Symkevi

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
 

 
 

 



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 This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Symkevi 100 mg/150 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 100 mg of tezacaftor and 150 mg of ivacaftor. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet) 
 
Yellow, capsule-shaped tablet debossed with “V100” on one side and plain on the other (dimensions 
15.9 mm x 8.5 mm). 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Symkevi is indicated in a combination regimen with ivacaftor 150 mg tablets for the treatment of 
patients with cystic fibrosis (CF) aged 12 years and older who are homozygous for the F508del 
mutation or who are heterozygous for the F508del mutation and have one of the following mutations 
in the cystic fibrosis transmembrane 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. 
 
4.2 Posology and method of administration 
 
Symkevi should only be prescribed by physicians 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 an indicated mutation using a genotyping assay. 
 
Posology 
 
Adults and adolescents aged 12 years and older In a combination regimen with ivacaftor 150 mg 
tablets 
 
The recommended dose is one Symkevi (tezacaftor 100 mg/ivacaftor 150 mg) tablet taken in the 
morning and one ivacaftor 150 mg tablet taken in the evening, 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. 
 



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If more than 6 hours have passed since the missed morning or evening dose, the patient should not 
take 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. 
 
Concomitant use of CYP3A inhibitors 
The dose of Symkevi and ivacaftor should be adjusted when co-administered with moderate and 
strong CYP3A inhibitors. 
 
When co-administered with moderate CYP3A inhibitors (e.g., fluconazole, erythromycin), the dose 
should be adjusted according to Table 1 (see sections 4.4 and 4.5). 
 

Table 1: Dosing recommendations for concomitant use with moderate CYP3A inhibitors 
 Day 1 Day 2 Day 3 Day 4* 

Morning Dose 
Tezacaftor 100 mg/ivacaftor 150 mg tablet  -  - 

Ivacaftor 150 mg tablet -  -  
Evening Dose 

Ivacaftor 150 mg tablet - - - - 
*Continue dosing with tezacaftor 100 mg/ivacaftor 150 mg or ivacaftor 150 mg tablets on alternate 
days. 

 
When co-administered with strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, 
voriconazole, telithromycin, and clarithromycin), the dose should be adjusted to one Symkevi tablet 
twice a week, taken approximately 3 to 4 days apart. The evening dose of ivacaftor should not be 
taken (see sections 4.4 and 4.5). 
 
Special populations 
 
Elderly people 
The safety, efficacy and pharmacokinetics of Symkevi in combination with ivacaftor have been 
examined in a limited number of elderly patients. No dose adjustment specific to this patient 
population is required (see section 5.2). 
 
Renal impairment 
No dose adjustment is recommended for patients with mild or moderate renal impairment. Caution is 
recommended in patients with severe renal impairment or end-stage renal disease (see sections 4.4 
and 5.2). 
 
Hepatic impairment 
For dose adjustment for patients with hepatic impairment, see Table 2. There is no experience of the 
use of Symkevi in patients with severe hepatic impairment (Child-Pugh Class C); therefore, its use is 
not recommended unless the benefits outweigh the risks. In such cases, Symkevi should be used at a 
reduced dose (see sections 4.4 and 5.2). 
 

Table 2: Dosing recommendations for patients with hepatic impairment 
 Mild (Child-Pugh 

Class A) 
Moderate (Child-Pugh 

Class B) 
Severe (Child-Pugh 

Class C) 

Morning 

No dose adjustment  One tablet of tezacaftor 
100 mg/ivacaftor 150 mg once 
daily 

Starting dose: One tablet of 
tezacaftor 100 mg/ivacaftor 
150 mg once daily. Dosing 
intervals should be modified 
according to clinical response 
and tolerability. 

Evening  No dose adjustment No ivacaftor 150 mg dose No ivacaftor 150 mg dose 
 



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Paediatric population 
 
The safety and efficacy of Symkevi in children aged less than 12 years has not yet been established. 
No data are available (see section 5.1). 
 
Method of administration 
 
For oral use. Patients should be instructed to swallow the tablets whole. The tablets should not be 
chewed, crushed, or broken before swallowing.  
 
Both Symkevi and ivacaftor tablets should be taken with fat-containing food, such as food 
recommended in standard nutritional guidelines (see section 5.2). 
 
Food or drink containing grapefruit or Seville oranges should be avoided during treatment (see 
section 4.5). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Symkevi in combination with ivacaftor should not be prescribed in patients with CF who are 
heterozygous for the F508del mutation and have a second CFTR mutation not listed in section 4.1. 
 
Effect on liver function tests 
 
Elevated transaminases are common in patients with CF, and have been observed in some patients 
treated with Symkevi in combination with ivacaftor, as well as with ivacaftor monotherapy. 
Assessments of transaminases (ALT or AST) 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 transaminase elevations, more frequent monitoring should be considered. In the event of 
significant 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 and 
laboratory tests closely followed until the abnormalities resolve. Following resolution of transaminase 
elevations, the benefits and risks of resuming treatment should be considered (see section 4.8). 
 
Hepatic impairment 
 
The use of Symkevi is not recommended in patients with severe hepatic impairment unless the 
benefits are expected to outweigh the risks (see sections 4.2 and 5.2). 
 
Renal impairment 
 
Caution is recommended while using Symkevi in combination with ivacaftor in patients with severe 
renal impairment or end-stage renal disease (see sections 4.2 and 5.2). 
 
Patients after organ transplantation 
 
Symkevi in combination with ivacaftor 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 ciclosporin or tacrolimus. 
 



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Interactions with medicinal products 
 
CYP3A inducers 
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 with 
strong CYP3A inducers is not recommended (see section 4.5). 
 
CYP3A inhibitors 
The dose of Symkevi and ivacaftor should be adjusted when used concomitantly with strong or 
moderate CYP3A inhibitors (see section 4.5 and Table 1 in section 4.2). 
 
Cataracts 
 
Cases of non-congenital lens opacities without impact on vision have been reported in paediatric 
patients treated with Symkevi in combination with ivacaftor, as well as with ivacaftor monotherapy. 
Although other risk factors were present in some cases (such as corticosteroid use and exposure to 
radiation), a possible risk attributable to treatment cannot be excluded. Baseline and follow-up 
ophthalmological examinations are recommended in paediatric patients initiating treatment with 
Symkevi in combination with ivacaftor (see section 5.3). 
 
Sodium content 
 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 
‘sodium-free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Medicinal products affecting the pharmacokinetics of tezacaftor and ivacaftor 
 
CYP3A inducers 
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%. Tezacaftor 
exposures can also be expected to decrease significantly during co-administration with strong CYP3A 
inducers; 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) 

 
CYP3A inhibitors 
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 should 
be adjusted when co-administered with strong CYP3A inhibitors (see Table 1 in section 4.2). 
 
Examples of strong CYP3A inhibitors include: 

• ketoconazole, itraconazole, posaconazole, and voriconazole 
• telithromycin and clarithromycin 

 
Physiologically based pharmacokinetic modeling suggested co-administration with fluconazole, a 
moderate 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 and 
ivacaftor should be adjusted when co-administered with moderate CYP3A inhibitors (see Table 1 in 
section 4.2). 
 



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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 ivacaftor and tezacaftor; therefore, food or drink containing 
grapefruit or Seville oranges 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 efflux 
transporters P-gp and Breast Cancer Resistance Protein (BCRP). Tezacaftor is not a substrate for 
OATP1B3. Exposure to tezacaftor 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 (tezacaftor metabolite) may be increased 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. Ivacaftor 
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 ivacaftor and M1-IVA, while any potential changes in M6-IVA exposures are not 
expected to be clinically relevant. 
 
 
Ciprofloxacin 
Co-administration of ciprofloxacin did not affect the exposure of ivacaftor or tezacaftor. No dose 
adjustment is required when Symkevi is co-administered with ciprofloxacin. 
 
Medicinal products affected by tezacaftor and ivacaftor 
 
CYP2C9 substrates 
Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) is 
recommended 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 
CYP3A substrates 
Co-administration with (oral) midazolam, a sensitive CYP3A substrate, did not affect midazolam 
exposure. No dose adjustment of CYP3A substrates is required when co-administered with Symkevi in 
combination with ivacaftor. 
 
Digoxin and other P-gp substrates 
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 with 
ivacaftor 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. 
 
Hormonal contraceptives 
Symkevi in combination with ivacaftor has been studied with an estrogen/progesterone oral 
contraceptive and was found to have no significant effect on the exposures of the hormonal 
contraceptive. Symkevi and ivacaftor are not expected to modify the efficacy of hormonal 
contraceptives. 
OATP1B1 substrates 



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Symkevi in combination with ivacaftor has been studied with pitavastatin, an OATP1B1 substrate, and 
was found to have no clinically relevant effect on the exposure of pitavastatin (1.24-fold increased 
exposure based on AUC).  No dose adjustment of OATP1B1 substrates is required when co-
administered with Symkevi.  
 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of tezacaftor 
or ivacaftor 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 therapy during pregnancy. 
 
Breast-feeding  
 
It is unknown whether tezacaftor, ivacaftor, or their metabolites are excreted in human milk. Available 
pharmacokinetic/toxicological data in animals have shown excretion of tezacaftor and ivacaftor 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 therapy 
taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. 
 
Fertility 
 
Tezacaftor 
There are no data available on the effect of tezacaftor on fertility in humans. Tezacaftor had no effects 
on fertility and reproductive performance indices in male and female rats at doses up to 
100 mg/kg/day. 
 
Ivacaftor 
There are no data available on the effect of ivacaftor on fertility in humans. Ivacaftor had an effect on 
fertility in rats (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Symkevi in combination with ivacaftor has a minor influence on the ability to drive and use machines. 
Dizziness has been reported in patients receiving Symkevi in combination with ivacaftor, as well as 
ivacaftor monotherapy (see section 4.8). Patients experiencing dizziness should be advised not to drive 
or use machines until symptoms abate. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The most common adverse reactions experienced by patients aged 12 years and older who received 
Symkevi in combination with ivacaftor in the pooled, placebo-controlled, Phase 3 studies were 
headache (14% versus 11% on placebo) and nasopharyngitis (12% versus 10% on placebo). 
 
Tabulated list of adverse reactions 
 



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Table 3 reflects adverse reaction observed with Symkevi in combination with ivacaftor in patients 
aged 12 years and older based on pooled data from three double-blind, placebo-controlled Phase 3 
clinical studies. Table 4 reflects adverse reactions observed in clinical studies in patients treated with 
ivacaftor 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). 
 

Table 3: Adverse reactions in patients treated with Symkevi in combination with ivacaftor 
MedDRA System Organ 

Class  
Adverse Reaction Frequency 

Infections and infestations Nasopharyngitis very common 

Nervous system disorder Headache very common Dizziness common 
Respiratory, thoracic and 
mediastinal disorders 

Sinus congestion common 

Gastrointestinal disorders  Nausea common 
 
 

Table 4: Adverse reactions in patients treated with ivacaftor monotherapy 
MedDRA System Organ 

Class 
Adverse Reactions Frequency 

Infections and infestations 
Upper respiratory tract infection, 
Nasopharyngitis  very common 

Rhinitis common 
Nervous system disorders Headache, Dizziness very common 

Ear and labyrinth disorders 

Ear pain, Ear discomfort, 
Tinnitus, Tympanic membrane 
hyperaemia, Vestibular disorder 

common 

Ear congestion  uncommon 

Respiratory, thoracic and 
mediastinal disorders 

Oropharyngeal pain, Nasal 
congestion very common 

Sinus congestion, Pharyngeal 
erythema common 

Gastrointestinal disorders Abdominal pain, Diarrhoea very common 
Hepatobiliary disorders Transaminase elevations very common 
Skin and subcutaneous tissue 
disorders Rash very common 

Reproductive system and breast 
disorders 

Breast mass  common 
Breast inflammation, 
Gynaecomastia, Nipple disorder, 
Nipple pain 

uncommon 

Investigations Bacteria in sputum  very common 
 
The safety data from 1042 patients 12 years and older treated with Symkevi in combination with 
ivacaftor for up to an additional 96 weeks in a long-term safety and efficacy rollover study (study 3)  
were consistent with the safety data from the placebo-controlled Phase 3 studies. 
 
Description of selected adverse reactions 
 
Laboratory abnormalities 
Transaminase elevations 
During the placebo-controlled Phase 3 studies (up to 24 weeks), the incidence of maximum 
transaminase (ALT or AST) >8, >5, or >3 x ULN were similar between Symkevi in combination with 



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ivacaftor- and placebo-treated patients; 0.2%, 1.0%, and 3.4% in Symkevi in combination with 
ivacaftor-treated patients, and 0.4%, 1.0%, and 3.4% in placebo-treated patients. One patient (0.2%) 
on therapy and two patients (0.4%) on placebo permanently discontinued treatment for elevated 
transaminases. No patients treated with Symkevi in combination with ivacaftor experienced a 
transaminase elevation >3 x ULN associated with elevated total bilirubin >2 x ULN. 
 
Paediatric population 
 
The safety profile is generally consistent among adolescents and adult patients. 
 
Other special populations 
 
The safety profile of Symkevi in combination with ivacaftor, including respiratory events (e.g., chest 
discomfort, dyspnea, and respiration abnormal), was generally similar across all subgroups of patients, 
including analysis by age, gender, and baseline percent predicted FEV1 (ppFEV1). 
 
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 the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There are no known risks due to overdose with Symkevi and there is no specific antidote available in 
the event of overdose. Treatment of overdose consists of general supportive measures including 
monitoring of vital signs and observation of the clinical status of the patient. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other respiratory system products; ATC code: R07AX31 
 
Mechanism of action 
 
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 mutant 
forms of CFTR (including F508del-CFTR) to increase the amount of CFTR protein delivered to the 
cell surface, resulting in increased chloride transport in vitro.  
 
Ivacaftor is a CFTR potentiator that potentiates the channel-open probability (or gating) of CFTR at 
the cell surface to increase chloride transport. For ivacaftor to function CFTR protein must be present 
at the cell surface. Ivacaftor can potentiate the CFTR protein delivered to the cell surface by 
tezacaftor, 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 CFTR 
at the cell surface and subsequently increasing airway surface liquid height, and ciliary beat frequency 
in vitro in human bronchial epithelial (HBE) cells from homozygous F508del CF patients. The exact 
mechanisms by which tezacaftor improves cellular processing and trafficking of F508del-CFTR and 
ivacaftor potentiates F508del-CFTR are not known.  
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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Pharmacodynamic effects 
 
Effects on sweat chloride 
In study 1 (patients homozygous for the F508del mutation), the treatment difference between Symkevi 
in combination with ivacaftor and placebo in mean absolute change from baseline in sweat chloride 
through week 24, was -10.1 mmol/L (95% CI: -11.4, -8.8; nominal P<0.0001*). 
 
In study 2 (patients heterozygous for the F508del mutation and a second mutation associated with 
residual CFTR activity), the treatment difference in mean absolute change from baseline in sweat 
chloride 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. 
*Nominal p-value, based on hierarchical testing procedure. 
 
ECG evaluation 
Neither tezacaftor nor ivacaftor prolong the QTcF interval in healthy subjects at 3 times the 
therapeutic dose. 
 
Clinical efficacy and safety 
 
The efficacy of Symkevi in combination with ivacaftor 150 mg tablet in patients with CF was 
demonstrated in two Phase 3, double-blind, controlled studies (study 1 and study 2), and one Phase 3, 
open-label extension study (study 3). 
 
Study 1 was a 24-week, randomized, double-blind, placebo-controlled study. A total of 504 patients 
aged 12 years and older (mean age 26.3 years) who were homozygous for the F508del mutation in the 
CFTR gene were randomized (1:1 randomization: 248 Symkevi in combination with ivacaftor, 
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% to 96.2%).  
 
Study 2 was a randomized, double-blind, placebo-controlled, 2-period, 3-treatment, 8-week crossover 
study. A total of 244 patients aged 12 years and older (mean age 34.8 years) who were heterozygous 
for the F508del mutation and a second mutation associated with residual CFTR activity were 
randomized to and received sequences of treatment that included Symkevi in combination with 
ivacaftor, ivacaftor, and placebo. Patients had a ppFEV1 at screening between 40 to 90%. The mean 
ppFEV1 at baseline was 62.3% (range: 34.6% to 93.5%).  
 
Patients in Studies 1 and 2 continued on their standard-of-care CF therapies during the studies (e.g., 
bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline), and were eligible to roll over 
into a 96-week open-label extension study (study 3). Patients had a confirmed 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 in 
pulmonary status such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium 
abscessus, 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 in patients with CF who were homozygous for the F508del mutation in the CFTR gene (Study 1) 
In tudy 1 treatment with Symkevi in combination with ivacaftor resulted in a statistically significant 
improvement in ppFEV1 (Table 5). The treatment difference between Symkevi (in combination 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, 4.8; P<0.0001). Mean improvement 
in ppFEV1 was observed at the first assessment on day 15 and sustained throughout 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 medications for CF, and 
geographic region. See Table 5 for a summary of primary and key secondary outcomes. 



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Table 5: Primary and key secondary efficacy analyses, full analysis set (study 1) 

Analysis Statistic Placebo N=256 

 Symkevi in 
combination 

with Ivacaftor  
N=248 

Primary 
ppFEV1 
Baseline value 
 
 
 
 
Average absolute change 
from baseline through 
week 24 (percentage 
points)** 

 
n/N 

Mean (SD) 

 
256/256 

60.4 (15.7)  

 
247/248 

59.6 (14.7) 
n/N 

Within-group change  
LS mean (95% CI) 

256/256 
-0.6 (-1.3, 0.0) 

245/248 
3.4 (2.7, 4.0) 

Treatment difference 
LS mean (95% CI) 

P value 

4.0 (3.1, 4.8) 
 

P<0.0001* 

Key Secondary 
ppFEV1 
Baseline value 
 
 
 
 
Relative change from 
baseline through week 24 
(%)** 

 
n/N 

Mean (SD) 

 
256/256 

60.4 (15.7) 

 
247/248 

59.6 (14.7)  
n/N 

Within-group change  
LS mean (95% CI) 

256/256 
-0.5 (-1.7, 0.6) 

245/248 
6.3 (5.1, 7.4) 

Treatment difference  
LS mean (95% CI) 

P value 

6.8 (5.3, 8.3) 
 

P<0.0001* 
Pulmonary exacerbations  
 
 
 
Number of pulmonary 
exacerbations from 
baseline through week 24 

Number of subjects with 
events (n)/N  

Number of events (estimated 
event rate per year†) 

88/256 
 

122 (0.99) 
 

62/248 
 

78 (0.64) 

Rate ratio (RR) (95% CI) 
P value 

0.65 (0.48, 0.88) 
P=0.0054* 

BMI 
Baseline value  
 
 
 
 
Absolute change from 
baseline at week 24 
(kg/m2)** 

 
n/N 

Mean (SD) 

 
256/256 

21.12 (2.88) 

 
248/248 

20.96 (2.95)  
n/N 

Within-group change  
LS mean (95% CI) 

245/256 
0.12 (0.03, 

0.22) 

237/248 
0.18 (0.08, 

0.28) 
Treatment difference  

LS mean (95% CI) 
P value 

0.06 (-0.08, 0.19) 
 

P=0.4127# 
CFQ-R respiratory domain 
score 
Baseline value  
 
 
 
 
Absolute change from 
baseline through week 24 
(points)** 

 
 

n/N 
Mean (SD) 

 
 

256/256 
69.9 (16.6) 

 
 

248/248 
70.1 (16.8) 

n/N 
Within-group change  

LS mean (95% CI) 

256/256 
-0.1 (-1.6, 1.4) 

246/248 
5.0 (3.5, 6.5) 

Treatment difference  
LS mean (95% CI) 

P value 

5.1 (3.2, 7.0) 
 

nominal P<0.0001± 



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Table 5: Primary and key secondary efficacy analyses, full analysis set (study 1) 

Analysis Statistic Placebo N=256 

 Symkevi in 
combination 

with Ivacaftor  
N=248 

ppFEV1: percent predicted forced expiratory volume in 1 second; SD: Standard Deviation; LS 
mean: 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-visit 
interaction 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 severe 
pulmonary exacerbations requiring hospitalization or IV antibiotic therapy (0.29) compared to placebo 
(0.54). The rate ratio versus placebo was 0.53 (95% CI: 0.34, 0.82; nominal P= 0.0042). Pulmonary 
exacerbations requiring IV antibiotic therapy were lower in the treatment group compared to placebo 
(RR: 0.53 [95% CI: 0.34, 0.82]; nominal P=0.0042). Pulmonary exacerbations requiring 
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 to 
week 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 CF 
including cough, sputum production, and difficulty breathing) the percentage of subjects with at least a 
4 point-increase from baseline (minimal clinically important difference) was 51.1% for Symkevi and 
35.7% for placebo at week 24. 
 
Study in patients with CF who were heterozygous for the F508del mutation and a second mutation 
associated with residual CFTR activity (Study 2) 
Of the 244 patients enrolled in study 2 the following indicated mutations associated with residual 
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 2 treatment with Symkevi in combination with ivacaftor resulted in a statistically significant 
improvement in ppFEV1 (Table 6). The treatment difference between Symkevi in combination with 
ivacaftor- and placebo-treated patients for the primary endpoint of mean absolute change 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-treated patients 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. Mean 
improvement in ppFEV1 was observed at the first assessment on day 15 and sustained throughout the 
8-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 medications 
for CF, and geographic region. See Table 6 for a summary of primary and key secondary outcomes. 
 



13 

Table 6: Primary and key secondary efficacy analyses, full analysis set (study 2) 

Analysis Statistic Placebo N=161 
Ivacaftor 

N=156 

Symkevi in 
Combination 

with 
Ivacaftor  

N=161 

ppFEV1 
Baseline value  
 
 
 
 
Absolute change 
from baseline to 
the average of 
week 4 and week 8 
(percentage 
points)** 

 
n/N 

Mean (SD) 

 
161/161 

62.2 (14.3) 

 
156/156 

62.1 (14.6) 

 
161/161 

62.1 (14.7)  
n/N 

Within-group change  
LS mean (95% CI) 

160/161 
-0.3 (-1.2, 

0.6) 

156/156 
4.4 (3.5, 5.3) 

159/161 
6.5 (5.6, 7.3) 

Treatment difference 
versus placebo LS mean 

(95% CI) 
P value 

NA 
 

NA 

4.7 (3.7, 5.8) 
 

P<0.0001* 

6.8 (5.7, 7.8) 
 

P<0.0001* 

Treatment difference 
versus IVA LS mean 

(95% CI) 

NA 
 

NA 
 

2.1 (1.2, 2.9) 
 

CFQ-R respiratory 
domain score 
Baseline value 
 
 
 
 
Absolute change 
from baseline to 
the average of 
week 4 and week 8 
(points)** 

 
 

n/N 
Mean (SD) 

 
 

161/161 
68.7 (18.3) 

 
 

156/156 
67.9 (16.9)  

 
 

161/161 
68.2 (17.5) 

n/N 
Within-group change  

LS mean (95% CI) 

160/161 
-1.0 (-2.9, 

1.0) 

156/156 
8.7 (6.8, 

10.7) 

161/161 
10.1 (8.2, 

12.1) 
Treatment difference 

versus placebo LS mean 
(95% CI) 

P value 

NA 
 

NA 

9.7 (7.2, 
12.2) 

P<0.0001* 

11.1 (8.7, 
13.6) 

P<0.0001* 

Treatment difference 
versus IVA LS mean 

(95% CI) 

NA 
 

NA 
 

1.4 (-1.0, 3.9) 
 

ppFEV1: percent predicted forced expiratory volume in 1 second; SD: Standard Deviation; LS 
mean: 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 
effects and 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 1 and study 2 included a total of 39 patients treated with Symkevi in combination with ivacaftor 
with ppFEV1 <40. There were 23 patients with ppFEV1 <40 at baseline receiving Symkevi and 
24 patients receiving placebo in study 1. The mean treatment difference between Symkevi and 
placebo-treated patients for absolute change in ppFEV1 through week 24 in this subgroup was 
3.5 percentage points (95% CI: 1.0, 6.1). There were 16 patients with ppFEV1 <40 at baseline 
receiving Symkevi, 13 receiving ivacaftor and 15 receiving placebo in study 2. The mean treatment 
difference between Symkevi and placebo-treated patients for absolute change in ppFEV1 through the 
average of week 4 and week 8 was 4.4 percentage points (95% CI: 1.1, 7.8). The mean treatment 
difference between ivacaftor and placebo-treated patients was 4.4 percentage points (95% CI: 0.9, 
7.9).  
 
Long-term safety and efficacy rollover study (Study 3) 
Study 3 was a Phase 3, open-label, multicenter, rollover, 96-week study to evaluate the safety and 
efficacy of long-term treatment with Symkevi in combination with ivacaftor in patients from studies 1 



14 

(n=462) and 2 (n=227). Efficacy was a secondary objective for study 3 and the efficacy endpoints 
were not adjusted for multiplicity. 
 
Patients who received placebo in both study 1 and study 2 demonstrated improvements in ppFEV1 
when treated with Symkevi in combination with ivacaftor in study 3 [Study 1: within-group 
change=2.1(95% CI: 0.8, 3.3) percentage points, study 2: within-group change=4.1 (95% CI: 2.2, 6.0)) 
percentage points]. Patients who received Symkevi in combination with ivacaftor in the parent studies 
and continued on treatment,  showed a slight attenuation in ppFEV1 in the extension study, however 
the overall treatment effect was still positive through 120 weeks and 104 weeks for study 1 and study 
2, respectively.  
 
Similar trends were observed for CFQ-R respiratory domain score, pulmonary exacerbation rate and 
BMI. 
 
Paediatric population 
 
Adolescents aged 12 years and older 
Adolescents were included together with adults in the trials. 
 
Adolescent patients with CF who were homozygous for the F508del mutation in the CFTR gene  
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 in 
study 1. Patients who received Symkevi in combination with ivacaftor in study 1 and continued on 
treatment showed sustained improvements in ppFEV1 through 96 weeks in study 3 [within-group 
change=1.5 (1.6) percentage points]. Patients who were previously treated with placebo and received 
Symkevi in combination with ivacaftor in study 3 showed an increase of 0.9 (1.7) percentage points.  
 
The mean absolute change (SE) from baseline in BMI z-value was -0.01(0.05) kg/m2 in the Symkevi 
in combination with ivacaftor group and 0.00 (0.05) kg/m2 in the placebo group in study 1. In study 3, 
the change in BMI z-value in the Symkevi in combination with ivacaftor group was maintained 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 mutation 
associated with residual CFTR activity 
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 group 
and -0.4 (1.2) percentage points in the placebo group in study 2. Patients who received Symkevi in 
combination with ivacaftor in study 2 and continued on treatment showed sustained improvements in 
ppFEV1 through 96 weeks in study 3 [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 3 showed an increase of 4.1 (4.5) percentage points 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 in 
combination with ivacaftor group, 0.20 (0.07) kg/m2 in the ivacaftor group and 0.04 (0.07) kg/m2 in the 
placebo group in study 2. In study 3, 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.   
 
Children aged less than 12 years 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Symkevi in combination with ivacaftor in children aged less than 12 years in cystic fibrosis, as per 
paediatric investigation plan (PIP) decision for the granted indication (see 4.2 for information on 
paediatric use). 
 



15 

5.2 Pharmacokinetic properties 
 
The pharmacokinetics of tezacaftor and ivacaftor are similar between healthy adult volunteers and 
patients with CF. Following once daily dosing of tezacaftor and twice-daily dosing of ivacaftor in 
patients with CF, plasma concentrations of tezacaftor and ivacaftor reach steady-state within 8 days 
and within 3 to 5 days, respectively, after starting treatment. At steady-state, the accumulation ratio is 
approximately 2.3 for tezacaftor and 3.0 for ivacaftor. Exposures of tezacaftor (administered alone or 
in combination with ivacaftor) increase in an approximately dose-proportional manner with increasing 
doses from 10 mg to 300 mg once daily. Key pharmacokinetic parameters for tezacaftor and ivacaftor 
at steady-state are shown in Table 7. 
 

Table 7: Mean (SD) pharmacokinetic parameters of tezacaftor and ivacaftor at steady state in 
patients with CF 

 Drug Cmax (mcg/mL) t½ (h) 
AUC0-24h or AUC0-12h 

(mcg∙h/mL)* 
Tezacaftor 100 mg once 
daily/ivacaftor 150 mg every 
12 hours 

Tezacaftor 6.52 (1.83) 156 (52.7) 82.7 (23.3) 

Ivacaftor 1.28 (0.440) 9.3 (1.7) 10.9 (3.89) 
*AUC0-24h for tezacaftor and AUC0-12h for ivacaftor 

 
Absorption 
 
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) tmax 
of ivacaftor was approximately 6 hours (3 to 10 hours) in the fed state. The AUC of tezacaftor did not 
change when given with fat-containing food relative to fasted conditions. The AUC of ivacaftor when 
given in combination with tezacaftor increased approximately 3-fold when given with fat-containing 
food; therefore, Symkevi and ivacaftor should be administered with fat-containing food. 
 
Distribution 
 
Tezacaftor is approximately 99% bound to plasma proteins, primarily to albumin. Ivacaftor is 
approximately 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 every 
12 hours in patients with CF in the fed state, the mean (±SD) for apparent volume of distribution of 
tezacaftor and ivacaftor was 271 (157) L and 206 (82.9) L, respectively. Neither tezacaftor nor 
ivacaftor partition preferentially into human red blood cells. 
 
Biotransformation 
 
Tezacaftor is metabolized extensively in humans. In vitro data suggested that tezacaftor is metabolized 
mainly by CYP3A4 and CYP3A5. Following oral administration of a single dose of 100 mg 
14C-tezacaftor to healthy male subjects, M1-TEZ, M2-TEZ, and M5-TEZ were the three major 
circulating metabolites of tezacaftor in humans, contributing to 15%, 31%, and 33% of total 
radioactivity, 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 similar 
potency to that of tezacaftor and is considered pharmacologically active. M2-TEZ is much less 
pharmacologically active than tezacaftor or M1-TEZ, and M5-TEZ is not considered 
pharmacologically active. Another minor circulating metabolite, M3-TEZ, is formed by direct 
glucuronidation of tezacaftor. 
 
Ivacaftor is also metabolized extensively in humans. In vitro and in vivo data indicate that ivacaftor is 
metabolized primarily by CYP3A4 and CYP3A5. M1-IVA and M6-IVA are the two major metabolites 
of ivacaftor in humans. M1-IVA has approximately one-sixth the potency of ivacaftor and is 
considered pharmacologically active. M6-IVA is not considered pharmacologically active. 



16 

 
 
The effect of the CYP3A4*22 heterozygous genotype on tezacaftor and ivacaftor exposure is 
consistent with the effect of co-administration of a weak CYP3A4 inhibitor, which is not clinically 
relevant. No dose-adjustment of tezacaftor and ivacaftor is considered necessary. No data are available 
for CYP3A4*22 homozygous genotype patients. 
 
Elimination 
 
After oral administration of tezacaftor 100 mg once daily in combination with ivacaftor 150 mg every 
12 hours in patients with CF in the fed state, the mean (±SD) for apparent clearance values of 
tezacaftor and ivacaftor were 1.31 (0.41) and 15.7 (6.38) L/h, respectively. After steady-state dosing of 
tezacaftor in combination with ivacaftor in CF patients, the mean (SD) terminal half-lives of tezacaftor 
and 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 parent 
compound. The mean (SD) elimination half-lives for M1-IVA and M6-IVA were 11.3 (2.12) h and 
14.4 (6.14) h, respectively. 
 
Following oral administration of 14C-tezacaftor, the majority of the dose (72%) was excreted in the 
faeces (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. Less 
than 1% of the administered dose was excreted in urine as unchanged tezacaftor, showing that renal 
excretion 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 the 
faeces after metabolic conversion. There was negligible urinary excretion of ivacaftor as unchanged 
drug. 
 
Hepatic impairment 
 
Following multiple doses of tezacaftor and ivacaftor for 10 days, subjects with moderately impaired 
hepatic function (Child-Pugh Class B, score 7 to 9) had an approximately 36% increase in AUC and a 
10% increase in Cmax for tezacaftor, and a 50% increase in ivacaftor AUC compared with healthy 
subjects matched for demographics. Based on these results, a modified regimen of Symkevi is 
recommended for patients with moderate hepatic impairment (see Table 2 in section 4.2). 
 
The impact of severe hepatic impairment (Child-Pugh Class C, score 10 to 15) on the 
pharmacokinetics of tezacaftor and ivacaftor has not been studied. The magnitude of increase in 
exposure in these patients is unknown but is expected to be higher than that observed in patients with 
moderate hepatic impairment. The use of Symkevi in patients with severe hepatic impairment is 
therefore not recommended unless the benefits outweigh the risks (see Table 2 in section 4.2). 
 
No dose adjustment is considered necessary for patients with mild hepatic impairment. 
 
Renal impairment 
 
Symkevi in combination with ivacaftor has not been studied in patients with moderate or severe renal 
impairment (creatinine clearance ≤30 mL/min) or in patients with end-stage renal disease. In a human 
pharmacokinetic study with tezacaftor alone, there was minimal elimination of tezacaftor and its 
metabolites in urine (only 13.7% of total radioactivity was recovered in the urine with 0.79% as 
unchanged medicinal product). 
 
In a human pharmacokinetic study with ivacaftor alone, there was minimal elimination of ivacaftor 
and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine). 
 



17 

In population pharmacokinetic analysis, data from 147 patients on tezacaftor or tezacaftor in 
combination with ivacaftor in Phase 2/3 clinical studies indicated that mild renal impairment 
(estimated glomerular filtration rate, estimated by the modification of diet in renal disease method, 
60 to ≤89 mL/min/1.73 m2) did not affect the clearance of tezacaftor significantly. No dose adjustment 
is recommended 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 renal disease. 
 
Gender 
 
The pharmacokinetic parameters of tezacaftor and ivacaftor are similar in males and females. 
 
Race  
 
Very limited PK data indicate comparable exposure to tezacaftor in white (n=652) and non-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. 
 
Elderly 
 
Clinical trials of Symkevi in combination with ivacaftor did not include patients over 75 years of age. 
The pharmacokinetic parameters of tezacaftor in combination with ivacaftor in the elderly patients (65 
to 72 years) are comparable to those in younger adults.  
 
Paediatric Population 
 
As presented in Table 8, the pharmacokinetic parameters of tezacaftor and ivacaftor in adolescents (12 
to 17 years) are comparable to those in adults when given in combination. The pharmacokinetics of 
tezacaftor/ivacaftor in children below 12 years of age has not been investigated. 
 

Table 8. Mean (SD) tezacaftor and ivacaftor exposure by age group 
Age group Dose Tezacaftor Mean (SD) 

AUCτ,ss (mcg∙h/mL) 
Ivacaftor Mean (SD) 
AUCτ,ss (mcg∙h/mL) 

Adolescents TEZ 100 mg qd/IVA 150 mg q12h 97.1 (35.8) 11.4 (5.5) 
Adults TEZ 100 mg qd/IVA 150 mg q12h 85.9 (28.0) 11.4 (4.14) 

 
5.3 Preclinical safety data  
 
Tezacaftor 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction 
and development. Placental transfer of tezacaftor was observed in pregnant rats. 
 
Ivacaftor 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. 
 
Ivacaftor was associated with slight decreases of the seminal vesicle weights, a decrease of overall 
fertility index and number of pregnancies in females mated with treated males and significant 
reductions in number of corpora lutea and implantation sites with subsequent reductions in the average 
litter 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 approximately 
5 times the systemic exposure of ivacaftor and its metabolites when administered as 
tezacaftor/ivacaftor in adult humans at the maximum recommended human dose (MRHD). 



18 

 
In the pre- and post-natal study ivacaftor 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 4 times the systemic exposure of ivacaftor and its metabolites when 
administered as tezacaftor/ivacaftor in adult humans at the MRHD. Placental transfer of ivacaftor was 
observed in pregnant rats and rabbits. 
 
Findings of cataracts were observed in juvenile rats dosed from postnatal day 7 through 35 at ivacaftor 
exposure levels of 0.25 times the MRHD based on systemic exposure of ivacaftor and its metabolites 
when administered as tezacaftor/ivacaftor. This finding has not been observed in fetuses derived from 
rat dams treated with ivacaftor on gestation days 7 to 17, in rat pups exposed to ivacaftor through milk 
ingestion up to postnatal day 20, in 7-week-old rats, nor in 3.5- to 5-month-old dogs treated with 
ivacaftor. 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 tezacaftor 
and ivacaftor to assess the potential for additive and/or synergistic toxicity did not produce any 
unexpected toxicities or interactions. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
Hypromellose acetate succinate 
Sodium laurilsulfate (E487) 
Hypromellose (E464) 
Microcrystalline cellulose (E460(i)) 
Croscarmellose sodium (E468) 
Magnesium stearate (E470b) 
 
Tablet film coat 
 
Hypromellose (E464) 
Hydroxypropyl cellulose (E463) 
Titanium dioxide (E171) 
Talc (E553b) 
Iron oxide yellow (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
4 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 



19 

 
Blister consisting of PCTFE (polychlorotrifluoroethylene)/PVC (polyvinyl chloride) with a 
paper-backed aluminum foil lidding. 
 
Pack size of 28 tablets (4 blister cards of 7 tablets each). 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Vertex Pharmaceuticals (Ireland) Limited 
28-32 Pembroke Street Upper 
Dublin 2, D02 EK84 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/18/1306/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 31 October 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 
 
  



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 



21 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Almac Pharma Services (Ireland) Limited 
Finnabair Industrial Estate 
Dundalk 
Co. Louth 
A91 P9KD 
Ireland 
 
Almac Pharma Services Ltd 
20 Seagoe Industrial Estate 
Portadown 
Craigavon 
BT63 5UA 
United Kingdom 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 
months following authorisation.  
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 



22 

• Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
 

  



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



25 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Symkevi 100 mg/150 mg film-coated tablets 
tezacaftor/ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 100 mg of tezacaftor and 150 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
Take the tablets with fat-containing food. 
 
Open  
Insert tab below to close 
 
You may start taking Symkevi on any day of the week. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



26 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Vertex Pharmaceuticals (Ireland) Limited 
28-32 Pembroke Street Upper 
Dublin 2, D02 EK84 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1306/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Symkevi 100 mg, 150 mg 
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 



27 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BLISTER CARD 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Symkevi 100 mg/150 mg film-coated tablets 
tezacaftor/ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 100 mg of tezacaftor and 150 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
7 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
Take the tablets with fat-containing food. 
 
Mon.  Tue.  Wed.  Thu.  Fri.  Sat.  Sun.  
 
You may start taking Symkevi on any day of the week. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
  
 



28 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Vertex Pharmaceuticals (Ireland) Limited 
28-32 Pembroke Street Upper 
Dublin 2, D02 EK84 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1306/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  



29 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Symkevi 100 mg/150 mg tablets 
tezacaftor/ivacaftor 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Vertex 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
  



30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 

  



31 

Package leaflet: Information for the patient 
 

Symkevi 100 mg/150 mg film-coated tablets 
tezacaftor/ivacaftor 

 
 

 This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of 
section 4 for how to report side effects. 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor or pharmacist. 
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Symkevi is and what it is used for 
2. What you need to know before you take Symkevi 
3. How to take Symkevi 
4. Possible side effects 
5. How to store Symkevi 
6. Contents of the pack and other information 
 
 
1. What Symkevi is and what it is used for 
 
Symkevi contains two active substances, tezacaftor and ivacaftor. The medicine helps lung cells to 
work better in some patients with cystic fibrosis (CF). CF is an inherited condition in which the lungs 
and the digestive system can become clogged with thick, sticky mucus.  
 
Symkevi works on a protein called CFTR (cystic fibrosis transmembrane conductance regulator), 
which is damaged in some people with CF (who have a mutation in the CFTR gene). Ivacaftor causes 
the protein to work better while tezacaftor increases the amount of protein at the cell surface. Symkevi 
is normally taken with ivacaftor, another medicine. 
 
Symkevi taken with ivacaftor is for long-term treatment of patients aged 12 and over who have CF 
with certain genetic mutations that result in reduced amount and/or function of the CFTR protein. 
 
Symkevi taken with ivacaftor helps your breathing by improving your lung function. You may also 
notice that you do not get ill as often and/or that it is easier to gain weight. 
 
 
2. What you need to know before you take Symkevi 
 
Do not take Symkevi 
• If you are allergic to tezacaftor, ivacaftor, or any of the other ingredients of this medicine (listed 

in section 6). 
Talk to your doctor, without taking the tablets, if this applies to you. 
 



32 

Warnings and precautions 
• Talk to your doctor if you have liver problems, or have had them previously. Your doctor may 

need to adjust your dose. 
 

• Your doctor will do some blood tests to check your liver before and during treatment with 
Symkevi, especially if your blood tests showed high liver enzymes in the past. Increased liver 
enzymes in the blood have been seen in patients with CF receiving Symkevi. 

Tell your doctor right away if you have any symptoms of liver problems. These are listed in 
section 4. 
 
• Your doctor may do eye examinations before and during treatment with Symkevi. Cloudiness of 

the eye lens (cataract) without any effect on vision has occurred in some children and adolescents 
receiving this treatment. 

 
• Talk to your doctor if you have kidney problems, or you have previously had them. 
 
• Talk to your doctor before starting treatment if you have received an organ transplant. 
 
Children under 12 
Symkevi is not to be used in children under the age of 12 years. It is not known if Symkevi is safe and 
effective in children under 12. 
 
Other medicines and Symkevi 
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other 
medicines. Some medicines can affect how Symkevi works or may make side effects more likely. In 
particular, tell your doctor if you take any of the medicines listed below. Your doctor may change the 
dose of one of the medicines if you take any of these. 
• Antifungal medicines (used for the treatment of fungal infections). These include ketoconazole, 

itraconazole, posaconazole, voriconazole and fluconazole. 
• Antibiotic medicines (used for the treatment of bacterial infections). These include telithromycin, 

clarithromycin, erythromycin, rifampicin and rifabutin. 
• Anticonvulsant medicines (used for the treatment of epilepsy and epileptic seizures or fits). 

These include phenobarbital, carbamazepine and phenytoin. 
• Herbal medicines. These include St. John’s wort (Hypericum perforatum). 
• Immunosuppressants (used after an organ transplantation). These include ciclosporin, 

tacrolimus, sirolimus and everolimus. 
• Cardiac glycosides (used for the treatment of some heart conditions). These include digoxin. 
• Anticoagulant medicines (used to prevent blood clots). These include warfarin. 
• Medicines for diabetes. These include glimepiride and glipizide. 
 
Symkevi with food and drink 
Avoid food or drinks containing grapefruit or Seville oranges (marmalade oranges) during treatment 
as these may increase the side effects of Symkevi by increasing the amount of Symkevi in your body. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine. 
• Pregnancy: It may be better to avoid using this medicine during pregnancy. Your doctor will help 

you decide what is best for you and your child. 
• Breast-feeding: It is not known if tezacaftor or ivacaftor pass into breast milk. Your doctor will 

consider the benefit of breast-feeding for the child and the benefit of treatment for you to help you 
decide whether to stop breast-feeding or to stop treatment. 

 



33 

Driving and using machines 
Symkevi in combination with ivacaftor can make you dizzy. If you feel dizzy, do not drive, cycle or 
use machines unless you are not affected. 
 
Important information about the contents of Symkevi 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 
‘sodium-free’. 
 
 
3. How to take Symkevi 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
The recommended dose: 
 
Symkevi is usually taken with ivacaftor. 
• In the morning, take one yellow Symkevi tablet. This is stamped with “V100”. 
• In the evening, take one ivacaftor 150 mg tablet. 
 
Take the tablets about 12 hours apart. 
 
Take both Symkevi and ivacaftor tablets with food that contains fat. Meals or snacks that contain 
fat include those prepared with butter or oils or those containing eggs. Other fat-containing foods are: 
• Cheese, whole milk, whole milk dairy products, yogurt, chocolate 
• Meats, oily fish 
• Avocados, hummus, soy-based products (tofu) 
• Nuts, fat-containing nutritional bars or drinks 
 
The tablets are for oral use. 
 
Swallow the tablet whole. Do not chew, crush or break the tablets before swallowing. 
 
You must keep using all your other medicines, unless your doctor tells you to stop. 
 
If you have liver problems, either moderate or severe, your doctor may need to reduce the dose of 
your tablets, because your liver will not process the medicine as fast as usual. 
 
If you take more Symkevi than you should 
Contact your doctor or pharmacist for advice. If possible, take your medicine and this leaflet with 
you. You may get side effects, including those mentioned in section 4 below. 
 
If you forget to take Symkevi 
• If you forget to take either your morning Symkevi or evening ivacaftor tablet, and you remember 

within 6 hours of the scheduled time you should have taken the tablet, take the forgotten tablet at 
once. 

• If more than 6 hours have passed, do not take the forgotten tablet. Just wait, and take your next 
tablet at the usual time. 

• Do not take 2 tablets to make up for a missed dose. 
 
If you stop taking Symkevi 
Your doctor will tell you how long you need to keep using Symkevi. It is important to take this 
medicine regularly. Do not make changes unless your doctor tells you. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 



34 

 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Possible signs of liver problems 
Increased liver enzymes in the blood are very common in patients with CF. These may be a sign of 
liver problems: 
• Pain or discomfort in the upper right area of the stomach (abdominal) area 
• Yellowing of the skin or the white part of the eyes 
• Loss of appetite 
• Nausea or vomiting 
• Dark urine 
Tell your doctor straight away if you have any of these symptoms. 
 
Side effects seen with Symkevi in combination with ivacaftor: 
Very common side effects 
(may affect more than 1 in 10 people) 
• Headache 
• Common cold 
 
Common side effects 
(may affect up to 1 in 10 people) 
• Feeling sick (nausea) 
• Blocked nose (sinus congestion) 
• Dizziness 
 
Side effects seen with ivacaftor:  
Very common side effects 
• Upper respiratory tract infection (the common cold), including sore throat and nasal congestion 
• Headache 
• Dizziness 
• Stomach (abdominal) ache 
• Diarrhoea 
• Increased liver enzymes in the blood 
• Rash 
• Changes in the type of bacteria in mucus 
 
Common side effects 
• Runny nose 
• Ear pain, ear discomfort 
• Ringing in the ears 
• Redness inside the ear 
• Inner ear disorder (feeling dizzy or spinning) 
• Sinus congestion 
• Redness in the throat 
• Breast mass 
 
Uncommon side effects 
(may affect up to 1 in 100 people) 
• Ear congestion 
• Breast inflammation 
• Enlargement of the breast in males 
• Nipple changes or pain 



35 

 
Additional side effects in children and adolescents 
Side effects in children and adolescents are similar to those observed in adults. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Symkevi 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the package after EXP. The expiry 
date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Symkevi contains 
• The active substances are tezacaftor and ivacaftor. Each film-coated tablet contains 100 mg of 

tezacaftor and 150 mg of ivacaftor. 
• The other ingredients are: 
− Tablet core: Hypromellose acetate succinate, sodium laurilsulfate (E487), hypromellose (E464), 

microcrystalline cellulose (E460(i)), croscarmellose sodium (E468), and magnesium stearate 
(E470b). 

− Tablet film coating: Hypromellose (E464), hydroxypropyl cellulose (E463), titanium dioxide 
(E171), talc (E553b), and iron oxide yellow (E172). 

 
See the end of section 2 for important information about the contents of Symkevi. 
 
What Symkevi looks like and contents of the pack 
Symkevi 100 mg tezacaftor/150 mg ivacaftor film-coated tablets are yellow, oval-shaped tablets 
stamped with “V100” on one side and plain on the other. 
 
Symkevi is available in the following pack size: 
Pack size of 28 tablets (4 blister cards, each with 7 tablets). 
 
Marketing Authorisation Holder and Manufacturer 
Marketing Authorisation Holder: 
Vertex Pharmaceuticals (Ireland) Limited 
28-32 Pembroke Street Upper 
Dublin 2, D02 EK84 
Ireland 
Tel: +353 (0)1 761 7299 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


36 

Manufacturer: 
Almac Pharma Services (Ireland) Limited 
Finnabair Industrial Estate 
Dundalk 
Co. Louth 
A91 P9KD 
Ireland 
 
Almac Pharma Services Limited 
Seagoe Industrial Estate 
Craigavon 
County Armagh 
BT63 5UA 
United Kingdom 
 
This leaflet was last revised in 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET