.9), respectively.

The tezacaftor 100 mg/ivacaftor 150 mg and ivacaftor 150 mg dose has not been investigated inclinical studies in children aged 6 to less than 12 years weighing 30 to < 40 kg.

Study 661-116 part A

Study 661-116 part A was a phase 3, open-label, multicentre, rollover, 96-week study to evaluate thesafety and efficacy of long-term treatment with Symkevi in combination with ivacaftor in patientsaged 6 years and older. Patients in study 661-116 part A rolled over from studies 661-113 part B(n=64) and 661-115 (n=66). Study 661-113 was a phase 3, open-label study to evaluate the safety andefficacy of Symkevi in combination with ivacaftor in patients 6 to less than 12 years of age. The LSmean estimates for 661-115 rollovers were calculated on patients who were randomized to thetezacaftor/ivacaftor arm in the parent study (n=53). Efficacy was a secondary objective for studypart A.

The changes observed during the parent studies were maintained over 96 weeks of treatment with

Symkevi in combination with ivacaftor:

At week 96, the LS mean absolute change from parent baseline in LCI2.5 for patients from study661-115 was -0.95 (95% CI: -1.38, -0.52).

The LS mean absolute change from parent baseline in CFQ-R respiratory domain for patients fromstudy 661-113 part B was 6.0 points (95% CI: 1.1, 10.8), and for patients from study 661-115 was6.4 points (95% CI: 3.5, 9.3).

The LS mean absolute change from parent baseline in BMI z-score for patients from study 661-113part B was -0.07 (SD: 0.61), and for patients from study 661-115 was 0.05 (SD: 0.52).

Children aged less than 6 years

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

Symkevi in combination with ivacaftor in one or more subsets of the paediatric population in cysticfibrosis. See section 4.2 for information on paediatric use.

The pharmacokinetics of tezacaftor and ivacaftor are similar between healthy adult volunteers andpatients with CF. Following once daily dosing of tezacaftor and twice-daily dosing of ivacaftor inpatients with CF, plasma concentrations of tezacaftor and ivacaftor reach steady-state within 8 daysand within 3 to 5 days, respectively, after starting treatment. At steady-state, the accumulation ratio isapproximately 2.3 for tezacaftor and 3.0 for ivacaftor. Exposures of tezacaftor (administered alone orin combination with ivacaftor) increase in an approximately dose-proportional manner with increasingdoses from 10 mg to 300 mg once daily. Key pharmacokinetic parameters for tezacaftor and ivacaftorat steady-state are shown in Table 8.

Table 8: Mean (SD) pharmacokinetic parameters of tezacaftor and ivacaftor at steady-state inpatients with CF

Active Cmax AUC0-24h or AUC0-12hsubstance (mcg/mL) t½ (h) (mcg∙h/mL)*

Tezacaftor 100 mg once Tezacaftor 6.52 (1.83) 156 (52.7) 82.7 (23.3)daily/ivacaftor 150 mg every12 hours Ivacaftor 1.28 (0.440) 9.3 (1.7) 10.9 (3.89)

*AUC0-24h for tezacaftor and AUC0-12h for ivacaftor

After a single dose in healthy subjects in the fed state, tezacaftor was absorbed with a median (range)time to maximum concentration (tmax) of approximately 4 hours (2 to 6 hours). The median (range) tmaxof ivacaftor was approximately 6 hours (3 to 10 hours) in the fed state. The AUC of tezacaftor did notchange when given with fat-containing food relative to fasted conditions. The AUC of ivacaftor whengiven in combination with tezacaftor increased approximately 3-fold when given with fat-containingfood; therefore, Symkevi and ivacaftor should be administered with fat-containing food.

Tezacaftor is approximately 99% bound to plasma proteins, primarily to albumin. Ivacaftor isapproximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin.

After oral administration of tezacaftor 100 mg once daily in combination with ivacaftor 150 mg every12 hours in patients with CF in the fed state, the mean (±SD) for apparent volume of distribution oftezacaftor and ivacaftor was 271 (157) L and 206 (82.9) L, respectively. Neither tezacaftor norivacaftor partition preferentially into human red blood cells.

Tezacaftor is metabolized extensively in humans. In vitro data suggested that tezacaftor is metabolizedmainly by CYP3A4 and CYP3A5. Following oral administration of a single dose of 100 mg14C-tezacaftor to healthy male subjects, M1-TEZ, M2-TEZ, and M5-TEZ were the three majorcirculating metabolites of tezacaftor in humans, contributing to 15%, 31%, and 33% of totalradioactivity, respectively. Under steady-state, for each of the metabolites, exposure to M1-TEZ,

M2-TEZ and M5-TEZ is approximately 1.5-fold higher than for tezacaftor. M1-TEZ has similarpotency to that of tezacaftor and is considered pharmacologically active. M2-TEZ is much lesspharmacologically active than tezacaftor or M1-TEZ, and M5-TEZ is not consideredpharmacologically active. Another minor circulating metabolite, M3-TEZ, is formed by directglucuronidation of tezacaftor.

Ivacaftor is also metabolized extensively in humans. In vitro and in vivo data indicate that ivacaftor ismetabolized primarily by CYP3A4 and CYP3A5. M1-IVA and M6-IVA are the two major metabolitesof ivacaftor in humans. M1-IVA has approximately one-sixth the potency of ivacaftor and isconsidered pharmacologically active. M6-IVA is not considered pharmacologically active.

The effect of the CYP3A4*22 heterozygous genotype on tezacaftor and ivacaftor exposure isconsistent with the effect of co-administration of a weak CYP3A4 inhibitor, which is not clinicallyrelevant. No dose-adjustment of tezacaftor and ivacaftor is considered necessary. No data are availablefor CYP3A4*22 homozygous genotype patients.

After oral administration of tezacaftor 100 mg once daily in combination with ivacaftor 150 mg every12 hours in patients with CF in the fed state, the mean (±SD) for apparent clearance values oftezacaftor and ivacaftor were 1.31 (0.41) and 15.7 (6.38) L/h, respectively. After steady-state dosing oftezacaftor in combination with ivacaftor in CF patients, the mean (SD) terminal half-lives of tezacaftorand ivacaftor were approximately 156 (52.7) and 9.3 (1.7) hours, respectively. The mean (SD)elimination half-lives for M1-TEZ, M2-TEZ and M5-TEZ were similar to that of the parentcompound. The mean (SD) elimination half-lives for M1-IVA and M6-IVA were 11.3 (2.12) h and14.4 (6.14) h, respectively.

Following oral administration of 14C-tezacaftor, the majority of the dose (72%) was excreted in thefaeces (unchanged or as the M2-TEZ metabolite) and about 14% was recovered in urine (mostly as

M2-TEZ metabolite), resulting in a mean overall recovery of 86% up to 21 days after the dose. Lessthan 1% of the administered dose was excreted in urine as unchanged tezacaftor, showing that renalexcretion is not the major pathway of tezacaftor elimination in humans.

Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in thefaeces after metabolic conversion. There was negligible urinary excretion of ivacaftor as unchangedmedicine.

Following multiple doses of tezacaftor and ivacaftor for 10 days, subjects with moderately impairedhepatic function (Child-Pugh Class B, score 7 to 9) had an approximately 36% increase in AUC and a10% increase in Cmax for tezacaftor, and a 50% increase in ivacaftor AUC compared with healthysubjects matched for demographics. Based on these results, a modified regimen of Symkevi isrecommended for patients with moderate hepatic impairment (see Table 3 in section 4.2).

The impact of severe hepatic impairment (Child-Pugh Class C, score 10 to 15) on thepharmacokinetics of tezacaftor and ivacaftor has not been studied. The magnitude of increase inexposure in these patients is unknown but is expected to be higher than that observed in patients withmoderate hepatic impairment. The use of Symkevi in patients with severe hepatic impairment istherefore not recommended unless the benefits outweigh the risks (see Table 3 in section 4.2).

No dose adjustment is considered necessary for patients with mild hepatic impairment.

Tezacaftor alone or in combination with ivacaftor has not been studied in patients with moderate orsevere renal impairment (creatinine clearance ≤ 30 mL/min) or in patients with end-stage renaldisease. In a human pharmacokinetic study with tezacaftor alone, there was minimal elimination oftezacaftor and its metabolites in urine (only 13.7% of total radioactivity was recovered in the urinewith 0.79% as unchanged medicinal product).

In a human pharmacokinetic study with ivacaftor alone, there was minimal elimination of ivacaftorand its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine).

In population pharmacokinetic analysis, data from 665 patients on tezacaftor or tezacaftor incombination with ivacaftor in phase 2/3 clinical studies indicated that mild renal impairment [N=147;estimated glomerular filtration rate (eGFR), estimated by the modification of diet in renal diseasemethod, 60 to ≤ 89 mL/min/1.73 m2] and moderate renal impairment (N=7; eGFR 30 to< 60 mL/min/1.73 m2) did not affect the clearance of tezacaftor significantly. No dose adjustment isrecommended for mild and moderate renal impairment. Caution is recommended when administering

Symkevi in combination with ivacaftor to patients with severe renal impairment or end-stage renaldisease.

The pharmacokinetic parameters of tezacaftor and ivacaftor are similar in males and females.

Very limited pharmacokinetic data indicate comparable exposure to tezacaftor in white (n=652) andnon-white (n=8) patients. Race had no clinically meaningful effect on the PK of ivacaftor in white(n=379) and non-white (n=29) patients based on a population PK analysis.

Clinical studies of Symkevi in combination with ivacaftor did not include patients over 75 years ofage. The pharmacokinetic parameters of tezacaftor in combination with ivacaftor in the elderlypatients (aged 65 to 72 years) are comparable to those in younger adults.

The pharmacokinetic parameters of tezacaftor and ivacaftor are presented in Table 9. Thepharmacokinetics of tezacaftor/ivacaftor in children below 6 years of age has not been investigated.

Table 9: Mean (SD) tezacaftor and ivacaftor exposure by age group

Age group Dose Tezacaftor Ivacaftor M1-TEZmean (SD) mean (SD) mean (SD)

AUC0-24h (mcg∙h/mL) AUC0-12h (mcg∙h/mL) AUC0-24h (mcg∙h/mL)6 to < 12 TEZ 50 mg qd/ 58.9 (17.5) 7.1 (1.95) 126 (30.0)years, IVA 75 mg q12h< 30 kg6 to < 12 TEZ 100 mg qd/ 107 (30.1) 11.8 (3.89) 193 (45.8)years, IVA 150 mg q12h≥ 30 kg*

Adolescents TEZ 100 mg qd/ 97.1 (35.8) 11.4 (5.5) 146 (35.7)

IVA 150 mg q12h

Adults TEZ 100 mg qd/ 85.9 (28.0) 11.4 (4.14) 126 (34.9)

IVA 150 mg q12h

*Exposures in ≥ 30 kg to < 40 kg weight range are predictions derived from the population PK model.

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 tezacaftor 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-gp. Lower brain levels of P-gpactivity in younger rats resulted in higher brain levels of tezacaftor and M1-TEZ. These findings arenot relevant for the indicated paediatric population 6 to 11 years of age, for whom levels of P-gpactivity 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.

Ivacaftor was associated with slight decreases of the seminal vesicle weights, a decrease of overallfertility index and number of pregnancies in females mated with treated males and significantreductions in number of corpora lutea and implantation sites with subsequent reductions in the averagelitter size and average number of viable embryos per litter in treated females. The No Observed

Adverse Effect Level (NOAEL) for fertility findings provides an exposure level of approximately5 times the systemic exposure of ivacaftor and its metabolites when administered astezacaftor/ivacaftor in adult humans at the maximum recommended human dose (MRHD).

In the pre- and post-natal study ivacaftor decreased survival and lactation indices and caused areduction in pup body weights. The NOAEL for viability and growth in the offspring provides anexposure level of approximately 4 times the systemic exposure of ivacaftor and its metabolites whenadministered as tezacaftor/ivacaftor in adult humans at the MRHD. Placental transfer of ivacaftor wasobserved in pregnant rats and rabbits.

Findings of cataracts were observed in juvenile rats dosed from postnatal day 7 to 35 at ivacaftorexposure levels of 0.25 times the MRHD based on systemic exposure of ivacaftor and its metaboliteswhen administered as tezacaftor/ivacaftor. This finding has not been observed in fetuses derived fromrat dams treated with ivacaftor on gestation days 7 to 17, in rat pups exposed to ivacaftor through milkingestion up to postnatal day 20, in 7-week-old rats, nor in 3.5- to 5-month-old dogs treated withivacaftor. The potential relevance of these findings in humans is unknown.

Tezacaftor/ivacaftor

Combination repeat-dose toxicity studies in rats and dogs involving the co-administration of tezacaftorand ivacaftor to assess the potential for additive and/or synergistic toxicity did not produce anyunexpected toxicities or interactions.

Hypromellose acetate succinate

Sodium laurilsulfate (E487)

Hypromellose 2910 (E464)

Microcrystalline cellulose (E460(i))

Croscarmellose sodium (E468)

Magnesium stearate (E470b)

Tablet film coat (Symkevi 50 mg/75 mg film-coated tablets)

Hypromellose 2910 (E464)

Hydroxypropyl cellulose (E463)

Titanium dioxide (E171)

Talc (E553b)

Tablet film coat (Symkevi 100 mg/150 mg film-coated tablets)

Hypromellose 2910 (E464)

Hydroxypropyl cellulose (E463)

Titanium dioxide (E171)

Talc (E553b)

Iron oxide yellow (E172)

Not applicable.

Symkevi 100 mg/150 mg film-coated tablets4 years

Symkevi 50 mg/75 mg film-coated tablets3 years

This medicinal product does not require any special storage conditions.

Blister consisting of PCTFE (polychlorotrifluoroethylene)/PVC (polyvinyl chloride) with apaper-backed aluminum foil lidding.

Pack size of 28 tablets (4 blister cards of 7 tablets each).

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/1/18/1306/001

EU/1/18/1306/002

Date of first authorisation: 31 October 2018

Date of latest renewal: 23 August 2023

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

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