Orkambi

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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 
 
Orkambi 100 mg/125 mg film-coated tablets 
Orkambi 200 mg/125 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Orkambi 100 mg/125 mg film-coated tablets 
 
Each film-coated tablet contains 100 mg of lumacaftor and 125 mg of ivacaftor. 
 
Orkambi 200 mg/125 mg film-coated tablets 
 
Each film-coated tablet contains 200 mg of lumacaftor and 125 mg of ivacaftor. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet) 
 
Orkambi 100 mg/125 mg film-coated tablets 
 
Pink, oval-shaped tablets (dimensions 14 × 7.6 × 4.9 mm) printed with “1V125” in black ink on one 
side. 
 
Orkambi 200 mg/125 mg film-coated tablets 
 
Pink, oval-shaped tablets (dimensions 14 × 8.4 × 6.8 mm) printed with “2V125” in black ink on one 
side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Orkambi tablets are indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years and 
older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance 
regulator (CFTR) gene (see sections 4.2, 4.4 and 5.1). 
 
4.2 Posology and method of administration 
 
Orkambi 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 the F508del mutation on both alleles of the CFTR gene. 
 



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Posology 
 
 
Table 1: Dosing recommendations in patients aged 6 years and older 

Age Dose Total daily dose 
6 to 11 years 2 tablets of lumacaftor 

100 mg/ivacaftor 125 mg every 
12 hours 

lumacaftor 400 mg/ 
ivacaftor 500 mg 

12 years and older 2 tablets of lumacaftor 
200 mg/ivacaftor 125 mg every 
12 hours 

lumacaftor 800 mg/ 
ivacaftor 500 mg 

 
Patients may start treatment on any day of the week. 
This medicinal product should be taken with fat-containing food. A fat-containing meal or snack 
should be consumed just before or just after dosing (see section 5.2). 
 
Missed dose 
If less than 6 hours have passed since the missed dose, the scheduled dose should be taken with fat-
containing food. If more than 6 hours have passed, the patient should be instructed to wait until the 
next scheduled dose. A double dose should not be taken to make up for the forgotten dose. 
 
Concomitant use of CYP3A inhibitors 
No dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking 
Orkambi. However, when initiating treatment in patients taking strong CYP3A inhibitors, reduce the 
dose to one tablet daily (lumacaftor 100 mg/ivacaftor 125 mg for patients aged 6 to 11 years; 
lumacaftor 200 mg/ivacaftor 125 mg for patients aged 12 years and older) for the first week of 
treatment to allow for the steady state induction effect of lumacaftor. Following this period, the 
recommended daily dose should be continued. 
 
If treatment is interrupted for more than one week and then re-initiated while taking strong CYP3A 
inhibitors, reduce the dose to one tablet daily (lumacaftor 100 mg/ivacaftor 125 mg for patients aged 6 
to 11 years; lumacaftor 200 mg/ivacaftor 125 mg for patients aged 12 years and older) for the first 
week of treatment re-initiation. Following this period, the recommended daily dose should be 
continued (see section 4.5). 
 
Special populations 
 
 
Renal impairment 
No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution is 
recommended in patients with severe renal impairment (creatinine clearance less than or equal to 
30 mL/min) or end-stage renal disease (see sections 4.4 and 5.2). 
 
Hepatic impairment 
No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). For 
patients with moderate hepatic impairment (Child-Pugh Class B), a dose reduction is recommended. 
 
There is no experience of the use of the medicinal product in patients with severe hepatic impairment 
(Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic 
impairment. Therefore, after weighing the risks and benefits of treatment, Orkambi should be used 
with caution in patients with severe hepatic impairment, at a reduced dose (see sections 4.4, 4.8 and 
5.2). 
 
For dose adjustments for patients with hepatic impairment see Table 2. 
 



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Table 2: Dose adjustment recommendations for patients with hepatic impairment 

Hepatic 
impairment Dose adjustment Total daily dose 

Mild hepatic 
impairment  
(Child-Pugh Class A) 

No dose adjustment 

For patients aged 6 
to 11 years 

400 mg lumacaftor + 500 mg 
ivacaftor 
 
For patients aged 12 years and older 
800 mg lumacaftor + 
500 mg ivacaftor 

Moderate hepatic 
impairment  
(Child-Pugh Class B) 

For patients aged 6 to 11 years 
2 tablets of 100 mg/125 mg in the 
morning + 1 tablet of 100 mg/125 
mg in the evening (12 hours later) 
  
For patients aged 12 years and older 
2 tablets of 200 mg/125 mg in the 
morning +  
1 tablet of 200 mg/125 mg in the 
evening (12 hours later) 

For patients aged 6 to 11 years 
300 mg lumacaftor + 
375 mg ivacaftor 
 
 
For patients aged 12 years and older 
600 mg lumacaftor + 
375 mg ivacaftor 

Severe hepatic 
impairment  
(Child-Pugh Class C) 

For patients aged 6 to 11 years 
1 tablet of 100 mg/125 mg in the 
morning + 
1 tablet of 100 mg/125 mg in the 
evening (12 hours later) 
or 
a reduced daily dose 
 
For patients aged 12 years and older 
1 tablet of 200 mg/125 mg in the 
morning +  
1 tablet of 200 mg/125 mg in the 
evening (12 hours later)  
or 
a reduced daily dose 

For patients aged 6 to 11 years 
200 mg lumacaftor + 
250 mg ivacaftor  
or 
a reduced daily dose 
 
 
 
For patients aged 12 years and older 
400 mg lumacaftor + 
250 mg ivacaftor  
or 
a reduced daily dose 

 
Paediatric population 
The safety and efficacy of Orkambi in children aged less than 2 years have not yet been established. 
No data are available (see section 5.1). 
 
Method of administration 
 
For oral use.  
 
Patients should be instructed to swallow the tablets whole. Patients should not chew, break, or dissolve 
the tablets. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 
 



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4.4 Special warnings and precautions for use 
 
Patients with CF who are heterozygous for the F508del mutation in the CFTR gene 
 
Lumacaftor/ivacaftor is not effective in patients with CF who have the F508del mutation on one allele 
plus a second allele with a mutation predicted to result in a lack of CFTR production or that is not 
responsive to ivacaftor in vitro (see section 5.1). 
 
Patients with CF who have a gating (Class III) mutation in the CFTR gene 
 
Lumacaftor/ivacaftor has not been studied in patients with CF who have a gating (Class III) mutation 
in the CFTR gene on one allele, with or without the F508del mutation on the other allele. Since the 
exposure of ivacaftor is very significantly reduced when dosed in combination with lumacaftor, 
lumacaftor/ivacaftor should not be used in these patients. 
 
Respiratory adverse reactions 
 
Respiratory adverse reactions (e.g., chest discomfort, dyspnoea, bronchospasm, and respiration 
abnormal) were more common during initiation of lumacaftor/ivacaftor therapy. Serious respiratory 
events were seen more frequently in patients with percent predicted forced expiratory volume in  1 
second (ppFEV1) <40, and may lead to discontinuation of the medicinal product. Clinical experience 
in patients with ppFEV1 < 40 is limited and additional monitoring of these patients is recommended 
during initiation of therapy (see section 4.8). A transient decline in FEV1 has also been observed in 
some patients following initiation of lumacaftor/ivacaftor. There is no experience of initiating 
treatment with lumacaftor/ivacaftor in patients having a pulmonary exacerbation and initiating 
treatment in patients having a pulmonary exacerbation is not advisable. 
 
Effect on blood pressure 
 
Increased blood pressure has been observed in some patients treated with lumacaftor/ivacaftor. Blood 
pressure should be monitored periodically in all patients during treatment (see section 4.8). 
 
Patients with advanced liver disease 
 
Abnormalities in liver function, including advanced liver disease, can be present in patients with CF. 
Worsening of liver function in patients with advanced liver disease has been reported. Liver function 
decompensation, including liver failure leading to death, has been reported in CF patients with pre-
existing cirrhosis with portal hypertension receiving lumacaftor/ivacaftor. Lumacaftor/ivacaftor should 
be used with caution in patients with advanced liver disease and only if the benefits are expected to 
outweigh the risks. If lumacaftor/ivacaftor is used in these patients, they should be closely monitored 
after the initiation of treatment and the dose should be reduced (see sections 4.2, 4.8, and 5.2). 
 
Hepatobiliary adverse reactions 
 
Elevated transaminases have been commonly reported in patients with CF receiving 
lumacaftor/ivacaftor. In some instances, these elevations have been associated with concomitant 
elevations in total serum bilirubin. Transaminase elevations have been observed more frequently in 
paediatric patients than in adult patients (see section 4.8). 
 
Because an association with liver injury cannot be excluded, assessments of liver function tests (ALT, 
AST and bilirubin) are recommended before initiating lumacaftor/ivacaftor, every 3 months during the 
first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin 
elevations, more frequent monitoring should be considered. 
 
In the event of significant elevation of ALT or AST, with or without elevated bilirubin (either ALT or 
AST > 5 x the upper limit of normal [ULN], or ALT or AST > 3 x ULN with bilirubin > 2 x ULN 
and/or clinical jaundice), dosing with lumacaftor/ivacaftor should be discontinued and laboratory tests 



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closely followed until the abnormalities resolve. A thorough investigation of potential causes should 
be conducted and patients should be followed closely for clinical progression. Following resolution of 
transaminase elevations, the benefits and risks of resuming dosing should be considered (see 
sections 4.2, 4.8, and 5.2). 
 
Interactions with medicinal products 
 
Substrates of CYP3A 
Lumacaftor is a strong inducer of CYP3A. Co-administration with sensitive CYP3A substrates or 
CYP3A substrates with a narrow therapeutic index is not recommended (see section 4.5). 
 
Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied 
upon as an effective method of contraception when co-administered with Orkambi (see section 4.5). 
 
Strong CYP3A inducers 
Ivacaftor is a substrate of CYP3A4 and CYP3A5. Therefore, co-administration with strong CYP3A 
inducers (e.g., rifampicin, St. John’s wort [Hypericum perforatum]) is not recommended (see 
section 4.5). 
 
Renal impairment 
 
Caution is recommended while using lumacaftor/ivacaftor in patients with severe renal impairment or 
end-stage renal disease (see sections 4.2 and 5.2). 
 
Cataracts 
 
Cases of non-congenital lens opacities without impact on vision have been reported in paediatric 
patients treated with lumacaftor/ivacaftor and ivacaftor monotherapy. Although other risk factors were 
present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable 
to ivacaftor cannot be excluded (see section 5.3). Baseline and follow-up ophthalmological 
examinations are recommended in paediatric patients initiating treatment with lumacaftor/ivacaftor. 
 
Patients after organ transplantation 
 
Lumacaftor/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 immunosuppressants. 
 
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 
 
Based on exposure and indicated doses, the interaction profile is considered to be the same for all 
strengths and pharmaceutical forms.  
 
Lumacaftor is a strong inducer of CYP3A and ivacaftor is a weak inhibitor of CYP3A when given as 
monotherapy. There is potential for other medicinal products to affect lumacaftor/ivacaftor when 
administered concomitantly, and also for lumacaftor/ivacaftor to affect other medicinal products. 
 
Potential for other medicinal products to affect lumacaftor/ivacaftor 
 
Inhibitors of CYP3A 
Co-administration of lumacaftor/ivacaftor with itraconazole, a strong CYP3A inhibitor, did not impact 
the exposure of lumacaftor, but increased ivacaftor exposure by 4.3-fold. Due to the induction effect of 



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lumacaftor on CYP3A, at steady-state, the net exposure of ivacaftor when co-administered with a 
CYP3A inhibitor is not expected to exceed that when given in the absence of lumacaftor at a dose of 
150 mg every 12 hours, the approved dose of ivacaftor monotherapy.  
 
No dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking 
lumacaftor/ivacaftor. However, when initiating lumacaftor/ivacaftor in patients taking strong CYP3A 
inhibitors, the dose should be adjusted (see sections 4.2 and 4.4). 
 
No dose adjustment is recommended when used with moderate or weak CYP3A inhibitors. 
 
Inducers of CYP3A 
Co-administration of lumacaftor/ivacaftor with rifampicin, a strong CYP3A inducer, had minimal 
effect on the exposure of lumacaftor, but decreased ivacaftor exposure (AUC) by 57%. Therefore, 
co-administration of lumacaftor/ivacaftor is not recommended with strong CYP3A inducers (see 
sections 4.2 and 4.4). 
 
No dose adjustment is recommended when used with moderate or weak CYP3A inducers. 
 
Potential for lumacaftor/ivacaftor to affect other medicinal products 
 
CYP3A substrates 
Lumacaftor is a strong inducer of CYP3A. Ivacaftor is a weak inhibitor of CYP3A when given as 
monotherapy. The net effect of lumacaftor/ivacaftor therapy is expected to be strong CYP3A 
induction. Therefore, concomitant use of lumacaftor/ivacaftor with CYP3A substrates may decrease 
the exposure of these substrates (see section 4.4). 
 
P-gp substrates 
In vitro studies indicated that lumacaftor has the potential to both inhibit and induce P-gp. 
Additionally, a clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of 
P-gp. Therefore, concomitant use of lumacaftor/ivacaftor with P-gp substrates (e.g., digoxin) may alter 
the exposure of these substrates. 
 
CYP2B6 and CYP2C substrates 
Interaction with CYP2B6 and CYP2C substrates has not been investigated in vivo. In vitro studies 
suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; 
however, inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in vitro 
studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of lumacaftor/ivacaftor 
may alter (i.e., either increase or decrease) the exposure of CYP2C8 and CYP2C9 substrates, decrease 
the exposure of CYP2C19 substrates, and substantially decrease the exposure of CYP2B6 substrates. 
 
Potential for lumacaftor/ivacaftor to interact with transporters 
 
In vitro experiments show that lumacaftor is a substrate for Breast Cancer Resistance Protein (BCRP). 
Co-administration of Orkambi with medicinal products that inhibit BCRP may increase plasma 
lumacaftor concentration. Lumacaftor inhibits the organic anion transporter (OAT) 1 and 3. 
Lumacaftor and ivacaftor are inhibitors of BCRP. Co-administration of Orkambi with medicinal 
products that are substrates for OAT1/3 and BCRP transport may increase plasma concentrations of 
such medicinal products. Lumacaftor and ivacaftor are not inhibitors of OATP1B1, OATP1B3, and 
organic cation transporter (OCT) 1 and 2. Ivacaftor is not an inhibitor of OAT1 and OAT3. 
 
Established and other potentially significant interactions 
 
Table 3 provides the established or predicted effect of lumacaftor/ivacaftor on other medicinal 
products or the effect of other medicinal products on lumacaftor/ivacaftor. The information reported in 
Table 3 mostly derives from in vitro studies. The recommendations provided under “Clinical 
comment” in Table 3 are based on interaction studies, clinical relevance, or predicted interactions due 
to elimination pathways. Interactions that have the most clinical relevance are listed first. 



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Table 3: Established and other potentially significant interactions - dose recommendations for 

use of lumacaftor/ivacaftor with other medicinal products 

Concomitant 
medicinal product 
class: 
Active substance name Effect Clinical comment 
Concomitant medicinal products of most clinical relevance 
Anti-allergics: 
montelukast 

 
↔ LUM, IVA 
 
 
 
↓ montelukast 
Due to the induction 
of CYP3A/2C8/2C9 
by LUM 

 
 
 
 
 
No dose adjustment for montelukast is 
recommended. Appropriate clinical 
monitoring should be employed, as is 
reasonable, when co-administered with 
lumacaftor/ivacaftor. Lumacaftor/ivacaftor 
may decrease the exposure of montelukast, 
which may reduce its efficacy. 

 
fexofenadine 

 
↔ LUM, IVA 
 
↑ or ↓ fexofenadine 
Due to potential 
induction or 
inhibition of P-gp 

 
 
 
Dose adjustment of fexofenadine may be 
required to obtain the desired clinical 
effect. Lumacaftor/ivacaftor may alter the 
exposure of fexofenadine. 

Antibiotics: 
clarithromycin, 
telithromycin 

 
↔ LUM 
↑ IVA 
Due to inhibition of 
CYP3A by 
clarithromycin, 
telithromycin 
 
↓ clarithromycin, 
telithromycin 
Due to induction of 
CYP3A by LUM 

 
No dose adjustment of 
lumacaftor/ivacaftor is recommended 
when clarithromycin or telithromycin are 
initiated in patients currently taking 
lumacaftor/ivacaftor. 
 
 
 
The dose of lumacaftor/ivacaftor should be 
reduced to one tablet daily for the first 
week of treatment when initiating 
lumacaftor/ 
ivacaftor in patients currently taking 
clarithromycin or telithromycin.  
 
An alternative to these antibiotics, such as 
azithromycin, should be considered. 
Lumacaftor/ivacaftor may decrease the 
exposures of clarithromycin and 
telithromycin, which may reduce their 
efficacy. 



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Concomitant 
medicinal product 
class: 
Active substance name Effect Clinical comment 
 
erythromycin 

 
↔ LUM 
↑ IVA 
Due to inhibition of 
CYP3A by 
erythromycin 
 
↓ erythromycin 
Due to induction of 
CYP3A by LUM 

 
No dose adjustment of 
lumacaftor/ivacaftor is recommended 
when co-administered with erythromycin. 
 
 
 
An alternative to erythromycin, such as 
azithromycin, should be considered. 
Lumacaftor/ivacaftor may decrease the 
exposure of erythromycin, which may 
reduce its efficacy. 

Anticonvulsants: 
carbamazepine, 
phenobarbital, 
phenytoin 

 
↔ LUM 
↓ IVA 
Due to induction of 
CYP3A by these 
anticonvulsants 
 
↓ carbamazepine, 
phenobarbital, 
phenytoin 
Due to induction of 
CYP3A by LUM 

 
 
 
 
 
 
 
Concomitant use of lumacaftor/ivacaftor 
with these anticonvulsants is not 
recommended. The exposures of ivacaftor 
and the anticonvulsant may be 
significantly decreased, which may reduce 
the efficacy of both active substances. 

Antifungals: 
itraconazole*, 
ketoconazole, 
posaconazole, 
voriconazole 

 
↔ LUM 
↑ IVA 
Due to inhibition of 
CYP3A by these 
antifungals 
 
↓ itraconazole, 
ketoconazole, 
voriconazole 
Due to induction of 
CYP3A by LUM 
 
↓ posaconazole 
Due to induction of 
UGT by LUM 

 
No dose adjustment of 
lumacaftor/ivacaftor is recommended 
when these antifungals are initiated in 
patients currently taking 
lumacaftor/ivacaftor. 
 
 
The dose of lumacaftor/ivacaftor should be 
reduced to one tablet daily for the first 
week of treatment when initiating 
lumacaftor/ 
ivacaftor in patients currently taking these 
antifungals. 
 
Concomitant use of lumacaftor/ivacaftor 
with these antifungals is not 
recommended. Patients should be 
monitored closely for breakthrough fungal 
infections if such medicinal products are 
necessary. Lumacaftor/ivacaftor may 
decrease the exposures of these 
antifungals, which may reduce their 
efficacy. 



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Concomitant 
medicinal product 
class: 
Active substance name Effect Clinical comment 
 
fluconazole 

 
↔ LUM 
↑ IVA 
Due to inhibition of 
CYP3A by 
fluconazole 
 
↓ fluconazole 
Due to induction by 
LUM; fluconazole is 
cleared primarily by 
renal excretion as 
unchanged drug; 
however, modest 
reduction in 
fluconazole exposure 
has been observed 
with strong inducers 

 
No dose adjustment of 
lumacaftor/ivacaftor is recommended 
when co-administered with fluconazole. 
 
 
 
A higher dose of fluconazole may be 
required to obtain the desired clinical 
effect. Lumacaftor/ivacaftor may decrease 
the exposure of fluconazole, which may 
reduce its efficacy. 

Anti-inflammatories: 
ibuprofen 

 
↔ LUM, IVA 
 
↓ ibuprofen 
Due to induction of 
CYP3A/2C8/2C9 by 
LUM 

 
 
 
A higher dose of ibuprofen may be 
required to obtain the desired clinical 
effect. Lumacaftor/ivacaftor may decrease 
the exposure of ibuprofen, which may 
reduce its efficacy. 

Anti-mycobacterials: 
rifabutin, rifampicin*, 
rifapentine 

 
↔ LUM 
↓ IVA 
Due to induction of 
CYP3A by anti-
mycobacterials 
 
↓ rifabutin 
Due to induction of 
CYP3A by LUM 
 
 
 
 
 
 
 
 
 
↔ rifampicin, 
rifapentine 

 
 
 
 
 
 
 
Concomitant use of lumacaftor/ivacaftor 
with these anti-mycobacterials is not 
recommended. The exposure of ivacaftor 
will be decreased, which may reduce the 
efficacy of lumacaftor/ivacaftor. 
 
A higher dose of rifabutin may be required 
to obtain the desired clinical effect. 
Lumacaftor/ivacaftor may decrease the 
exposure of rifabutin, which may reduce 
its efficacy. 



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Concomitant 
medicinal product 
class: 
Active substance name Effect Clinical comment 
Benzodiazepines: 
midazolam, triazolam 

 
↔ LUM, IVA 
 
↓ midazolam, 
triazolam 
Due to induction of 
CYP3A by LUM 

 
 
 
Concomitant use of lumacaftor/ivacaftor 
with these benzodiazepines is not 
recommended. Lumacaftor/ivacaftor will 
decrease the exposures of midazolam and 
triazolam, which will reduce their efficacy. 

Hormonal 
contraceptives: 
ethinyl estradiol, 
norethindrone, and 
other progestogens 

 
↓ ethinyl estradiol, 
norethindrone, and 
other progestogens 
Due to induction of 
CYP3A/UGT by 
LUM 

 
Hormonal contraceptives, including oral, 
injectable, transdermal, and implantable, 
should not be relied upon as an effective 
method of contraception when 
co-administered with lumacaftor/ivacaftor. 
Lumacaftor/ivacaftor may decrease the 
exposure of hormonal contraceptives, 
which may reduce their efficacy. 

Immunosuppressants: 
ciclosporin, everolimus, 
sirolimus, tacrolimus 
(used after organ 
transplant) 

 
↔ LUM, IVA 
 
↓ ciclosporin, 
everolimus, sirolimus, 
tacrolimus 
Due to induction of 
CYP3A by LUM 

 
 
 
Concomitant use of lumacaftor/ivacaftor 
with these immunosuppressants is not 
recommended. Lumacaftor/ivacaftor will 
decrease the exposure of these 
immunosuppressants, which may reduce 
the efficacy of these immunosuppressants. 
The use of lumacaftor/ivacaftor in organ 
transplant patients has not been studied. 

Proton pump 
inhibitors: 
esomeprazole, 
lansoprazole, 
omeprazole 

 
↔ LUM, IVA 
 
↓ esomeprazole, 
lansoprazole, 
omeprazole 
Due to induction of 
CYP3A/2C19 by 
LUM 

 
 
 
A higher dose of these proton pump 
inhibitors may be required to obtain the 
desired clinical effect. 
Lumacaftor/ivacaftor may decrease the 
exposures of these proton pump inhibitors, 
which may reduce their efficacy. 

Herbals: 
St. John’s wort 
(Hypericum 
perforatum) 

 
↔ LUM 
↓ IVA 
Due to induction of 
CYP3A by St. John’s 
wort 

 
Concomitant use of lumacaftor/ivacaftor 
with St. John’s wort is not recommended. 
The exposure of ivacaftor will be 
decreased, which may reduce the efficacy 
of lumacaftor/ivacaftor. 

Other concomitant medicinal products of clinical relevance 
Antiarrhythmics: 
digoxin 

 
↔ LUM, IVA 
 
↑ or ↓ digoxin 
Due to potential 
induction or 
inhibition of P-gp 

 
 
 
The serum concentration of digoxin should 
be monitored and the dose should be 
titrated to obtain the desired clinical effect. 
Lumacaftor/ivacaftor may alter the 
exposure of digoxin. 



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Concomitant 
medicinal product 
class: 
Active substance name Effect Clinical comment 
Anticoagulants: 
dabigatran 
 
 

 
↔ LUM, IVA 
 
↑ or ↓ dabigatran 
Due to potential 
induction or 
inhibition of P-gp 

 
 
 
Appropriate clinical monitoring should be 
employed when co-administered with 
lumacaftor/ivacaftor. Dose adjustment of 
dabigatran may be required to obtain the 
desired clinical effect. 
Lumacaftor/ivacaftor may alter the 
exposure of dabigatran. 

 
warfarin 

 
↔ LUM, IVA 
 
↑ or ↓ warfarin 
Due to potential 
induction or 
inhibition of CYP2C9 
by LUM 

 
 
 
The international normalised ratio (INR) 
should be monitored when warfarin 
co-administration with 
lumacaftor/ivacaftor is required. 
Lumacaftor/ivacaftor may alter the 
exposure of warfarin. 

Antidepressants: 
citalopram, 
escitalopram, sertraline 

 
↔ LUM, IVA 
 
↓ citalopram, 
escitalopram, 
sertraline 
Due to induction of 
CYP3A/2C19 by 
LUM 

 
 
 
A higher dose of these antidepressants 
may be required to obtain the desired 
clinical effect. Lumacaftor/ivacaftor may 
decrease the exposures of these 
antidepressants, which may reduce their 
efficacy. 

 
bupropion 

 
↔ LUM, IVA 
 
↓ bupropion 
Due to induction of 
CYP2B6 by LUM 

 
 
 
A higher dose of bupropion may be 
required to obtain the desired clinical 
effect. Lumacaftor/ivacaftor may decrease 
the exposure of bupropion, which may 
reduce its efficacy. 

Corticosteroids, 
systemic: 
methylprednisolone, 
prednisone 

 
↔ LUM, IVA 
 
↓ methylprednisolone, 
prednisone 
Due to induction of 
CYP3A by LUM 

 
 
 
 
A higher dose of these systemic 
corticosteroids may be required to obtain 
the desired clinical effect. 
Lumacaftor/ivacaftor may decrease the 
exposures of methylprednisolone and 
prednisone, which may reduce their 
efficacy. 



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Concomitant 
medicinal product 
class: 
Active substance name Effect Clinical comment 
H2 blockers: 
ranitidine 

 
↔ LUM, IVA 
 
↑ or ↓ ranitidine 
Due to potential 
induction or 
inhibition of P-gp 

 
 
 
Dose adjustment of ranitidine may be 
required to obtain the desired clinical 
effect. Lumacaftor/ivacaftor may alter the 
exposure of ranitidine. 

Oral hypoglycemics: 
repaglinide 

 
↔ LUM, IVA 
 
↓ repaglinide 
Due to induction of 
CYP3A/2C8 by LUM 

 
 
 
A higher dose of repaglinide may be 
required to obtain the desired clinical 
effect. Lumacaftor/ivacaftor may decrease 
the exposure of repaglinide, which may 
reduce its efficacy. 

Note: ↑ = increase, ↓ = decrease, ↔ = no change; LUM = lumacaftor; IVA = ivacaftor. 
* Based on clinical interaction studies. All other interactions shown are predicted. 
 
False positive urine tests for THC 
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in 
patients receiving Orkambi. An alternative confirmatory method should be considered to verify results. 
 
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 
lumacaftor/ivacaftor in pregnant women. Animal studies with lumacaftor and ivacaftor do not indicate 
direct or indirect harmful effects with respect to developmental and reproductive toxicity, whereas 
effects were noted with ivacaftor only at maternally toxic doses (see section 5.3). As a precautionary 
measure, it is preferable to avoid the use of lumacaftor/ivacaftor during pregnancy unless the clinical 
condition of the mother requires treatment with lumacaftor/ivacaftor. 
 
Breast-feeding 
 
It is unknown whether lumacaftor and/or ivacaftor and metabolites are excreted in human milk. 
Available pharmacokinetic data in animals have shown excretion of both lumacaftor and ivacaftor into 
the milk of lactating female rats. As such, risks to the suckling child cannot be excluded. A decision 
must be made whether to discontinue breast-feeding or to discontinue/abstain from lumacaftor/ 
ivacaftor therapy taking into account the benefit of breast-feeding for the child and the benefit of 
therapy for the mother. 
 
Fertility 
 
No human data on the effects of lumacaftor and/or ivacaftor on fertility are available. Lumacaftor had 
no effects on fertility and reproductive performance indices in male and female rats. Ivacaftor impaired 
fertility and reproductive performance indices in male and female rats (see section 5.3). 
 



14 

4.7 Effects on ability to drive and use machines 
 
Ivacaftor, which is one of the active components of Orkambi, has a minor influence on the ability to 
drive and use machines. Ivacaftor may cause dizziness (see section 4.8). 
 
Patients experiencing dizziness while taking Orkambi 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 in Phase 3 clinical studies were dyspnoea (14.0% versus 7.8% on 
placebo), diarrhoea (11.0% versus 8.4% on placebo), and nausea (10.2% versus 7.6% on placebo). 
 
Serious adverse reactions included hepatobiliary events, e.g., transaminase elevations, cholestatic 
hepatitis and hepatic encephalopathy. 
 
Tabulated list of adverse reactions 
 
Adverse reactions identified from the 24-week, placebo-controlled, Phase 3 studies (trials 1 and 2) in 
patients aged 12 years and older and from a 24-week, placebo-controlled study in patients aged 6 to 
11 years (trial 7), who are homozygous for the F508del mutation in the CFTR gene are presented in 
Table 4 and are listed by system organ class and frequency. Adverse reactions observed with ivacaftor 
alone are also provided in Table 4. Adverse reactions are ranked under the MedDRA frequency 
classification: 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); and not known (frequency cannot be estimated 
using the available data). 
 



15 

Table 4: Adverse reactions in lumacaftor/ivacaftor-treated patients and in patients treated with 
ivacaftor alone 

System organ class Frequency Adverse reactions 
Infections and infestations very common Nasopharyngitis* 

common Upper respiratory tract infection, rhinitis 
Vascular disorders uncommon Hypertension 
Nervous system disorders very common Headache, dizziness* 

uncommon Hepatic encephalopathy† 
Ear and labyrinth disorders common Ear pain*, ear discomfort*, tinnitus*, tympanic 

membrane hyperaemia*, vestibular disorder* 
uncommon Ear congestion* 

Respiratory, thoracic and 
mediastinal disorders 

very common Nasal congestion, dyspnoea, productive cough, 
sputum increased 

common Respiration abnormal, oropharyngeal pain, 
sinus congestion*, rhinorrhoea, pharyngeal 
erythema*, bronchospasm 

Gastrointestinal disorders very common Abdominal pain*, abdominal pain upper, 
diarrhoea, nausea 

common Flatulence, vomiting 
Hepatobiliary disorders common Transaminase elevations 

uncommon Cholestatic hepatitis‡ 
Skin and subcutaneous tissue 
disorders 

common Rash 

Reproductive system and 
breast disorders 

common Menstruation irregular, dysmenorrhoea, 
metrorrhagia, breast mass* 

uncommon Menorrhagia, amenorrhoea, polymenorrhoea, 
breast inflammation*, gynaecomastia*, nipple 
disorder*, nipple pain*, oligomenorrhoea 

Investigations very common Bacteria in sputum* 
common Blood creatine phosphokinase increased 
uncommon Blood pressure increased 

* Adverse reactions and frequencies observed in patients in clinical studies with ivacaftor monotherapy 
† 1 patient out of 738 
‡ 2 patients out of 738 
 
The safety data from 1,029 patients aged 12 years and older who were homozygous for the F508del 
mutation in the CFTR gene treated with lumacaftor/ivacaftor for up to an additional 96 weeks in the 
long-term safety and efficacy rollover study (trial 3) were similar to the 24-week, placebo-controlled 
studies (see section 5.1). 
 
Description of selected adverse reactions 
 
Hepatobiliary adverse reactions 
During trials 1 and 2, the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and 
> 3 x ULN was 0.8%, 2.0%, and 5.2%; and 0.5%, 1.9%, and 5.1% in lumacaftor/ivacaftor- and 
placebo-treated patients, respectively. The incidence of transaminase-related adverse reactions was 
5.1% and 4.6% in lumacaftor/ivacaftor-treated patients and those who received placebo, respectively. 
Seven patients who received lumacaftor/ivacaftor had liver-related serious adverse reactions with 
elevated transaminases, including 3 with concurrent elevation in total bilirubin. Following 
discontinuation of lumacaftor/ivacaftor, liver function tests returned to baseline or improved 
substantially in all patients (see section 4.4). 



16 

 
Among 7 patients with pre-existing cirrhosis and/or portal hypertension who received 
lumacaftor/ivacaftor in the placebo-controlled, Phase 3 studies, worsening liver function with 
increased ALT, AST, bilirubin, and hepatic encephalopathy was observed in one patient. The event 
occurred within 5 days of the start of dosing and resolved following discontinuation of 
lumacaftor/ivacaftor (see section 4.4). 
 
Post–marketing cases of liver function decompensation including liver failure leading to death have 
been reported in CF patients with pre-existing cirrhosis with portal hypertension who were treated with 
lumacaftor/ivacaftor (see section 4.4). 
 
Respiratory adverse reactions 
During trials 1 and 2, the incidence of respiratory adverse reactions (e.g., chest discomfort, dyspnoea, 
bronchospasm, and respiration abnormal) was 26.3% in lumacaftor/ivacaftor-treated patients compared 
to 17.0% in patients who received placebo. The incidence of these adverse reactions was more 
common in patients with lower pre-treatment FEV1. Approximately three-quarters of the events began 
during the first week of treatment, and in most patients the events resolved without dosing 
interruption. The majority of adverse reactions were mild or moderate in severity, non-serious and did 
not result in treatment discontinuation (see section 4.4). 
 
During a 24-week, open label, Phase 3b clinical study (trial 5) in 46 patients aged 12 years and older 
with advanced lung disease (ppFEV1 < 40) [mean ppFEV1 29.1 at baseline (range: 18.3 to 42.0)], the 
incidence of respiratory adverse reactions was 65.2%. In the subgroup of 28 patients who were 
initiated at the full dose of lumacaftor/ivacaftor (2 tablets every 12 hours), the incidence was 71.4%, 
and in the 18 patients who were initiated at a reduced dose of lumacaftor/ivacaftor (1 tablet every 12 
hours for up to 2 weeks, and subsequently increased to the full dose), the incidence was 55.6%. Of the 
patients who were initiated lumacaftor/ivacaftor at the full dose, one patient had a serious respiratory 
adverse reaction, three patients subsequently had their dose reduced, and three patients discontinued 
treatment. No serious respiratory adverse reactions, dose reductions or discontinuations were seen in 
patients who were initiated at the half dose (see section 4.4). 
 
Menstrual abnormalities 
During trials 1 and 2, the incidence of combined menstrual abnormalities (amenorrhoea, 
dysmenorrhoea, menorrhagia, menstruation irregular, metrorrhagia, oligomenorrhoea, and 
polymenorrhoea) was 9.9 % in lumacaftor/ivacaftor-treated female patients and 1.7% in 
placebo-treated females. These menstrual events occurred more frequently in the subset of female 
patients who were taking hormonal contraceptives (25.0%) versus patients who were not taking 
hormonal contraceptives (3.5%) (see section 4.5). Most of these reactions were mild or moderate in 
severity and non-serious. In lumacaftor/ivacaftor-treated patients, approximately two-thirds of these 
reactions resolved, and the median duration was 10 days. 
 
Increased blood pressure 
During trials 1 and 2, adverse reactions related to increased blood pressure (e.g., hypertension, blood 
pressure increased) were reported in 0.9% (7/738) of patients treated with lumacaftor/ivacaftor and in 
no patients who received placebo. 
 
In patients treated with lumacaftor/ivacaftor (mean baseline 114 mmHg systolic and 69 mmHg 
diastolic), the maximum increase from baseline in mean systolic and diastolic blood pressure was 
3.1 mmHg and 1.8 mmHg, respectively. In patients who received placebo (mean baseline 114 mmHg 
systolic and 69 mmHg diastolic), the maximum increase from baseline in mean systolic and diastolic 
blood pressure was 0.9 mmHg and 0.9 mmHg, respectively. 
 
The proportion of patients who experienced a systolic blood pressure value > 140 mmHg or a diastolic 
blood pressure > 90 mmHg on at least two occasions was 3.4% and 1.5% in patients treated with 
lumacaftor/ivacaftor, respectively, compared with 1.6% and 0.5% in patients who received placebo 
(see section 4.4). 
 



17 

Paediatric population 
 
Safety data were evaluated in 60 patients aged 2 to 5 years (trial 8), 161 patients aged 6 to 11 years 
(trials 6 and 7) and in 194 patients aged 12 to 17 years with CF who are homozygous for the F508del 
mutation and who received lumacaftor/ivacaftor in clinical studies. Patients aged 12 to 17 years were 
included in trials 1 and 2. 
The safety profile in these paediatric patients is generally consistent with that in adult patients.  
 
Long-term safety data from a 96-week rollover extension study in 57 patients aged 2 years and older 
who were homozygous for the F508del mutation in the CFTR gene were generally consistent with the 
24-week parent study in patients aged 2 to 5 years (trial 8) and safety data in patients aged 6 to 
11 years. 
 
Long-term safety data from a 96-week rollover extension study in 239 patients aged 6 years and older 
who were homozygous for the F508del mutation in the CFTR gene (trial 9) were generally consistent 
with the 24-week parent studies in patients aged 6 to 11 years (trial 6 and trial 7). 
 
Description of selected adverse reactions for patients aged 6 to 11 years 
Hepatobiliary adverse reactions 
During the 24-week, open-label Phase 3 clinical study in 58 patients aged 6 to 11 years (trial 6), the 
incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and >3 x ULN was 5.3%, 8.8%, 
and 19.3%. No patients had total bilirubin levels > 2 x ULN. Lumacaftor/ivacaftor dosing was 
maintained or successfully resumed after interruption in all patients with transaminase elevations, 
except 1 patient who discontinued treatment permanently. 
 
During the 24-week, placebo-controlled Phase 3 clinical study in 204 patients aged 6 to 11 years 
(trial 7), the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and > 3 x ULN was 
1.0%, 4.9%, and 12.6% in the lumacaftor/ivacaftor patients, and 2.0%, 3.0%, and 7.9% in the 
placebo-treated patients. No patients had total bilirubin levels > 2 x ULN. Two patients in the 
lumacaftor/ivacaftor group and two patients in the placebo group discontinued treatment permanently 
due to transaminase elevations. 
 
Respiratory adverse reactions 
During the 24-week, open-label Phase 3 clinical study (trial 6) in 58 patients aged 6 to 11 years (mean 
baseline ppFEV1 was 91.4), the incidence of respiratory adverse reactions was 6.9% (4/58). 
 
During the 24-week, placebo-controlled Phase 3 clinical study (trial 7) in patients aged 6 to 11 years 
(mean baseline ppFEV1 was 89.8), the incidence of respiratory adverse reactions was 18.4% in 
lumacaftor/ivacaftor patients and 12.9% in placebo patients. A decline in ppFEV1 at initiation of 
therapy was observed during serial post dose spirometry assessments. The absolute change from pre-
dose at 4-6 hours post-dose was -7.7 on day 1 and -1.3 on day 15 in lumacaftor/ivacaftor patients. The 
post-dose decline was resolved by week 16. 
 
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 
 
No specific antidote is available for overdose with lumacaftor/ivacaftor. Treatment of overdose 
consists of general supportive measures including monitoring of vital signs and observation of the 
clinical status of the patient. 
 

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


18 

Adverse reactions that occurred at an increased incidence of ≥ 5% in the supratherapeutic dose period 
compared with the therapeutic dose period were headache, generalised rash, and increased 
transaminase. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other respiratory system products; ATC code: R07AX30 
 
Mechanism of action 
 
The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. 
The F508del mutation impacts the CFTR protein in multiple ways, primarily by causing a defect in 
cellular processing and trafficking that reduces the quantity of CFTR at the cell surface. The small 
amount of F508del-CFTR that reaches the cell surface has low channel-open probability (defective 
channel gating). Lumacaftor is a CFTR corrector that acts directly on F508del-CFTR to improve its 
cellular processing and trafficking, thereby increasing the quantity of functional CFTR at the cell 
surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the 
channel-open probability (or gating) of the CFTR protein at the cell surface. The combined effect of 
lumacaftor and ivacaftor is increased quantity and function of F508del-CFTR at the cell surface, 
resulting in increased chloride ion transport. The exact mechanisms by which lumacaftor improves 
cellular processing and trafficking of F508del-CFTR and ivacaftor potentiates F508del-CFTR are not 
known. 
 
Pharmacodynamic effects 
 
Effects on sweat chloride 
Changes in sweat chloride in response to lumacaftor alone or in combination with ivacaftor were 
evaluated in a double-blind, placebo-controlled, Phase 2 clinical trial in patients with CF aged 18 years 
and older. In this trial, 10 patients (homozygous for F508del-CFTR mutation) completed dosing with 
lumacaftor alone 400 mg q12h for 28 days followed by the addition of ivacaftor 250 mg q12h for an 
additional 28 days, and 25 patients (homozygous or heterozygous for F508del) completed dosing with 
placebo. The treatment difference between lumacaftor 400 mg q12h alone and placebo evaluated as 
mean change in sweat chloride from baseline to day 28 was statistically significant at -8.2 mmol/L 
(95% CI: -14, -2). The treatment difference between the combination of lumacaftor 400 mg/ivacaftor 
250 mg q12h and placebo evaluated as mean change in sweat chloride from baseline to day 56 was 
statistically significant at -11 mmol/L (95% CI: -18, -4). 
 
In trial 7 (see Clinical efficacy and safety) in patients homozygous for the F508del-CFTR mutation 
aged 6 to 11 years, the treatment difference (LS mean) in sweat chloride for the absolute change at 
week 24 as compared to placebo was -24.9 mmol/L (nominal P < 0.0001). The treatment difference 
(LS mean) in sweat chloride for the average absolute change at day 15 and at week 4 as compared to 
placebo was -20.8 mmol/L (95% CI: -23.4, -18.2; nominal P < 0.0001). 
 
Changes in FEV1 
Changes in ppFEV1 in response to lumacaftor alone or in combination with ivacaftor were also 
evaluated in the double-blind, placebo-controlled, Phase 2 trial in patients with CF aged 18 years and 
older. The treatment difference between lumacaftor 400 mg q12h alone and placebo evaluated as mean 
absolute change in ppFEV1 was -4.6 percentage points (95% CI: -9.6, 0.4) from baseline to day 28, 4.2 
percentage points (95% CI: –1.3, 9.7) from baseline to day 56, and 7.7 percentage points (95% CI: 2.6, 
12.8; statistically significant) from day 28 to day 56 (following the addition of ivacaftor to lumacaftor 
monotherapy). 
 
Decrease in heart rate 



19 

During the 24-week, placebo-controlled, Phase 3 studies, a maximum decrease in mean heart rate of 
6 beats per minute (bpm) from baseline was observed on day 1 and day 15 around 4 to 6 hours after 
dosing. After day 15, heart rate was not monitored in the period after dosing in these studies. From 
week 4, the change in mean heart rate at pre-dose ranged from 1 to 2 bpm below baseline among 
patients treated with lumacaftor/ivacaftor. The percentage of patients with heart rate values < 50 bpm 
on treatment was 11% for patients who received lumacaftor/ivacaftor, compared to 4.9% for patients 
who received placebo. 
 
Cardiac electrophysiology 
No meaningful changes in QTc interval or blood pressure were observed in a thorough QT clinical 
study evaluating lumacaftor 600 mg once daily/ivacaftor 250 mg q12h and lumacaftor 1000 mg once 
daily/ivacaftor 450 mg q12h. 
 
Clinical efficacy and safety 
 
Trials in patients with CF aged 12 years and above who are homozygous for the F508del mutation in 
the CFTR gene 
The efficacy of lumacaftor/ivacaftor in patients with CF who are homozygous for the F508del 
mutation in the CFTR gene was evaluated in two randomised, double-blind, placebo-controlled clinical 
trials of 1,108 clinically stable patients with CF, in which 737 patients were randomised to and dosed 
with lumacaftor/ivacaftor. Patients in both trials were randomised 1:1:1 to receive lumacaftor 600 mg 
once daily/ivacaftor 250 mg q12h, lumacaftor 400 mg q12h/ivacaftor 250 mg q12h, or placebo. 
Patients took the study drug with fat-containing food for 24 weeks in addition to their prescribed CF 
therapies (e.g., bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). Patients from 
these trials were eligible to roll over into a blinded extension study. 
 
Trial 1 evaluated 549 patients with CF who were aged 12 years and older (mean age 25.1 years) with 
percent predicted FEV1 (ppFEV1) at screening between 40-90 (mean ppFEV1 60.7 at baseline [range: 
31.1 to 94.0]). Trial 2 evaluated 559 patients aged 12 years and older (mean age 25.0 years) with 
ppFEV1 at screening between 40-90 (mean ppFEV1 60.5 at baseline [range: 31.3 to 99.8]). Patients 
with a history of colonisation with organisms such as Burkholderia cenocepacia, Burkholderia dolosa, 
or Mycobacterium abscessus or who had 3 or more abnormal liver function tests (ALT, AST, AP, 
GGT ≥ 3 times the ULN or total bilirubin ≥ 2 times the ULN) were excluded. 
 
The primary efficacy endpoint in both studies was the absolute change from baseline in ppFEV1 at 
week 24. Other efficacy variables included relative change from baseline in ppFEV1, absolute change 
from baseline in BMI, absolute change from baseline in CFQ-R Respiratory Domain, the proportion of 
patients achieving ≥ 5% relative change from baseline in ppFEV1 at week 24, and the number of 
pulmonary exacerbations (including those requiring hospitalisation or IV antibiotic therapy) through 
week 24. 
 
In both trials, treatment with lumacaftor/ivacaftor resulted in a statistically significant improvement in 
ppFEV1 (Table 5). Mean improvement in ppFEV1 was rapid in onset (day 15) and sustained 
throughout the 24-week treatment period. At day 15, the treatment difference between lumacaftor 
400 mg/ivacaftor 250 mg q12h and placebo for the mean absolute change (95% CI) in ppFEV1 from 
baseline was 2.51 percentage points in the pooled trials 1 and 2 (P < 0.0001). Improvements in 
ppFEV1 were observed regardless of age, disease severity, sex and geographic region. The Phase 3 
trials of lumacaftor/ivacaftor included 81 patients with ppFEV1 < 40 at baseline. The treatment 
difference in this subgroup was comparable to that observed in patients with ppFEV1 ≥ 40. At 
week-24, the treatment difference between lumacaftor 400 mg/ivacaftor 250 mg q12h and placebo for 
the mean absolute change (95% CI) in ppFEV1 from baseline in the pooled trials 1 and 2 were 3.39 
percentage points (P = 0.0382) for patients with ppFEV1 < 40 and 2.47 percentage points (P < 0.0001) 
for patients with ppFEV1 ≥ 40. 
 



20 

Table 5: Summary of primary and key secondary outcomes in trial 1 and trial 2* 
 Trial 1 Trial 2 Pooled (trial 1 and trial 2) 

Placebo 
(n = 184) 

LUM 400 mg 
q12h/ IVA 

250 mg q12h 
(n = 182) 

Placebo 
(n = 187) 

LUM 400 mg 
q12h/IVA 

250 mg q12h 
(n = 187) 

Placebo 
(n = 371) 

LUM 400 mg 
q12h/IVA 

250 mg q12h 
(n = 369) 

Absolute change in 
ppFEV1 at week 24 
(percentage points) 

Treatment 
difference – 

2.41 
(P = 0.0003) † – 

2.65 
(P = 0.0011) † – 

2.55 
(P < 0.0001) 

Within-group 
change 

-0.73 
(P = 0.2168) 

1.68 
(P = 0.0051) 

-0.02 
(P = 0.9730) 

2.63 
(P < 0.0001) 

-0.39 
(P < 0.3494) 

2.16 
(P < 0.0001) 

Relative change in 
ppFEV1 at week 24 
(%) 

Treatment 
difference – 

4.15 
(P = 0.0028)† – 

4.69 
( P =0.0009)† – 

4.4 
(P < 0.0001) 

Within-group 
change 

-0.85 
(P = 0.3934) 

3.3 
(P = 0.0011) 

0.16 
(P = 0.8793) 

4.85 
(P < 0.0001) 

-0.34 
(P = 0.6375) 

4.1 
(P < 0.0001) 

Absolute change in 
BMI at week 24 
(kg/m2) 

Treatment 
difference – 

0.13 
(P = 0.1938) – 

0.36 
(P < 0.0001)† – 

0.24 
(P = 0.0004) 

Within-group 
change 

0.19 
(P = 0.0065) 

0.32 
(P < 0.0001) 

0.07 
(P = 0.2892) 

0.43 
(P < 0.0001) 

0.13 
(P = 0.0066) 

0.37 
(P < 0.0001) 

Absolute change in 
CFQ-R 
Respiratory 
Domain Score at 
week 24 (points) 

Treatment 
difference – 

1.5 
(P = 0.3569) – 

2.9 
(P = 0.0736) – 

2.2 
(P = 0.0512) 

Within-group 
change 

1.1 
(P = 0.3423) 

2.6 
(P = 0.0295) 

2.8 
(P = 0.0152) 

5.7 
(P < 0.0001) 

1.9 
(P = 0.0213) 

4.1 
(P < 0.0001) 

Proportion of 
patients with ≥5% 
relative change in 
ppFEV1 at week 24 

% 25% 32% 26% 41% 26% 37% 

Odds ratio – 1.43 (P = 0.1208) – 
1.90 

(P = 0.0032) – 
1.66 

(P = 0.0013) 

Number of 
pulmonary 
exacerbations 
through week 24 

# of events 
(rate per 48 

wks) 
112 (1.07) 73 (0.71) 139 (1.18) 79 (0.67) 251 (1.14) 152 (0.70) 

Rate ratio – 0.66 (P = 0.0169) – 
0.57 

(P = 0.0002) – 
0.61 

(P < 0.0001) 

* In each study, a hierarchical testing procedure was performed within each active treatment arm for primary and secondary 
endpoints vs. placebo; at each step, P ≤ 0.0250 and all previous tests also meeting this level of significance was required for 
statistical significance. 

† Indicates statistical significance confirmed in the hierarchical testing procedure. 
 
At week 24, the proportion of patients who remained free from pulmonary exacerbations was 
significantly higher for patients treated with lumacaftor/ivacaftor compared with placebo. In the 
pooled analysis, the rate ratio of exacerbations through week 24 in subjects treated with 
lumacaftor/ivacaftor (lumacaftor 400 mg/ivacaftor 250 mg q12h; n = 369) was 0.61 (P < 0.0001), 
representing a reduction of 39% relative to placebo. The event rate per year, annualised to 48 weeks, 
was 0.70 in the lumacaftor/ivacaftor group and 1.14 in the placebo group. Treatment with 
lumacaftor/ivacaftor significantly decreased the risk for exacerbations requiring hospitalisation versus 
placebo by 61% (rate ratio=0.39, P < 0.0001; event rate per 48 weeks 0.17 for lumacaftor/ivacaftor and 
0.45 for placebo) and reduced exacerbations requiring treatment with intravenous antibiotics by 56% 
(rate ratio = 0.44, P < 0.0001; event rate per 48 weeks 0.25 for lumacaftor/ivacaftor and 0.58 for 
placebo). These results were not considered statistically significant within the framework of the testing 
hierarchy for the individual studies. 
 
Long-term safety and efficacy rollover trial 
Trial 3 was a Phase 3, parallel-group, multicentre, rollover extension study in patients with CF that 
included patients aged 12 years and older from trial 1 and trial 2. This extension trial was designed to 
evaluate the safety and efficacy of long-term treatment of lumacaftor/ivacaftor. Of the 1,108 patients 
who received any treatment in trial 1 or trial 2, 1,029 (93%) were dosed and received active treatment 
(lumacaftor 600 mg once daily/ivacaftor 250 mg q12h or lumacaftor 400 mg q12h/ivacaftor 
250 mg q12h) in trial 3 for up to an additional 96 weeks (i.e., up to a total of 120 weeks). The primary 



21 

efficacy analysis of this extension study included data up to week 72 of trial 3 with a sensitivity 
analysis that included data up to week 96 of trial 3.  
 
Patients treated with lumacaftor/ivacaftor in trial 1 or trial 2 showed an effect that was maintained with 
respect to baseline after an additional 96 weeks through trial 3. For patients who transitioned from 
placebo to active treatment similar changes as those observed in patients treated with 
lumacaftor/ivacaftor in trial 1 or trial 2 were seen (see Table 5). Results from trial 3 are presented in 
Figure 1 and Table 6. 
 
Figure 1. Absolute change from baseline in percent predicted FEV1 at each visit† 
 

 
† From trials 1, 2 and 3. 
 

 
 
 
 
Table 6: Long-term effect of lumacaftor/ivacaftor in trial 3* 
 
 Placebo transitioned to  

Lumacaftor 400 mg q12h/ 
Ivacaftor 250 mg q12h  

(n = 176)** 

Lumacaftor 400 mg q12h/ 
Ivacaftor 250 mg q12h  

(n = 369)† 

Baseline and endpoint Mean (SD) 
LS Means 
(95% CI) P value Mean (SD) 

LS Means 
(95% CI) P value 

Baseline ppFEV1‡ 60.2 (14.7)   60.5 (14.1)   
Absolute change from baseline ppFEV1 (percentage points) 
 
Extension week 72  

 (n = 134) 
1.5  

(0.2, 2.9) 
 

(n = 75) 

 
0.0254 

 (n = 273) 
0.5  

(-0.4, 1.5) 
 

(n = 147) 

 
0.2806 

Extension week 96   0.8  
(-0.8, 2.3) 

 

0.3495  0.5  
(-0.7, 1.6) 

 

0.4231 

Relative change from baseline ppFEV1 (%)  
 
Extension week 72  

 (n = 134) 
2.6 

 (0.2, 5.0) 
 

(n = 75) 

 
0.0332 

 (n = 273) 
1.4  

(-0.3, 3.2) 
 

(n = 147) 

 
0.1074 

Extension week 96   1.1  
(-1.7, 3.9) 

 

0.4415  1.2  
(-0.8, 3.3) 

 

0.2372 

Baseline BMI (kg/m2)‡ 20.9 (2.8)   21.5 (3.0)   



22 

* A total of 82% (421 of 516 eligible patients) completed 72 weeks of this study; 42% completed 96 weeks. Majority of 
patients discontinued for reasons other than safety. 

** For patients rolled over from trials 1 and 2 (placebo-to-lumacaftor/ivacaftor group) total exposure was up to 96 weeks. 
Presentation of the lumacaftor 400 mg q12h/ivacaftor 250 mg q12h dose group is consistent with recommended posology. 

*** The event rate per patient-year was annualised to 48 weeks. 
† For patients rolled over from trials 1 and 2 (lumacaftor/ivacaftor-to-lumacaftor/ivacaftor group) total exposure was up to 

120 weeks. Presentation of the lumacaftor 400 mg q12h/ivacaftor 250 mg q12h dose group is consistent with 
recommended posology. 

‡ Baseline for the placebo transitioned to lumacaftor 400 mg q12h/ivacaftor 250 mg q12h group was the trial 3 baseline. 
Baseline for the lumacaftor 400 mg q12h/ivacaftor 250 mg q12h group was the trial 1 and 2 baseline. 

 
Trial in patients with CF who are heterozygous for the F508del mutation in the CFTR gene 
Trial 4 was a multicentre, double–blind, randomised, placebo–controlled, Phase 2 trial in 125 patients 
with CF aged 18 years and older who had a ppFEV1 of 40 to 90, inclusive, and have the F508del 
mutation on one allele plus a second allele with a mutation predicted to result in the lack of CFTR 
production or a CFTR that is not responsive to ivacaftor in vitro. 
 
Patients received either lumacaftor/ivacaftor (n = 62) or placebo (n = 63) in addition to their prescribed 
CF therapies. The primary endpoint was improvement in lung function as determined by the mean 
absolute change from baseline at day 56 in ppFEV1. Treatment with lumacaftor/ivacaftor resulted in no 
significant improvement in ppFEV1 relative to placebo in patients with CF heterozygous for the 
F508del mutation in the CFTR gene (treatment difference 0.60 [P = 0.5978]) and no meaningful 
improvements in BMI or weight (see section 4.4). 
 
Trials in patients with CF aged 6 to 11 years old who are homozygous for the F508del mutation in the 
CFTR gene 
Trial 7 was a 24-week, placebo-controlled, Phase 3 clinical study in 204 patients with CF aged 6 to 
11 years old (mean age 8.8 years). Trial 7 evaluated subjects with lung clearance index (LCI2.5) ≥ 7.5 

Absolute change from baseline in BMI (kg/m2) 
 
Extension week 72  

 (n = 145) 
0.62  

(0.45, 0.79) 
 

(n = 80) 

 
< 0.0001 

 (n = 289) 
0.69  

(0.56, 0.81) 
 

(n = 155) 

 
< 0.0001 

Extension week 96   0.76  
(0.56, 0.97) 

 

< 0.0001  0.96  
(0.81, 1.11) 

 

< 0.0001 

Baseline CFQ-R 
Respiratory Domain Score 
(points)‡ 

70.4 (18.5)   68.3 (18.0)   

Absolute change in CFQ-R Respiratory Domain Score (points) 
 
 
Extension week 72  

 (n = 135) 
3.3  

(0.7, 5.9) 
 

(n = 81) 

 
0.0124 

 (n = 269) 
5.7  

(3.8, 7.5) 
 

(n = 165) 

 
< 0.0001 

Extension week 96   0.5  
(-2.7, 3.6) 

 

0.7665  3.5  
(1.3, 5.8) 

 

0.0018 

Number of Pulmonary exacerbations (events) ** † *** 

 
Number of events per 
patient- year (95% CI) (rate 
per 48 wks) 
 
Number of events requiring 
hospitalization per patient-
year (95% CI) (rate per 48 
wks) 
 
Number of events requiring 
intravenous antibiotics per 
patient-year (95% CI) (rate 
per 48 wks) 

  
0.69 

(0.56, 0.85) 
 
 

0.30 
(0.22, 0.40) 

 
 
 

0.37 
(0.29, 0.49) 

   
0.65 

(0.56, 0.75) 
 
 

0.24 
(0.19, 0.29) 

 
 
 

0.32 
(0.26, 0.38) 

 



23 

at the initial screening visit (mean LCI2.5 10.28 at baseline [range: 6.55 to 16.38]) and ppFEV1 ≥ 70 at 
screening (mean ppFEV1 89.8 at baseline [range: 48.6 to 119.6]). Patients received either lumacaftor 
200 mg/ivacaftor 250 mg every 12 hours (n = 103) or placebo (n = 101) in addition to their prescribed 
CF therapies. Patients who had 2 or more abnormal liver function tests (ALT, AST, AP, 
GGT ≥ 3 times the ULN), or ALT or AST > 5 times ULN, or total bilirubin > 2 times ULN were 
excluded. 
 
The primary efficacy endpoint was absolute change in LCI2.5 from baseline through week 24. Key 
secondary endpoints included average absolute change from baseline in sweat chloride at day 15 and 
week 4 and at week 24 (see Pharmacodynamic effects), absolute change from baseline in BMI at 
week 24, absolute change from baseline in CFQ-R Respiratory Domain through week 24. These 
results are presented in Table 7 below: 
 
Table 7: Summary of primary and key secondary outcomes in trial 7 

 

Placebo 
(n = 101) 

LUM 200 mg/IVA 
250 mg q12h 

(n = 103) 
Primary endpoint 

Absolute change in lung 
clearance index (LCI2.5) from 
baseline through week 24 

Treatment difference – -1.09 (P < 0.0001) 

Within-group change 0.08 (P = 0.5390) -1.01 (P < 0.0001) 

Key Secondary Endpoints* 

Absolute change in BMI at 
week 24 (kg/m2) 

Treatment difference – 0.11 (P = 0.2522) 

Within-group change 0.27 (P = 0.0002) 
0.38 

(P < 0.0001) 

Absolute change in CFQ-R 
Respiratory Domain Score 
through week 24 (points) 

Treatment difference – 2.5 (P = 0.0628) 

Within-group change 3.0 (P = 0.0035) 
5.5 

(P < 0.0001) 
* Trial included key secondary and other secondary endpoints. 
 
Percent predicted FEV1 was also evaluated as a clinically meaningful other secondary endpoint. In the 
lumacaftor/ivacaftor patients, the treatment difference for absolute change in ppFEV1 from baseline 
through week 24 was 2.4 (P = 0.0182). 
 
Patients with CF aged 6 years and older from trial 6 and trial 7 were included in a phase 3, multicentre, 
rollover extension study (trial 9). This extension trial was designed to evaluate the safety and efficacy 
of long-term treatment of lumacaftor/ivacaftor. Of the 262 patients who received any treatment in 
trial 6 or trial 7, 239 (91%) were dosed and received active treatment (patients 6 to <12 years of age 
received lumacaftor 200 mg q12h/ivacaftor 250 mg q12h; patients ≥12 years of age received 
lumacaftor 400 mg q12h/ivacaftor 250 mg q12h) in the extension study for up to an additional 
96 weeks (i.e., up to a total of 120 weeks) (see section 4.8). Secondary efficacy results and pulmonary 
exacerbation event rate per patient year are presented in Table 8. 
 



24 

 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Orkambi in one or more subsets of the paediatric population in cystic fibrosis (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The exposure (AUC) of lumacaftor is approximately 2-fold higher in healthy adult volunteers 
compared to exposure in patients with CF. The exposure of ivacaftor is similar between healthy adult 
volunteers and patients with CF. After twice-daily dosing, steady-state plasma concentrations of 
lumacaftor and ivacaftor in healthy subjects were generally reached after approximately 7 days of 
treatment, with an accumulation ratio of approximately 1.9 for lumacaftor. The steady-state exposure 

Table 8: Long-term effect of lumacaftor/ivacaftor in trial 9 
 
 Placebo transitioned to  

lumacaftor / ivacaftor  
(P-L/I) 

(n = 96)* 

Lumacaftor / ivacaftor –  
lumacaftor / ivacaftor   

(L/I-L/I) 
(n = 143)* 

Baseline and endpoint Mean (SD) 
LS Mean 
(95% CI) Mean (SD) 

LS Mean 
(95% CI) 

 n = 101  n = 128  
Baseline LCI2.5‡** 10.26 (2.24)  10.24 (2.42)  
Absolute change from baseline in LCI2.5  

 
Extension week 96 

 (n = 69) 
-0.86 

(-1.33, -0.38) 
 

 (n = 88) 
-0.85 

(-1.25, -0.45) 
  

 n = 101  n = 161  
Baseline BMI (kg/m2)‡ 16.55 (1.96)  16.56 (1.77)  
Absolute change from baseline in BMI (kg/m2) 

 
Extension week 96  

 (n = 83) 
2.04  

(1.77, 2.31)  
 

 (n =130) 
1.78  

(1.56, 1.99) 
 

 n = 78  n = 135  
Baseline CFQ-R‡ 
Respiratory Domain Score 
(points) 

77.1  
(15.5) 

 78.5  
(14.3) 

 

Absolute change in CFQ-R Respiratory Domain Score (points) 

 
Extension week 96  

 (n = 65) 
6.6  

(3.1, 10.0) 
 

 (n = 108) 
7.4 

(4.8, 10.0) 
 

Number of pulmonary exacerbations (events) (trial 7 FAS and ROS)† 

 
Number of events per 
patient- year (95% CI)  
 

 n = 96 
0.30 

(0.21, 0.43) 
 

 n = 103 
0.45 

(0.33, 0.61) 
 

*Subjects treated with placebo in trial 7 (n=96) and transitioned onto active LUM/IVA treatment in the extension study 
(P-L/I). Subjects treated with LUM/IVA in either parent study [trial 6 (n=49) or trial 7 (n=94)] and continued active 
LUM/IVA treatment in the extension (L/I-L/I).  
‡Baseline for both groups (P-L/I and L/I-L/I) was the trial 6 and trial 7 (parent study) baseline and the corresponding n 
refers to the analysis set in the parent study. 
**The LCI sub-study included 117 subjects in the L/I-L/I group and 96 subjects in the P-L/I group. 
†FAS = full analysis set (n=103) includes subjects who received L/I in trial 7 and in trial 9, assessed over the 
cumulative study period for L/I; ROS = rollover set (n=96) includes subjects who received placebo in trial 7 and L/I in 
trial 9, assessed over the current study period in for trial 9.  



25 

of ivacaftor is lower than that of day 1 due to the CYP3A induction effect of lumacaftor (see 
section 4.5). 
 
After oral administration of lumacaftor 400 mg q12h/ivacaftor 250 mg q12h in a fed state, the 
steady-state mean (± SD) for AUC0-12h and Cmax were 198 (64.8) µg∙h/mL and 25.0 (7.96) µg/mL for 
lumacaftor, respectively, and 3.66 (2.25) µg∙h/mL and 0.602 (0.304) µg/mL for ivacaftor, respectively. 
After oral administration of ivacaftor alone as 150 mg q12h in a fed state, the steady-state mean (± SD) 
for AUC0-12h and Cmax were 9.08 (3.20) µg∙h/mL and 1.12 (0.319) µg/mL, respectively. 
 
Absorption 
 
Following multiple oral doses of lumacaftor, the exposure of lumacaftor generally increased 
proportional to dose over the range of 50 mg to 1000 mg every 24 hours. The exposure of lumacaftor 
increased approximately 2.0-fold when given with fat-containing food relative to fasted conditions. 
The median (range) tmax of lumacaftor is approximately 4.0 hours (2.0; 9.0) in the fed state. 
 
Following multiple oral dose administration of ivacaftor in combination with lumacaftor, the exposure 
of ivacaftor generally increased with dose from 150 mg every 12 hours to 250 mg every 12 hours. The 
exposure of ivacaftor when given in combination with lumacaftor increased approximately 3-fold 
when given with fat-containing food in healthy volunteers. Therefore, lumacaftor/ivacaftor should be 
administered with fat-containing food. The median (range) tmax of ivacaftor is approximately 4.0 hours 
(2.0; 6.0) in the fed state. 
 
Distribution 
 
Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin. After oral 
administration of 400 mg every 12 hours in patients with CF in a fed state, the typical apparent 
volumes of distribution for the central and peripheral compartments [coefficient of variation as a 
percentage (CV)] were estimated to be 23.5 L (48.7%) and 33.3 L (30.5%), respectively. 
 
Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and 
albumin. After oral administration of ivacaftor 250 mg every 12 hours in combination with lumacaftor, 
the typical apparent volumes of distribution for the central and peripheral compartments (CV) were 
estimated to be 95.0 L (53.9%) and 201 L (26.6%), respectively. 
 
In vitro studies indicate that lumacaftor is a substrate of Breast Cancer Resistance Protein (BCRP). 
 
Biotransformation 
 
Lumacaftor is not extensively metabolised in humans, with the majority of lumacaftor excreted 
unchanged in the faeces. In vitro and in vivo data indicate that lumacaftor is mainly metabolised via 
oxidation and glucuronidation. 
 
Ivacaftor is extensively metabolised in humans. In vitro and in vivo data indicate that ivacaftor is 
primarily metabolised by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. 
M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. 
M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active. 
 
Elimination 
 
Following oral administration of lumacaftor, the majority of lumacaftor (51%) is excreted unchanged 
in the faeces. There was negligible urinary excretion of lumacaftor as unchanged drug. The apparent 
terminal half-life is approximately 26 hours. The typical apparent clearance, CL/F (CV), of lumacaftor 
was estimated to be 2.38 L/h (29.4%) for patients with CF. 
 
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 



26 

drug. In healthy subjects, the half-life of ivacaftor when given with lumacaftor is approximately 9 
hours. The typical CL/F (CV) of ivacaftor when given in combination with lumacaftor was estimated 
to be 25.1 L/h (40.5%) for patients with CF. 
 
Special populations 
 
Hepatic impairment 
 
Following multiple doses of lumacaftor/ivacaftor for 10 days, subjects with moderately impaired 
hepatic function (Child-Pugh Class B, score 7 to 9) had higher exposures (AUC0-12h by approximately 
50% and Cmax by approximately 30%) compared with healthy subjects matched for demographics. The 
impact of mild hepatic impairment (Child-Pugh Class A, score 5 to 6) on pharmacokinetics of 
lumacaftor given in combination with ivacaftor has not been studied, but the increase in exposure is 
expected to be less than 50%. 
 
Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C, 
score 10 to 15), but exposure is expected to be higher than in patients with moderate hepatic 
impairment (see sections 4.2, 4.4, and 4.8). 
 
Renal impairment 
 
Pharmacokinetic studies have not been performed with lumacaftor/ivacaftor in patients with renal 
impairment. In a human pharmacokinetic study with lumacaftor alone, there was minimal elimination 
of lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine 
with 0.18% as unchanged parent). 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). A population pharmacokinetic analysis of clearance versus creatinine 
clearance shows no trend for subjects with mild and moderate renal impairment (see section 4.2). 
 
Elderly 
 
The safety and efficacy of lumacaftor/ivacaftor in patients aged 65 years or older have not been 
evaluated. 
 
Gender 
 
The effect of gender on lumacaftor pharmacokinetics was evaluated using a population 
pharmacokinetics analysis of data from clinical studies of lumacaftor given in combination with 
ivacaftor. Results indicate no clinically relevant difference in pharmacokinetic parameters for 
lumacaftor or ivacaftor between males and females. No dose adjustments are necessary based on 
gender. 
 
Paediatric population 
The exposures are similar between adults and the paediatric population based on population (PK) 
analyses as presented in Table 9: 
 
Table 9: Mean (SD) lumacaftor and ivacaftor exposure by age group 

Age group Dose 
Mean lumacaftor 

(SD) 
AUCss (μg/mL*h) 

Mean ivacaftor (SD) 
AUCss (μg/mL*h) 

Patients aged 6 to 11 years lumacaftor 200 mg/ivacaftor 
250 mg every 12 hours  

203 (57.4) 5.26 (3.08) 

Patients aged 12 to less than 
18 years  

lumacaftor 400 mg/ivacaftor 
250 mg every 12 hours  

241 (61.4) 3.90 (1.56) 

 



27 

5.3 Preclinical safety data 
 
Lumacaftor 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to 
reproduction and development. Specific studies to evaluate the phototoxic potential of lumacaftor were 
not conducted; however, evaluation of the available non-clinical and clinical data suggests no 
phototoxic liability. 
 
Ivacaftor 
 
Effects in repeated dose studies were observed only at exposures considered sufficiently in excess 
(> 25-, > 45-, and > 35-fold for mice, rats, and dogs, respectively) of the maximum human exposure of 
ivacaftor when administered as Orkambi, indicating little relevance to clinical use. Non-clinical data 
reveal no special hazard for humans based on conventional studies of genotoxicity and carcinogenic 
potential. 
 
Safety pharmacology 
Ivacaftor produced concentration-dependent inhibitory effect on hERG (human ether-à-go-go related 
gene) tail currents, with an IC15 of 5.5 µM, compared to the Cmax (1.5 µM) for ivacaftor at the 
therapeutic dose for lumacaftor/ivacaftor. However, no ivacaftor-induced QT prolongation was 
observed in a dog telemetry study at single doses up to 60 mg/kg or in ECG measurements from 
repeat-dose studies of up to 1 year duration at the 60 mg/kg/day dose level in dogs (Cmax after 
365 days = 36.2 to 47.6 μM). Ivacaftor produced a dose-related but transient increase in the blood 
pressure parameters in dogs at single oral doses up to 60 mg/kg (see section 5.1).  
 
Pregnancy and fertility 
Ivacaftor was not teratogenic when dosed orally to pregnant rats and rabbits during the organogenesis 
stage of foetal development at doses approximately 7 times (ivacaftor and metabolite exposure) and 46 
times the ivacaftor exposure in humans at the therapeutic lumacaftor/ivacaftor dose, respectively. At 
maternally toxic doses in rats, ivacaftor produced reductions in foetal body weight; an increase in the 
incidence of variations in cervical ribs, hypoplastic ribs, and wavy ribs; and sternal irregularities, 
including fusions. The significance of these findings for humans is unknown. 
 
Ivacaftor impaired fertility and reproductive performance indices in male and female rats at 
200 mg/kg/day (yielding exposures approximately 11 and 7 times, respectively, those obtained with 
the maximum recommended human dose of the ivacaftor component of Orkambi based on summed 
AUCs of ivacaftor and its metabolites extrapolated from day 90 exposures at 150 mg/kg/day in the 
6-month repeat-dose toxicity study and gestation day 17 exposures in the pilot embryofoetal 
development study in this species) when dams were dosed prior to and during early pregnancy. No 
effects on male or female fertility and reproductive performance indices were observed at 
≤ 100 mg/kg/day (yielding exposures approximately 8 and 5 times, respectively, those obtained with 
the maximum recommended human dose of the ivacaftor component of Orkambi based on summed 
AUCs of ivacaftor and its metabolites extrapolated from day 90 exposures at 100 mg/kg/day in the 
6-month repeat-dose toxicity study and gestation day 17 exposures in the embryofoetal development 
study in this species). Placental transfer of ivacaftor was observed in pregnant rats and rabbits. 
 
Peri- and post-natal development 
Ivacaftor did not cause developmental defects in the offspring of pregnant rats dosed orally from 
pregnancy through parturition and weaning at 100 mg/kg/day (yielding exposures that were 
approximately 4 times those obtained with the maximum recommended human dose of the ivacaftor 
component of Orkambi based on summed AUCs of ivacaftor and its metabolites). Doses above 
100 mg/kg/day resulted in survival and lactation indices that were 92% and 98% of control values, 
respectively, as well as reductions in pup body weights.  
 



28 

Juvenile animals 
Findings of cataracts were observed in juvenile rats dosed with ivacaftor at 0.32 times the maximum 
recommended human dose based on systemic exposure of ivacaftor and its metabolites when 
co-administered with lumacaftor as Orkambi. Cataracts were not observed in foetuses derived from rat 
dams treated during the organogenesis stage of foetal development, in rat pups exposed to a certain 
extent through milk ingestion prior to weaning, or in repeated dose toxicity studies with ivacaftor. The 
potential relevance of these findings in humans is unknown. 
 
Lumacaftor and ivacaftor 
 
Repeat-dose toxicity studies involving the co-administration of lumacaftor and ivacaftor revealed no 
special hazard for humans in terms of potential for additive and/or synergistic toxicities. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
Cellulose, microcrystalline 
Croscarmellose sodium 
Hypromellose acetate succinate 
Povidone (K30) 
Sodium laurilsulfate 
Magnesium stearate 
 
Coating 
 
Polyvinyl alcohol 
Titanium dioxide (E171) 
Macrogol (3350) 
Talc 
Carmine (E120) 
Brilliant blue FCF aluminium lake (E133) 
Indigo carmine aluminium lake (E132) 
 
Printing ink 
 
Shellac 
Iron oxide black (E172) 
Propylene glycol 
Ammonia solution, concentrated 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
Orkambi 100 mg/125 mg film-coated tablets 
 
3 years 
 
Orkambi 200 mg/125 mg film-coated tablets 
 
4 years 



29 

 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Blister consisting of PolyChloroTriFluoroEthylene (PCTFE)/PolyVinyl Chloride (PVC) with a 
paper-backed aluminium foil lidding.  
 
Orkambi 100 mg/125 mg film-coated tablets 
 
Pack containing 112 (4 packs of 28) film-coated tablets. 
 
Orkambi 200 mg/125 mg film-coated tablets 
 
Pack containing 28 film-coated tablets. 
Multipacks containing 112 (4 packs of 28) film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
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/1/15/1059/001 
EU/1/15/1059/003 
EU/1/15/1059/005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 November 2015 
Date of latest renewal:  
 
 
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. 

http://www.ema.europa.eu/


30 

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 
 
Orkambi 100 mg/125 mg granules in sachet 
Orkambi 150 mg/188 mg granules in sachet 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Orkambi 100 mg/125 mg granules in sachet 
 
Each sachet contains 100 mg of lumacaftor and 125 mg of ivacaftor. 
 
Orkambi 150 mg/188 mg granules in sachet 
 
Each sachet contains 150 mg of lumacaftor and 188 mg of ivacaftor. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Granules 
 
White to off-white granules. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Orkambi granules are indicated for the treatment of cystic fibrosis (CF) in patients aged 2 years and 
older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance 
regulator (CFTR) gene (see sections 4.2, 4.4 and 5.1). 
 
4.2 Posology and method of administration 
 
Orkambi 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 the F508del mutation on both alleles of the CFTR gene. 
 
Posology 
 
Table 1: Dosing recommendations in patients aged 2 years and older 



31 

Age Orkambi dose Total daily dose 
2 to 5 years and 
weighing less than 14 kg 

One sachet of lumacaftor 
100 mg/ivacaftor 125 mg every 12 
hours 

lumacaftor 200 mg/ 
ivacaftor 250 mg 

2 to 5 years and 
weighing 14 kg or 
greater  

One sachet of lumacaftor 
150 mg/ivacaftor 188 mg every 12 
hours 

lumacaftor 300 mg/ 
ivacaftor 376 mg 

6 years and older See Orkambi tablets SmPC for further details 
 
Patients may start treatment on any day of the week. 
This medicinal product should be taken with fat-containing food. A fat-containing meal or snack 
should be consumed just before or just after dosing (see section 5.2). 
 
Missed dose 
If less than 6 hours have passed since the missed dose, the scheduled dose should be taken with fat-
containing food. If more than 6 hours have passed, the patient should be instructed to wait until the 
next scheduled dose. A double dose should not be taken to make up for the forgotten dose. 
 
Concomitant use of CYP3A inhibitors 
No dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking 
Orkambi. However, when initiating treatment in patients taking strong CYP3A inhibitors, reduce the 
dose to one sachet (lumacaftor 100 mg/ivacaftor 125 mg for patients aged 2 to 5 years and weighing 
less than 14 kg; lumacaftor 150 mg/ivacaftor 188 mg for patients aged 2 to 5 years and weighing 14 kg 
or greater) every other day for the first week of treatment to allow for the steady state induction effect 
of lumacaftor. Following this period, the recommended daily dose should be continued. 
 
If treatment is interrupted for more than one week and then re-initiated while taking strong CYP3A 
inhibitors, reduce the dose to one sachet (lumacaftor 100 mg/ivacaftor 125 mg for patients aged 2 to 
5 years and weighing less than 14 kg; lumacaftor 150 mg/ivacaftor 188 mg for patients aged 2 to 
5 years and weighing 14 kg or greater) every other day for the first week of treatment re-initiation. 
Following this period, the recommended daily dose should be continued (see section 4.5). 
 
Special populations 
 
Renal impairment 
No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution is 
recommended in patients with severe renal impairment (creatinine clearance less than or equal to 
30 mL/min) or end-stage renal disease (see sections 4.4 and 5.2). 
 
Hepatic impairment 
No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). For 
patients with moderate hepatic impairment (Child-Pugh Class B), a dose reduction is recommended. 
 
There is no experience of the use of the medicinal product in patients with severe hepatic impairment 
(Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic 
impairment. Therefore, after weighing the risks and benefits of treatment, Orkambi should be used 
with caution in patients with severe hepatic impairment at a reduced dose (see sections 4.4, 4.8 and 
5.2). 
 
For dose adjustments for patients with hepatic impairment see Table 2. 
 



32 

Table 2: Dose adjustment recommendations for patients with hepatic impairment 
Hepatic impairment Dose adjustment Total daily dose 

Mild hepatic 
impairment  
(Child-Pugh Class A) 

No dose adjustment 

For patients aged 2 to 5 years 
and < 14 kg 

lumacaftor 200 mg + ivacaftor 250 mg 
 
For patients aged 2 to 5 years 
and ≥ 14 kg 

lumacaftor 300 mg + ivacaftor 376 mg 
 

Moderate hepatic 
impairment  
(Child-Pugh Class B) 

1 sachet every morning 
and 1 sachet in the 
evening every other day. 

For patients aged 2 to 5 years 
and < 14 kg 

day 1: lumacaftor 200 mg + ivacaftor 250 mg 
day 2: lumacaftor 100 mg + ivacaftor 125 mg 

 
For patients aged 2 to 5 years and ≥ 14 kg 

day 1: lumacaftor 300 mg + ivacaftor 376 mg 
day 2: lumacaftor 150 mg + ivacaftor 188 mg 

 

Severe hepatic 
impairment  
(Child-Pugh Class C) 

1 sachet per day or less 
frequently 

For patients aged 2 to 5 years 
and < 14 kg 

lumacaftor 100 mg + ivacaftor 125 mg 
 
For patients aged 2 to5 years and ≥ 14 kg 

lumacaftor 150 mg + ivacaftor 188 mg 
 

 
Paediatric population 
The safety and efficacy of Orkambi in children aged less than 2 years have not yet been established. 
No data are available (see section 5.1). 
 
Method of administration 
 
For oral use.  
 
Each sachet is for single use only. 
 
The entire content of each sachet of granules should be mixed with one teaspoon (5 mL) of 
age-appropriate soft food or liquid and the mixture completely consumed. Some examples of soft 
foods include puréed fruits, flavoured yogurt, and milk or juice. Food or liquid should be at room 
temperature or below. Once mixed, the product has been shown to be stable for one hour, and 
therefore should be ingested during this period.  
 
4.3 Contraindications 
 
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Patients with CF who are heterozygous for the F508del mutation in the CFTR gene 
 
Lumacaftor/ivacaftor is not effective in patients with CF who have the F508del mutation on one allele 
plus a second allele with a mutation predicted to result in a lack of CFTR production or that is not 
responsive to ivacaftor in vitro (see section 5.1). 
 



33 

Patients with CF who have a gating (Class III) mutation in the CFTR gene 
 
Lumacaftor/ivacaftor has not been studied in patients with CF who have a gating (Class III) mutation 
in the CFTR gene on one allele, with or without the F508del mutation on the other allele. Since the 
exposure of ivacaftor is very significantly reduced when dosed in combination with lumacaftor, 
lumacaftor/ivacaftor should not be used in these patients. 
 
Respiratory adverse reactions 
 
Respiratory adverse reactions (e.g., chest discomfort, dyspnoea, bronchospasm, and respiration 
abnormal) were more common during initiation of lumacaftor/ivacaftor therapy. Serious respiratory 
events were seen more frequently in patients with percent predicted forced expiratory volume in the 
1st second (ppFEV1) <40, and may lead to discontinuation of the medicinal product. Clinical 
experience in patients with ppFEV1 <40 is limited and additional monitoring of these patients is 
recommended during initiation of therapy (see section 4.8). A transient decline in FEV1 has also been 
observed in some patients following initiation of lumacaftor/ivacaftor. There is no experience of 
initiating treatment with lumacaftor/ivacaftor in patients having a pulmonary exacerbation and 
initiating treatment in patients having a pulmonary exacerbation is not advisable. 
 
Effect on blood pressure 
 
Increased blood pressure has been observed in some patients treated with lumacaftor/ivacaftor. Blood 
pressure should be monitored periodically in all patients during treatment (see section 4.8). 
 
Patients with advanced liver disease 
 
Abnormalities in liver function, including advanced liver disease, can be present in patients with CF. 
Worsening of liver function in patients with advanced liver disease has been reported. Liver function 
decompensation, including liver failure leading to death, has been reported in CF patients with pre-
existing cirrhosis with portal hypertension receiving lumacaftor/ivacaftor. Lumacaftor/ivacaftor should 
be used with caution in patients with advanced liver disease and only if the benefits are expected to 
outweigh the risks. If lumacaftor/ivacaftor is used in these patients, they should be closely monitored 
after the initiation of treatment and the dose should be reduced (see sections 4.2, 4.8, and 5.2). 
 
Hepatobiliary adverse reactions 
 
Elevated transaminases have been commonly reported in patients with CF receiving 
lumacaftor/ivacaftor. In some instances, these elevations have been associated with concomitant 
elevations in total serum bilirubin. Transaminase elevations have been observed more frequently in 
paediatric patients than in adult patients. Among different age paediatric cohorts, in the 2 to 5 years old 
patients, transaminase elevations have been observed more frequently than in the 6 to 11 years old (see 
section 4.8). 
 
Because an association with liver injury cannot be excluded, assessments of liver function tests (ALT, 
AST and bilirubin) are recommended before initiating lumacaftor/ivacaftor, every 3 months during the 
first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin 
elevations, more frequent monitoring should be considered. 
 
In the event of significant elevation of ALT or AST, with or without elevated bilirubin (either ALT or 
AST > 5 x the upper limit of normal [ULN], or ALT or AST > 3 x ULN with bilirubin > 2 x ULN 
and/or clinical jaundice), dosing with lumacaftor/ivacaftor should be discontinued and laboratory tests 
closely followed until the abnormalities resolve. A thorough investigation of potential causes should 
be conducted and patients should be followed closely for clinical progression. Following resolution of 
transaminase elevations, the benefits and risks of resuming dosing should be considered (see 
sections 4.2, 4.8, and 5.2). 
 



34 

Interactions with medicinal products 
 
Substrates of CYP3A 
Lumacaftor is a strong inducer of CYP3A. Co-administration with sensitive CYP3A substrates or 
CYP3A substrates with a narrow therapeutic index is not recommended (see section 4.5). 
 
Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied 
upon as an effective method of contraception when co-administered with Orkambi (see section 4.5). 
 
Strong CYP3A inducers 
Ivacaftor is a substrate of CYP3A4 and CYP3A5. Therefore, co-administration with strong CYP3A 
inducers (e.g., rifampicin, St. John’s wort [Hypericum perforatum]) is not recommended (see 
section 4.5). 
 
Renal impairment 
 
Caution is recommended while using lumacaftor/ivacaftor in patients with severe renal impairment or 
end-stage renal disease (see sections 4.2 and 5.2). 
 
Cataracts 
 
Cases of non-congenital lens opacities without impact on vision have been reported in paediatric 
patients treated with lumacaftor/ivacaftor and ivacaftor monotherapy. Although other risk factors were 
present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable 
to ivacaftor cannot be excluded (see section 5.3). Baseline and follow-up ophthalmological 
examinations are recommended in paediatric patients initiating treatment with lumacaftor/ivacaftor. 
 
Patients after organ transplantation 
 
Lumacaftor/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 immunosuppressants. 
 
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 
 
Based on exposure and indicated doses, the interaction profile is considered to be the same for all 
strengths and pharmaceutical forms. 
 
Lumacaftor is a strong inducer of CYP3A and ivacaftor is a weak inhibitor of CYP3A when given as 
monotherapy. There is potential for other medicinal products to affect lumacaftor/ivacaftor when 
administered concomitantly, and also for lumacaftor/ivacaftor to affect other medicinal products. 
 
Potential for other medicinal products to affect lumacaftor/ivacaftor 
 
Inhibitors of CYP3A 
Co-administration of lumacaftor/ivacaftor with itraconazole, a strong CYP3A inhibitor, did not impact 
the exposure of lumacaftor, but increased ivacaftor exposure by 4.3-fold. Due to the induction effect of 
lumacaftor on CYP3A, at steady-state, the net exposure of ivacaftor when co-administered with a 
CYP3A inhibitor is not expected to exceed that when given in the absence of lumacaftor at a dose of 
150 mg every 12 hours, the approved dose of ivacaftor monotherapy.  
 



35 

No dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking 
lumacaftor/ivacaftor. However, when initiating lumacaftor/ivacaftor in patients taking strong CYP3A 
inhibitors, the dose should be adjusted (see sections 4.2 and 4.4). 
 
No dose adjustment is recommended when used with moderate or weak CYP3A inhibitors. 
 
Inducers of CYP3A 
Co-administration of lumacaftor/ivacaftor with rifampicin, a strong CYP3A inducer, had minimal 
effect on the exposure of lumacaftor, but decreased ivacaftor exposure (AUC) by 57%. Therefore, 
co-administration of lumacaftor/ivacaftor is not recommended with strong CYP3A inducers (see 
sections 4.2 and 4.4). 
 
No dose adjustment is recommended when used with moderate or weak CYP3A inducers. 
 
Potential for lumacaftor/ivacaftor to affect other medicinal products 
 
CYP3A substrates 
Lumacaftor is a strong inducer of CYP3A. Ivacaftor is a weak inhibitor of CYP3A when given as 
monotherapy. The net effect of lumacaftor/ivacaftor therapy is expected to be strong CYP3A 
induction. Therefore, concomitant use of lumacaftor/ivacaftor with CYP3A substrates may decrease 
the exposure of these substrates (see section 4.4). 
 
P-gp substrates 
In vitro studies indicated that lumacaftor has the potential to both inhibit and induce P-gp. 
Additionally, a clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of 
P-gp. Therefore, concomitant use of lumacaftor/ivacaftor with P-gp substrates (e.g., digoxin) may alter 
the exposure of these substrates. 
 
CYP2B6 and CYP2C substrates 
Interaction with CYP2B6 and CYP2C substrates has not been investigated in vivo. In vitro studies 
suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; 
however, inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in vitro 
studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of lumacaftor/ivacaftor 
may alter (i.e., either increase or decrease) the exposure of CYP2C8 and CYP2C9 substrates, decrease 
the exposure of CYP2C19 substrates, and substantially decrease the exposure of CYP2B6 substrates. 
 
Potential for lumacaftor/ivacaftor to interact with transporters 
 
In vitro experiments show that lumacaftor is a substrate for Breast Cancer Resistance Protein (BCRP). 
Co-administration of Orkambi with medicinal products that inhibit BCRP may increase plasma 
lumacaftor concentration. Lumacaftor inhibits the organic anion transporter (OAT) 1 and 3. 
Lumacaftor and ivacaftor are inhibitors of BCRP. Co-administration of Orkambi with medicinal 
products that are substrates for OAT1/3 and BCRP transport may increase plasma concentrations of 
such medicinal products. Lumacaftor and ivacaftor are not inhibitors of OATP1B1, OATP1B3, and 
organic cation transporter (OCT) 1 and 2. Ivacaftor is not an inhibitor of OAT1 and OAT3. 
 
Established and other potentially significant interactions 
 
Table 3 provides the established or predicted effect of lumacaftor/ivacaftor on other medicinal 
products or the effect of other medicinal products on lumacaftor/ivacaftor. The information reported in 
Table 3 mostly derives from in vitro studies. The recommendations provided under “Clinical 
comment” in Table 3 are based on interaction studies, clinical relevance, or predicted interactions due 
to elimination pathways. Interactions that have the most clinical relevance are listed first. 
 



36 

Table 3: Established and other potentially significant interactions - dose recommendations for 
use of lumacaftor/ivacaftor with other medicinal products 

Concomitant 
medicinal product 
class: 
Active substance name Effect Clinical comment 
Concomitant medicinal products of most clinical relevance 
Anti-allergics: 
montelukast 

 
↔ LUM, IVA 
 
 
 
↓ montelukast 
Due to the induction 
of CYP3A/2C8/2C9 
by LUM 

 
 
 
 
 
No dose adjustment for montelukast is 
recommended. Appropriate clinical 
monitoring should be employed, as is 
reasonable, when co-administered with 
lumacaftor/ivacaftor. Lumacaftor/ivacaftor 
may decrease the exposure of montelukast, 
which may reduce its efficacy. 

 
fexofenadine 

 
↔ LUM, IVA 
 
↑ or ↓ fexofenadine 
Due to potential 
induction or 
inhibition of P-gp 

 
 
 
Dose adjustment of fexofenadine may be 
required to obtain the desired clinical 
effect. Lumacaftor/ivacaftor may alter the 
exposure of fexofenadine. 

Antibiotics: 
clarithromycin, 
telithromycin 

 
↔ LUM 
↑ IVA 
Due to inhibition of 
CYP3A by 
clarithromycin, 
telithromycin 
 
↓ clarithromycin, 
telithromycin 
Due to induction of 
CYP3A by LUM 

 
No dose adjustment of 
lumacaftor/ivacaftor is recommended 
when clarithromycin or telithromycin are 
initiated in patients currently taking 
lumacaftor/ivacaftor. 
 
 
The dose of lumacaftor/ivacaftor should be 
reduced to one sachet every other day for 
the first week of treatment when initiating 
lumacaftor/ivacaftor in patients currently 
taking clarithromycin or telithromycin.  
 
An alternative to these antibiotics, such as 
azithromycin, should be considered. 
Lumacaftor/ivacaftor may decrease the 
exposures of clarithromycin and 
telithromycin, which may reduce their 
efficacy. 



37 

Concomitant 
medicinal product 
class: 
Active substance name Effect Clinical comment 
 
erythromycin 

 
↔ LUM 
↑ IVA 
Due to inhibition of 
CYP3A by 
erythromycin 
 
↓ erythromycin 
Due to induction of 
CYP3A by LUM 

 
No dose adjustment of 
lumacaftor/ivacaftor is recommended 
when co-administered with erythromycin. 
 
 
 
An alternative to erythromycin, such as 
azithromycin, should be considered. 
Lumacaftor/ivacaftor may decrease the 
exposure of erythromycin, which may 
reduce its efficacy. 

Anticonvulsants: 
carbamazepine, 
phenobarbital, 
phenytoin 

 
↔ LUM 
↓ IVA 
Due to induction of 
CYP3A by these 
anticonvulsants 
 
↓ carbamazepine, 
phenobarbital, 
phenytoin 
Due to induction of 
CYP3A by LUM 

 
 
 
 
 
 
 
Concomitant use of lumacaftor/ivacaftor 
with these anticonvulsants is not 
recommended. The exposures of ivacaftor 
and the anticonvulsant may be 
significantly decreased, which may reduce 
the efficacy of both active substances. 

Antifungals: 
itraconazole*, 
ketoconazole, 
posaconazole, 
voriconazole 

 
↔ LUM 
↑ IVA 
Due to inhibition of 
CYP3A by these 
antifungals 
 
↓ itraconazole, 
ketoconazole, 
voriconazole 
Due to induction of 
CYP3A by LUM 
 
↓ posaconazole 
Due to induction of 
UGT by LUM 

 
No dose adjustment of 
lumacaftor/ivacaftor is recommended 
when these antifungals are initiated in 
patients currently taking 
lumacaftor/ivacaftor. 
 
The dose of lumacaftor/ivacaftor should be 
reduced to one sachet every other day for 
the first week of treatment when initiating 
lumacaftor/ivacaftor in patients currently 
taking these antifungals. 
 
Concomitant use of lumacaftor/ivacaftor 
with these antifungals is not 
recommended. Patients should be 
monitored closely for breakthrough fungal 
infections if such drugs are necessary. 
Lumacaftor/ivacaftor may decrease the 
exposures of these antifungals, which may 
reduce their efficacy. 



38 

Concomitant 
medicinal product 
class: 
Active substance name Effect Clinical comment 
 
fluconazole 

 
↔ LUM 
↑ IVA 
Due to inhibition of 
CYP3A by 
fluconazole 
 
↓ fluconazole 
Due to induction by 
LUM; fluconazole is 
cleared primarily by 
renal excretion as 
unchanged drug; 
however, modest 
reduction in 
fluconazole exposure 
has been observed 
with strong inducers 

 
No dose adjustment of 
lumacaftor/ivacaftor is recommended 
when co-administered with fluconazole. 
 
 
 
A higher dose of fluconazole may be 
required to obtain the desired clinical 
effect. Lumacaftor/ivacaftor may decrease 
the exposure of fluconazole, which may 
reduce its efficacy. 

Anti-inflammatories: 
ibuprofen 

 
↔ LUM, IVA 
 
↓ ibuprofen 
Due to induction of 
CYP3A/2C8/2C9 by 
LUM 

 
 
 
A higher dose of ibuprofen may be 
required to obtain the desired clinical 
effect. Lumacaftor/ivacaftor may decrease 
the exposure of ibuprofen, which may 
reduce its efficacy. 

Anti-mycobacterials: 
rifabutin, rifampicin*, 
rifapentine 

 
↔ LUM 
↓ IVA 
Due to induction of 
CYP3A by anti-
mycobacterials 
 
↓ rifabutin 
Due to induction of 
CYP3A by LUM 
 
 
 
 
 
 
 
 
 
↔ rifampicin, 
rifapentine 

 
 
 
 
 
 
 
Concomitant use of lumacaftor/ivacaftor 
with these anti-mycobacterials is not 
recommended. The exposure of ivacaftor 
will be decreased, which may reduce the 
efficacy of lumacaftor/ivacaftor. 
 
A higher dose of rifabutin may be required 
to obtain the desired clinical effect. 
Lumacaftor/ivacaftor may decrease the 
exposure of rifabutin, which may reduce 
its efficacy. 



39 

Concomitant 
medicinal product 
class: 
Active substance name Effect Clinical comment 
Benzodiazepines: 
midazolam, triazolam 

 
↔ LUM, IVA 
 
↓ midazolam, 
triazolam 
Due to induction of 
CYP3A by LUM 

 
 
 
Concomitant use of lumacaftor/ivacaftor 
with these benzodiazepines is not 
recommended. Lumacaftor/ivacaftor will 
decrease the exposures of midazolam and 
triazolam, which will reduce their efficacy. 

Hormonal 
contraceptives: 
ethinyl estradiol, 
norethindrone, and 
other progestogens 

 
↓ ethinyl estradiol, 
norethindrone, and 
other progestogens 
Due to induction of 
CYP3A/UGT by 
LUM 

 
Hormonal contraceptives, including oral, 
injectable, transdermal, and implantable, 
should not be relied upon as an effective 
method of contraception when 
co-administered with lumacaftor/ivacaftor. 
Lumacaftor/ivacaftor may decrease the 
exposure of hormonal contraceptives, 
which may reduce their efficacy. 

Immunosuppressants: 
ciclosporin, everolimus, 
sirolimus, tacrolimus 
(used after organ 
transplant) 

 
↔ LUM, IVA 
 
↓ ciclosporin, 
everolimus, sirolimus, 
tacrolimus 
Due to induction of 
CYP3A by LUM 

 
 
 
Concomitant use of lumacaftor/ivacaftor 
with these immunosuppressants is not 
recommended. Lumacaftor/ivacaftor will 
decrease the exposure of these 
immunosuppressants, which may reduce 
the efficacy of these immunosuppressants. 
The use of lumacaftor/ivacaftor in organ 
transplant patients has not been studied. 

Proton pump 
inhibitors: 
esomeprazole, 
lansoprazole, 
omeprazole 

 
↔ LUM, IVA 
 
↓ esomeprazole, 
lansoprazole, 
omeprazole 
Due to induction of 
CYP3A/2C19 by 
LUM 

 
 
 
A higher dose of these proton pump 
inhibitors may be required to obtain the 
desired clinical effect. 
Lumacaftor/ivacaftor may decrease the 
exposures of these proton pump inhibitors, 
which may reduce their efficacy. 

Herbals: 
St. John’s wort 
(Hypericum 
perforatum) 

 
↔ LUM 
↓ IVA 
Due to induction of 
CYP3A by St. John’s 
wort 

 
Concomitant use of lumacaftor/ivacaftor 
with St. John’s wort is not recommended. 
The exposure of ivacaftor will be 
decreased, which may reduce the efficacy 
of lumacaftor/ivacaftor. 

Other concomitant medicinal products of clinical relevance 
Antiarrhythmics: 
digoxin 

 
↔ LUM, IVA 
 
↑ or ↓ digoxin 
Due to potential 
induction or 
inhibition of P-gp 

 
 
 
The serum concentration of digoxin should 
be monitored and the dose should be 
titrated to obtain the desired clinical effect. 
Lumacaftor/ivacaftor may alter the 
exposure of digoxin. 



40 

Concomitant 
medicinal product 
class: 
Active substance name Effect Clinical comment 
Anticoagulants: 
dabigatran 
 
 

 
↔ LUM, IVA 
 
↑ or ↓ dabigatran 
Due to potential 
induction or 
inhibition of P-gp 

 
 
 
Appropriate clinical monitoring should be 
employed when co-administered with 
lumacaftor/ivacaftor. Dose adjustment of 
dabigatran may be required to obtain the 
desired clinical effect. 
Lumacaftor/ivacaftor may alter the 
exposure of dabigatran. 

 
warfarin 

 
↔ LUM, IVA 
 
↑ or ↓ warfarin 
Due to potential 
induction or 
inhibition of CYP2C9 
by LUM 

 
 
 
The international normalised ratio (INR) 
should be monitored when warfarin 
co-administration with 
lumacaftor/ivacaftor is required. 
Lumacaftor/ivacaftor may alter the 
exposure of warfarin. 

Antidepressants: 
citalopram, 
escitalopram, sertraline 

 
↔ LUM, IVA 
 
↓ citalopram, 
escitalopram, 
sertraline 
Due to induction of 
CYP3A/2C19 by 
LUM 

 
 
 
A higher dose of these antidepressants 
may be required to obtain the desired 
clinical effect. Lumacaftor/ivacaftor may 
decrease the exposures of these 
antidepressants, which may reduce their 
efficacy. 

 
bupropion 

 
↔ LUM, IVA 
 
↓ bupropion 
Due to induction of 
CYP2B6 by LUM 

 
 
 
A higher dose of bupropion may be 
required to obtain the desired clinical 
effect. Lumacaftor/ivacaftor may decrease 
the exposure of bupropion, which may 
reduce its efficacy. 

Corticosteroids, 
systemic: 
methylprednisolone, 
prednisone 

 
↔ LUM, IVA 
 
↓ methylprednisolone, 
prednisone 
Due to induction of 
CYP3A by LUM 

 
 
 
 
A higher dose of these systemic 
corticosteroids may be required to obtain 
the desired clinical effect. 
Lumacaftor/ivacaftor may decrease the 
exposures of methylprednisolone and 
prednisone, which may reduce their 
efficacy. 



41 

Concomitant 
medicinal product 
class: 
Active substance name Effect Clinical comment 
H2 blockers: 
ranitidine 

 
↔ LUM, IVA 
 
↑ or ↓ ranitidine 
Due to potential 
induction or 
inhibition of P-gp 

 
 
 
Dose adjustment of ranitidine may be 
required to obtain the desired clinical 
effect. Lumacaftor/ivacaftor may alter the 
exposure of ranitidine. 

Oral hypoglycemics: 
repaglinide 

 
↔ LUM, IVA 
 
↓ repaglinide 
Due to induction of 
CYP3A/2C8 by LUM 

 
 
 
A higher dose of repaglinide may be 
required to obtain the desired clinical 
effect. Lumacaftor/ivacaftor may decrease 
the exposure of repaglinide, which may 
reduce its efficacy. 

Note: ↑ = increase, ↓ = decrease, ↔ = no change; LUM = lumacaftor; IVA = ivacaftor. 
* Based on clinical interaction studies. All other interactions shown are predicted. 
 
False positive urine tests for THC  
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in 
patients receiving Orkambi. An alternative confirmatory method should be considered to verify results. 
 
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 
lumacaftor/ivacaftor in pregnant women. Animal studies with lumacaftor and ivacaftor do not indicate 
direct or indirect harmful effects with respect to developmental and reproductive toxicity, whereas 
effects were noted with ivacaftor only at maternally toxic doses (see section 5.3). As a precautionary 
measure, it is preferable to avoid the use of lumacaftor/ivacaftor during pregnancy unless the clinical 
condition of the mother requires treatment with lumacaftor/ivacaftor. 
 
Breast-feeding 
 
It is unknown whether lumacaftor and/or ivacaftor and metabolites are excreted in human milk. 
Available pharmacokinetic data in animals have shown excretion of both lumacaftor and ivacaftor into 
the milk of lactating female rats. As such, risks to the suckling child cannot be excluded. A decision 
must be made whether to discontinue breast-feeding or to discontinue/abstain from 
lumacaftor/ivacaftor therapy taking into account the benefit of breast-feeding for the child and the 
benefit of therapy for the mother. 
 
Fertility 
 
No human data on the effects of lumacaftor and/or ivacaftor on fertility are available. Lumacaftor had 
no effects on fertility and reproductive performance indices in male and female rats. Ivacaftor impaired 
fertility and reproductive performance indices in male and female rats(see section 5.3). 
 



42 

4.7 Effects on ability to drive and use machines 
 
Ivacaftor, which is one of the active components of Orkambi, has a minor influence on the ability to 
drive and use machines. Ivacaftor may cause dizziness (see section 4.8). 
 
Patients experiencing dizziness while taking Orkambi 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 in Phase 3 clinical studies were dyspnoea (14.0% versus 7.8% on 
placebo), diarrhoea (11.0% versus 8.4% on placebo), and nausea (10.2% versus 7.6% on placebo). 
 
Serious adverse reactions included hepatobiliary events, e.g., transaminase elevations, cholestatic 
hepatitis and hepatic encephalopathy. 
 
Tabulated list of adverse reactions 
 
Adverse reactions identified from the 24-week, placebo-controlled, Phase 3 studies (trials 1 and 2) in 
patients aged 12 years and older and from a 24-week, placebo-controlled study in patients aged 6 to 
11 years (trial 7), who are homozygous for the F508del mutation in the CFTR gene are presented in 
Table 4 and are listed by system organ class and frequency. Adverse reactions observed with ivacaftor 
alone are also provided in Table 4. Adverse reactions are ranked under the MedDRA frequency 
classification: 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); and not known (frequency cannot be estimated 
using the available data). 
 
Table 4: Adverse reactions in lumacaftor/ivacaftor-treated patients and in patients treated with 

ivacaftor alone 

System organ class Frequency Adverse reactions 
Infections and infestations very common Nasopharyngitis* 

common Upper respiratory tract infection, rhinitis 
Vascular disorders uncommon Hypertension 
Nervous system disorders very common Headache, dizziness* 

uncommon Hepatic encephalopathy† 
Ear and labyrinth disorders common Ear pain*, ear discomfort*, tinnitus*, tympanic 

membrane hyperaemia*, vestibular disorder* 
uncommon Ear congestion* 

Respiratory, thoracic and 
mediastinal disorders 

very common Nasal congestion, dyspnoea, productive cough, 
sputum increased 

common Respiration abnormal, oropharyngeal pain, 
sinus congestion*, rhinorrhoea, pharyngeal 
erythema*, bronchospasm 

Gastrointestinal disorders very common Abdominal pain*, abdominal pain upper, 
diarrhoea, nausea 

common Flatulence, vomiting 
Hepatobiliary disorders common Transaminase elevations 

uncommon Cholestatic hepatitis‡ 



43 

Skin and subcutaneous tissue 
disorders 

common Rash 

Reproductive system and 
breast disorders 

common Menstruation irregular, dysmenorrhoea, 
metrorrhagia, breast mass* 

uncommon Menorrhagia, amenorrhoea, polymenorrhoea, 
breast inflammation*, gynaecomastia*, nipple 
disorder*, nipple pain*, oligomenorrhoea 

Investigations very common Bacteria in sputum* 
common Blood creatine phosphokinase increased 
uncommon Blood pressure increased 

*Adverse reactions and frequencies observed in patients in clinical studies with ivacaftor monotherapy .  
† 1 patient out of 738 
‡ 2 patients out of 738 
 
The safety data from 1,029 patients aged 12 years and older who were homozygous for the F508del 
mutation in the CFTR gene treated with lumacaftor/ivacaftor for up to an additional 96 weeks in the 
long-term safety and efficacy rollover study (trial 3) were similar to the 24-week, placebo-controlled 
studies (see section 5.1). 
 
Description of selected adverse reactions 
 
Hepatobiliary adverse reactions 
During trials 1 and 2, the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and 
> 3 x ULN was 0.8%, 2.0%, and 5.2%; and 0.5%, 1.9%, and 5.1% in lumacaftor/ivacaftor- and 
placebo-treated patients, respectively. The incidence of transaminase-related adverse reactions was 
5.1% and 4.6% in lumacaftor/ivacaftor-treated patients and those who received placebo, respectively. 
Seven patients who received lumacaftor/ivacaftor had liver-related serious adverse reactions with 
elevated transaminases, including 3 with concurrent elevation in total bilirubin. Following 
discontinuation of lumacaftor/ivacaftor, liver function tests returned to baseline or improved 
substantially in all patients (see section 4.4). 
 
Among 7 patients with pre-existing cirrhosis and/or portal hypertension who received 
lumacaftor/ivacaftor in the placebo-controlled, Phase 3 studies, worsening liver function with 
increased ALT, AST, bilirubin, and hepatic encephalopathy was observed in one patient. The event 
occurred within 5 days of the start of dosing and resolved following discontinuation of 
lumacaftor/ivacaftor (see section 4.4). 
 
Post–marketing cases of liver function decompensation including liver failure leading to death have 
been reported in CF patients with pre-existing cirrhosis with portal hypertension who were treated with 
lumacaftor/ivacaftor (see section 4.4). 
 
Respiratory adverse reactions 
During trials 1 and 2, the incidence of respiratory adverse reactions (e.g., chest discomfort, dyspnoea, 
bronchospasm, and respiration abnormal) was 26.3% in lumacaftor/ivacaftor-treated patients compared 
to 17.0% in patients who received placebo. The incidence of these adverse reactions was more 
common in patients with lower pre-treatment FEV1. Approximately three-quarters of the adverse 
reactions began during the first week of treatment, and in most patients the events resolved without 
dosing interruption. The majority of events were mild or moderate in severity, non-serious and did not 
result in treatment discontinuation (see section 4.4). 
 
During a 24-week, open label, Phase 3b clinical study (trial 5) in 46 patients aged 12 years and older 
with advanced lung disease (ppFEV1 < 40) [mean ppFEV1 29.1 at baseline (range: 18.3 to 42.0)], the 
incidence of respiratory adverse reactions was 65.2%. In the subgroup of 28 patients who were 
initiated at the full dose of lumacaftor/ivacaftor (2 tablets every 12 hours), the incidence was 71.4%, 
and in the 18 patients who were initiated at a reduced dose of lumacaftor/ivacaftor (1 tablet every 12 



44 

hours for up to 2 weeks, and subsequently increased to the full dose), the incidence was 55.6%. Of the 
patients who were initiated lumacaftor/ivacaftor at the full dose, one patient had a serious respiratory 
adverse reaction, three patients subsequently had their dose reduced, and three patients discontinued 
treatment. No serious respiratory adverse reactions, dose reductions or discontinuations were seen in 
patients who were initiated at the half dose (see section 4.4). 
 
Menstrual abnormalities 
During trials 1 and 2, the incidence of combined menstrual abnormalities (amenorrhoea, 
dysmenorrhoea, menorrhagia, menstruation irregular, metrorrhagia, oligomenorrhoea, and 
polymenorrhoea) was 9.9% in lumacaftor/ivacaftor-treated female patients and 1.7% in 
placebo-treated females. These menstrual events occurred more frequently in the subset of female 
patients who were taking hormonal contraceptives (25.0%) versus patients who were not taking 
hormonal contraceptives (3.5%) (see section 4.5). Most of these reactions were mild or moderate in 
severity and non-serious. In lumacaftor/ivacaftor-treated patients, approximately two-thirds of these 
reactions resolved, and the median duration was 10 days. 
 
Increased blood pressure 
During trials 1 and 2, adverse reactions related to increased blood pressure (e.g., hypertension, blood 
pressure increased) were reported in 0.9% (7/738) of patients treated with lumacaftor/ivacaftor and in 
no patients who received placebo. 
 
In patients treated with lumacaftor/ivacaftor (mean baseline 114 mmHg systolic and 69 mmHg 
diastolic), the maximum increase from baseline in mean systolic and diastolic blood pressure was 3.1 
mmHg and 1.8 mmHg, respectively. In patients who received placebo (mean baseline 114 mmHg 
systolic and 69 mmHg diastolic), the maximum increase from baseline in mean systolic and diastolic 
blood pressure was 0.9 mmHg and 0.9 mmHg, respectively. 
 
The proportion of patients who experienced a systolic blood pressure value > 140 mmHg or a diastolic 
blood pressure > 90 mmHg on at least two occasions was 3.4% and 1.5% in patients treated with 
lumacaftor/ivacaftor, respectively, compared with 1.6% and 0.5% in patients who received placebo 
(see section 4.4). 
 
Paediatric population 
 
Safety data were evaluated in 60 patients aged 2 to 5 years (trial 8), 161 patients aged 6 to 11 years 
(trials 6 and 7) and in 194 patients aged 12 to 17 years with CF who are homozygous for the F508del 
mutation and who received lumacaftor/ivacaftor in clinical studies. Patients aged 12 to 17 years were 
included in trials 1 and 2. 
 
The safety profile in these paediatric patients is generally consistent with that in adult patients. 
 
Long-term safety data from a 96-week rollover extension study in 57 patients aged 2 years and older 
who were homozygous for the F508del mutation in the CFTR gene were generally consistent with the 
24-week parent study in patients aged 2 to 5 years (trial 8) and safety data in patients aged 6 to 
11 years. 
 
Long-term safety data from a 96-week rollover extension study in 239 patients aged 6 years and older 
who were homozygous for the F508del mutation in the CFTR gene (trial 9) were generally consistent 
with the 24-week parent studies in patients aged 6 to 11 years (trial 6 and trial 7). 
Description of selected adverse reactions for paediatric patients aged 2 to 11 years 
Hepatobiliary adverse reactions 
During the 24-week, open-label Phase 3 clinical study in 58 patients aged 6 to 11 years (trial 6), the 
incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and > 3 x ULN was 5.3%, 8.8%, 
and 19.3%. No patients had total bilirubin levels > 2 x ULN. Lumacaftor/ivacaftor dosing was 
maintained or successfully resumed after interruption in all patients with transaminase elevations, 
except 1 patient who discontinued treatment permanently. 
 



45 

During the 24-week, placebo-controlled Phase 3 clinical study in 204 patients aged 6 to 11 years 
(trial 7), the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and > 3 x ULN was 
1.0%, 4.9%, and 12.6% in the lumacaftor/ivacaftor patients, and 2.0%, 3.0%, and 7.9% in the 
placebo-treated patients. No patients had total bilirubin levels > 2 x ULN. Two patients in the 
lumacaftor/ivacaftor group and two patients in the placebo group discontinued treatment permanently 
due to transaminase elevations. 
 
During the 24-week, open-label Phase 3 clinical study in 60 patients aged 2 through 5 years (trial 8), 
the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and > 3 x ULN was 8.3% 
(5/60), 11.7% (7/60), and 15.0% (9/60). No patients had total bilirubin levels > 2 x ULN. Three 
patients discontinued lumacaftor/ivacaftor treatment permanently due to transaminase elevations. 
 
Respiratory adverse reactions 
During the 24-week, open-label Phase 3 clinical study (trial 6) in 58 patients aged 6 to 11 years (mean 
baseline ppFEV1 was 91.4), the incidence of respiratory adverse reactions was 6.9% (4/58). 
 
During the 24-week, placebo-controlled Phase 3 clinical study (trial 7) in patients aged 6 to 11 years 
(mean baseline ppFEV1 was 89.8), the incidence of respiratory adverse reactions was 18.4% in 
lumacaftor/ivacaftor patients and 12.9% in placebo patients. A decline in ppFEV1 at initiation of 
therapy was observed during serial post dose spirometry assessments. The absolute change from pre-
dose at 4 to 6 hours post-dose was -7.7 on day 1 and -1.3 on day 15 in lumacaftor/ivacaftor patients. 
The post-dose decline was resolved by week 16. 
 
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 
 
No specific antidote is available for overdose with lumacaftor/ivacaftor. Treatment of overdose 
consists of general supportive measures including monitoring of vital signs and observation of the 
clinical status of the patient. 
 
Adverse reactions that occurred at an increased incidence of ≥ 5% in the supratherapeutic dose period 
compared with the therapeutic dose period were headache, generalised rash, and increased 
transaminase. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other respiratory system products; ATC code: R07AX30 
 
Mechanism of action 
 
The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. 
The F508del mutation impacts the CFTR protein in multiple ways, primarily by causing a defect in 
cellular processing and trafficking that reduces the quantity of CFTR at the cell surface. The small 
amount of F508del-CFTR that reaches the cell surface has low channel-open probability (defective 
channel gating). Lumacaftor is a CFTR corrector that acts directly on F508del-CFTR to improve its 
cellular processing and trafficking, thereby increasing the quantity of functional CFTR at the cell 
surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the 
channel-open probability (or gating) of the CFTR protein at the cell surface. The combined effect of 

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


46 

lumacaftor and ivacaftor is increased quantity and function of F508del-CFTR at the cell surface, 
resulting in increased chloride ion transport. The exact mechanisms by which lumacaftor improves 
cellular processing and trafficking of F508del-CFTR and ivacaftor potentiates F508del-CFTR are not 
known. 
 
Pharmacodynamic effects 
 
Effects on sweat chloride 
Changes in sweat chloride in response to lumacaftor alone or in combination with ivacaftor were 
evaluated in a double-blind, placebo-controlled, Phase 2 clinical trial in patients with CF aged 18 years 
and older. In this trial, 10 patients (homozygous for F508del-CFTR mutation) completed dosing with 
lumacaftor alone 400 mg q12h for 28 days followed by the addition of ivacaftor 250 mg q12h for an 
additional 28 days, and 25 patients (homozygous or heterozygous for F508del) completed dosing with 
placebo. The treatment difference between lumacaftor 400 mg q12h alone and placebo evaluated as 
mean change in sweat chloride from baseline to day 28 was statistically significant at -8.2 mmol/L 
(95% CI: -14, -2). The treatment difference between the combination of lumacaftor 400 mg/ivacaftor 
250 mg q12h and placebo evaluated as mean change in sweat chloride from baseline to day 56 was 
statistically significant at -11 mmol/L (95% CI: -18, -4). 
 
In trial 7 (see Clinical efficacy and safety) in patients homozygous for the F508del-CFTR mutation 
aged 6 to 11 years, the treatment difference (LS mean) in sweat chloride for the absolute change at 
week 24 as compared to placebo was -24.9 mmol/L (nominal P < 0.0001). The treatment difference 
(LS mean) in sweat chloride for the average absolute change at day 15 and at week 4 as compared to 
placebo was -20.8 mmol/L (95% CI: -23.4, -18.2; nominal P < 0.0001).  
 
In trial 8 in patients homozygous for F508del-CFTR mutation aged 2 to 5 years, the mean absolute 
within-group change in sweat chloride from baseline at week 24 was -31.7 mmol/L (95% 
CI: -35.7, -27.6). In addition, the mean absolute change in sweat chloride from week 24 at week 26 
following the 2-week washout period (to evaluate off-drug response) was an increase of 33.0 mmol/L 
(95% CI: 28.9, 37.1; nominal P < 0.0001), representing a return to baseline after treatment washout. At 
week 24, 16% of children had a reduction in sweat chloride below 60 mmol/L, and none below 
30 mmol/L. 
 
Changes in FEV1 
Changes in ppFEV1 in response to lumacaftor alone or in combination with ivacaftor were also 
evaluated in the double-blind, placebo-controlled, Phase 2 trial in patients with CF aged 18 years and 
older. The treatment difference between lumacaftor 400 mg q12h alone and placebo evaluated as mean 
absolute change in ppFEV1 was -4.6 percentage points (95% CI: -9.6, 0.4) from baseline to day 28, 4.2 
percentage points (95% CI: –1.3, 9.7) from baseline to day 56, and 7.7 percentage points (95% CI: 2.6, 
12.8; statistically significant) from day 28 to day 56 (following the addition of ivacaftor to lumacaftor 
monotherapy). 
 
Decrease in heart rate 
During the 24-week, placebo-controlled, Phase 3 studies, a maximum decrease in mean heart rate of 
6 beats per minute (bpm) from baseline was observed on day 1 and day 15 around 4 to 6 hours after 
dosing. After day 15, heart rate was not monitored in the period after dosing in these studies. From 
week 4, the change in mean heart rate at pre-dose ranged from 1 to 2 bpm below baseline among 
patients treated with lumacaftor/ivacaftor. The percentage of patients with heart rate values < 50 bpm 
on treatment was 11% for patients who received lumacaftor/ivacaftor, compared to 4.9% for patients 
who received placebo. 
 
Cardiac electrophysiology 
No meaningful changes in QTc interval or blood pressure were observed in a thorough QT clinical 
study evaluating lumacaftor 600 mg once daily/ivacaftor 250 mg q12h and lumacaftor 1000 mg once 
daily/ivacaftor 450 mg q12h. 
 
Clinical efficacy and safety 



47 

 
Trials in patients with CF aged 12 years and above who are homozygous for the F508del mutation in 
the CFTR gene 
The efficacy of lumacaftor/ivacaftor in patients with CF who are homozygous for the F508del 
mutation in the CFTR gene was evaluated in two randomised, double-blind, placebo-controlled clinical 
trials of 1,108 clinically stable patients with CF, in which 737 patients were randomised to and dosed 
with lumacaftor/ivacaftor. Patients in both trials were randomised 1:1:1 to receive lumacaftor 600 mg 
once daily/ivacaftor 250 mg q12h, lumacaftor 400 mg q12h/ivacaftor 250 mg q12h, or placebo. 
Patients took the study drug with fat-containing food for 24 weeks in addition to their prescribed CF 
therapies (e.g., bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). Patients from 
these trials were eligible to roll over into a blinded extension study. 
 
Trial 1 evaluated 549 patients with CF who were aged 12 years and older (mean age 25.1 years) with 
percent predicted FEV1 (ppFEV1) at screening between 40-90 (mean ppFEV1 60.7 at baseline [range: 
31.1 to 94.0]). Trial 2 evaluated 559 patients aged 12 years and older (mean age 25.0 years) with 
ppFEV1 at screening between 40-90 (mean ppFEV1 60.5 at baseline [range: 31.3 to 99.8]). Patients 
with a history of colonisation with organisms such as Burkholderia cenocepacia, Burkholderia dolosa, 
or Mycobacterium abscessus or who had 3 or more abnormal liver function tests (ALT, AST, AP, 
GGT ≥ 3 times the ULN or total bilirubin ≥ 2 times the ULN) were excluded. 
 
The primary efficacy endpoint in both studies was the absolute change from baseline in ppFEV1 at 
week 24. Other efficacy variables included relative change from baseline in ppFEV1, absolute change 
from baseline in BMI, absolute change from baseline in CFQ-R Respiratory Domain, the proportion of 
patients achieving ≥ 5% relative change from baseline in ppFEV1 at week 24, and the number of 
pulmonary exacerbations (including those requiring hospitalisation or IV antibiotic therapy) through 
week 24. 
 
In both trials, treatment with lumacaftor/ivacaftor resulted in a statistically significant improvement in 
ppFEV1 (Table 5). Mean improvement in ppFEV1 was rapid in onset (day 15) and sustained 
throughout the 24-week treatment period. At day 15, the treatment difference between lumacaftor 
400 mg/ivacaftor 250 mg q12h and placebo for the mean absolute change (95% CI) in ppFEV1 from 
baseline was 2.51 percentage points in the pooled trials 1 and 2 (P < 0.0001). Improvements in 
ppFEV1 were observed regardless of age, disease severity, sex and geographic region. The Phase 3 
trials of lumacaftor/ivacaftor included 81 patients with ppFEV1 < 40 at baseline. The treatment 
difference in this subgroup was comparable to that observed in patients with ppFEV1 ≥ 40. At 
week 24, the treatment difference between lumacaftor 400 mg/ivacaftor 250 mg q12h and placebo for 
the mean absolute change (95% CI) in ppFEV1 from baseline in the pooled trials 1 and 2 were 3.39 
percentage points (P = 0.0382) for patients with ppFEV1 < 40 and 2.47 percentage points (P < 0.0001) 
for patients with ppFEV1 ≥ 40. 
 
Table 5: Summary of primary and key secondary outcomes in trial 1 and trial 2* 

 Trial 1 Trial 2 Pooled (trial 1 and trial 2) 

Placebo 
(n = 184) 

LUM 400 mg 
q12h/ IVA 

250 mg q12h 
(n = 182) 

Placebo 
(n = 187) 

LUM 400 mg 
q12h/IVA 

250 mg q12h 
(n = 187) 

Placebo 
(n = 371) 

LUM 400 mg 
q12h/IVA 

250 mg q12h 
(n = 369) 

Absolute change in 
ppFEV1 at week 24 
(percentage points) 

Treatment 
difference – 

2.41 
(P = 0.0003) † – 

2.65 
(P = 0.0011) † – 

2.55 
(P < 0.0001) 

Within-group 
change 

-0.73 
(P = 0.2168) 

1.68 
(P = 0.0051) 

-0.02 
(P = 0.9730) 

2.63 
(P < 0.0001) 

-0.39 
(P < 0.3494) 

2.16 
(P < 0.0001) 

Relative change in 
ppFEV1 at week 24 
(%) 

Treatment 
difference – 

4.15 
(P = 0.0028)† – 

4.69 
( P =0.0009)† – 

4.4 
(P < 0.0001) 

Within-group 
change 

-0.85 
(P = 0.3934) 

3.3 
(P = 0.0011) 

0.16 
(P = 0.8793) 

4.85 
(P < 0.0001) 

-0.34 
(P = 0.6375) 

4.1 
(P < 0.0001) 

Absolute change in 
BMI at week 24 
(kg/m2) 

Treatment 
difference – 

0.13 
(P = 0.1938) – 

0.36 
(P < 0.0001)† – 

0.24 
(P = 0.0004) 

Within-group 
change 

0.19 
(P = 0.0065) 

0.32 
(P < 0.0001) 

0.07 
(P = 0.2892) 

0.43 
(P < 0.0001) 

0.13 
(P = 0.0066) 

0.37 
(P < 0.0001) 



48 

Absolute change in 
CFQ-R 
Respiratory 
Domain Score at 
week 24 (points) 

Treatment 
difference – 

1.5 
(P = 0.3569) – 

2.9 
(P = 0.0736) – 

2.2 
(P = 0.0512) 

Within-group 
change 

1.1 
(P = 0.3423) 

2.6 
(P = 0.0295) 

2.8 
(P = 0.0152) 

5.7 
(P < 0.0001) 

1.9 
(P = 0.0213) 

4.1 
(P < 0.0001) 

Proportion of 
patients with ≥5% 
relative change in 
ppFEV1 at week 24 

% 25% 32% 26% 41% 26% 37% 

Odds ratio – 1.43 (P = 0.1208) – 
1.90 

(P = 0.0032) – 
1.66 

(P = 0.0013) 

Number of 
pulmonary 
exacerbations 
through week 24 

# of events 
(rate per 48 

wks) 
112 (1.07) 73 (0.71) 139 (1.18) 79 (0.67) 251 (1.14) 152 (0.70) 

Rate ratio – 0.66 (P = 0.0169) – 
0.57 

(P = 0.0002) – 
0.61 

(P < 0.0001) 

* In each study, a hierarchical testing procedure was performed within each active treatment arm for primary and secondary 
endpoints vs. placebo; at each step, P ≤ 0.0250 and all previous tests also meeting this level of significance was required for 
statistical significance. 

† Indicates statistical significance confirmed in the hierarchical testing procedure. 
 
At week 24, the proportion of patients who remained free from pulmonary exacerbations was 
significantly higher for patients treated with lumacaftor/ivacaftor compared with placebo. In the 
pooled analysis, the rate ratio of exacerbations through week 24 in subjects treated with 
lumacaftor/ivacaftor (lumacaftor 400 mg/ivacaftor 250 mg q12h; n = 369) was 0.61 (P < 0.0001), 
representing a reduction of 39% relative to placebo. The event rate per year, annualised to 48 weeks, 
was 0.70 in the lumacaftor/ivacaftor group and 1.14 in the placebo group. Treatment with 
lumacaftor/ivacaftor significantly decreased the risk for exacerbations requiring hospitalisation versus 
placebo by 61% (rate ratio = 0.39, P < 0.0001; event rate per 48 weeks 0.17 for lumacaftor/ivacaftor 
and 0.45 for placebo) and reduced exacerbations requiring treatment with intravenous antibiotics by 
56% (rate ratio = 0.44, P < 0.0001; event rate per 48 weeks 0.25 for lumacaftor/ivacaftor and 0.58 for 
placebo). These results were not considered statistically significant within the framework of the testing 
hierarchy for the individual studies. 
 
Long-term safety and efficacy rollover trial 
Trial 3 was a Phase 3, parallel-group, multicentre, rollover extension study in patients with CF that 
included patients aged 12 years and older from trial 1 and trial 2. This extension trial was designed to 
evaluate the safety and efficacy of long-term treatment of lumacaftor/ivacaftor. Of the 1,108 patients 
who received any treatment in trial 1 or trial 2, 1,029 (93%) were dosed and received active treatment 
(lumacaftor 600 mg once daily/ivacaftor 250 mg q12h or lumacaftor 400 mg q12h/ivacaftor 
250 mg q12h) in trial 3 for up to an additional 96 weeks (i.e., up to a total of 120 weeks). The primary 
efficacy analysis of this extension study included data up to week 72 of trial 3 with a sensitivity 
analysis that included data up to week 96 of trial 3.  
 
Patients treated with lumacaftor/ivacaftor in trial 1 or trial 2 showed an effect that was maintained with 
respect to baseline after an additional 96 weeks through trial 3. For patients who transitioned from 
placebo to active treatment similar changes as those observed in patients treated with 
lumacaftor/ivacaftor in trial 1 or trial 2 were seen (see Table 5). Results from trial 3 are presented in 
Figure 1 and Table 6. 
 
 



49 

Figure 1. Absolute change from baseline in percent predicted FEV1 at each visit† 
 

 
† From trials 1, 2 and 3. 
 

 
 
 
 
Table 6: Long-term effect of lumacaftor/ivacaftor in trial 3* 
 
 Placebo transitioned to  

Lumacaftor 400 mg q12h/ 
Ivacaftor 250 mg q12h  

(n = 176)** 

Lumacaftor 400 mg q12h/ 
Ivacaftor 250 mg q12h  

(n = 369)† 

Baseline and endpoint Mean (SD) 
LS Means 
(95% CI) P value Mean (SD) 

LS Means 
(95% CI) P value 

Baseline ppFEV1‡ 60.2 (14.7)   60.5 (14.1)   
Absolute change from baseline ppFEV1 (percentage points) 
 
Extension week 72  

 (n = 134) 
1.5  

(0.2, 2.9) 
 

(n = 75) 

 
0.0254 

 (n = 273) 
0.5  

(-0.4, 1.5) 
 

(n = 147) 

 
0.2806 

Extension week 96   0.8  
(-0.8, 2.3) 

 

0.3495  0.5  
(-0.7, 1.6) 

 

0.4231 

Relative change from baseline ppFEV1 (%)  
 
Extension week 72  

 (n = 134) 
2.6 

 (0.2, 5.0) 
 

(n = 75) 

 
0.0332 

 (n = 273) 
1.4  

(-0.3, 3.2) 
 

(n = 147) 

 
0.1074 

Extension week 96   1.1  
(-1.7, 3.9) 

 

0.4415  1.2  
(-0.8, 3.3) 

 

0.2372 

Baseline BMI (kg/m2)‡ 20.9 (2.8)   21.5 (3.0)   
Absolute change from baseline in BMI (kg/m2) 
 
Extension week 72  

 (n = 145) 
0.62  

(0.45, 0.79) 
 

(n = 80) 

 
< 0.0001 

 (n = 289) 
0.69  

(0.56, 0.81) 
 

(n = 155) 

 
< 0.0001 

Extension week 96   0.76  
(0.56, 0.97) 

 

< 0.0001  0.96  
(0.81, 1.11) 

 

< 0.0001 



50 

* A total of 82% (421 of 516 eligible patients) completed 72 weeks of this study; 42% completed 96 weeks. Majority of 
patients discontinued for reasons other than safety. 

** For patients rolled over from trials 1 and 2 (placebo-to-lumacaftor/ivacaftor group) total exposure was up to 96 weeks. 
Presentation of the lumacaftor 400 mg q12h/ivacaftor 250 mg q12h dose group is consistent with recommended posology. 

*** The event rate per patient-year was annualised to 48 weeks. 
† For patients rolled over from trials 1 and 2 (lumacaftor/ivacaftor-to-lumacaftor/ivacaftor group) total exposure was up to 

120 weeks. Presentation of the lumacaftor 400 mg q12h/ivacaftor 250 mg q12h dose group is consistent with 
recommended posology. 

‡ Baseline for the placebo transitioned to lumacaftor 400 mg q12h/ivacaftor 250 mg q12h group was the trial 3 baseline. 
Baseline for the lumacaftor 400 mg q12h/ivacaftor 250 mg q12h group was the trial 1 and 2 baseline. 

 
Trial in patients with CF who are heterozygous for the F508del mutation in the CFTR gene 
Trial 4 was a multicentre, double–blind, randomised, placebo–controlled, Phase 2 trial in 125 patients 
with CF aged 18 years and older who had a ppFEV1 of 40 to 90, inclusive, and have the F508del 
mutation on one allele plus a second allele with a mutation predicted to result in the lack of CFTR 
production or a CFTR that is not responsive to ivacaftor in vitro. 
 
Patients received either lumacaftor/ivacaftor (n = 62) or placebo (n = 63) in addition to their prescribed 
CF therapies. The primary endpoint was improvement in lung function as determined by the mean 
absolute change from baseline at day 56 in ppFEV1. Treatment with lumacaftor/ivacaftor resulted in no 
significant improvement in ppFEV1 relative to placebo in patients with CF heterozygous for the 
F508del mutation in the CFTR gene (treatment difference 0.60 [P = 0.5978]) and no meaningful 
improvements in BMI or weight (see section 4.4). 
 
Trials in patients with CF aged 6 to 11 years old who are homozygous for the F508del mutation in the 
CFTR gene 
Trial 7 was a 24-week, placebo-controlled, Phase 3 clinical study in 204 patients with CF aged 6 to 
11 years old (mean age 8.8 years). Trial 7 evaluated subjects with lung clearance index (LCI2.5) ≥ 7.5 
at the initial screening visit (mean LCI2.5 10.28 at baseline [range: 6.55 to 16.38]) and ppFEV1 ≥ 70 at 
screening (mean ppFEV1 89.8 at baseline [range: 48.6 to 119.6]). Patients received either lumacaftor 
200 mg/ivacaftor 250 mg every 12 hours (n = 103) or placebo (n = 101) in addition to their prescribed 
CF therapies. Patients who had 2 or more abnormal liver function tests (ALT, AST, AP, 
GGT ≥ 3 times the ULN), or ALT or AST > 5 times ULN, or total bilirubin > 2 times ULN were 
excluded. 
 

Baseline CFQ-R 
Respiratory Domain Score 
(points)‡ 

70.4 (18.5)   68.3 (18.0)   

Absolute change in CFQ-R Respiratory Domain Score (points) 
 
 
Extension week 72  

 (n = 135) 
3.3  

(0.7, 5.9) 
 

(n = 81) 

 
0.0124 

 (n = 269) 
5.7  

(3.8, 7.5) 
 

(n = 165) 

 
< 0.0001 

Extension week 96   0.5  
(-2.7, 3.6) 

 

0.7665  3.5  
(1.3, 5.8) 

 

0.0018 

Number of Pulmonary exacerbations (events) ** † *** 

 
Number of events per 
patient- year (95% CI) (rate 
per 48 wks) 
 
Number of events requiring 
hospitalization per patient-
year (95% CI) (rate per 48 
wks) 
 
Number of events requiring 
intravenous antibiotics per 
patient-year (95% CI) (rate 
per 48 wks) 

  
0.69 

(0.56, 0.85) 
 
 

0.30 
(0.22, 0.40) 

 
 
 

0.37 
(0.29, 0.49) 

   
0.65 

(0.56, 0.75) 
 
 

0.24 
(0.19, 0.29) 

 
 
 

0.32 
(0.26, 0.38) 

 



51 

The primary efficacy endpoint was absolute change in LCI2.5 from baseline through week 24. Key 
secondary endpoints included average absolute change from baseline in sweat chloride at day 15 and 
week 4 and at week 24 (see Pharmacodynamic effects), absolute change from baseline in BMI at 
week 24, absolute change from baseline in CFQ-R Respiratory Domain through week 24. These 
results are presented in Table 7 below: 
 
Table 7: Summary of primary and key secondary outcomes in trial 7 

 

Placebo 
(n = 101) 

LUM 200 mg/IVA 
250 mg q12h 

(n = 103) 
Primary Endpoint 

Absolute change in lung 
clearance index (LCI2.5) from 
baseline through week 24 

Treatment difference – -1.09 (P < 0.0001) 

Within-group change 0.08 (P = 0.5390) -1.01 (P < 0.0001) 

Key Secondary Endpoints* 

Absolute change in BMI at 
week 24 (kg/m2) 

Treatment difference – 0.11 (P = 0.2522) 

Within-group change 0.27 (P = 0.0002) 
0.38 

(P < 0.0001) 

Absolute change in CFQ-R 
Respiratory Domain Score 
through week 24 (points) 

Treatment difference – 2.5 (P = 0.0628) 

Within-group change 3.0 (P = 0.0035) 
5.5 

(P < 0.0001) 
* Trial included key secondary and other secondary endpoints. 
 
Percent predicted FEV1 was also evaluated as a clinically meaningful other secondary endpoint. In the 
lumacaftor/ivacaftor patients, the treatment difference for absolute change in ppFEV1 from baseline 
through week 24 was 2.4 (P = 0.0182). 
 
Patients with CF aged 6 years and older from trial 6 and trial 7 were included in a phase 3, multicentre, 
rollover extension study (trial 9). This extension trial was designed to evaluate the safety and efficacy 
of long-term treatment of lumacaftor/ivacaftor. Of the 262 patients who received any treatment in 
trial 6 or trial 7, 239 (91%) were dosed and received active treatment (patients 6 to <12 years of age 
received lumacaftor 200 mg q12h/ivacaftor 250 mg q12h; patients ≥12 years of age received 
lumacaftor 400 mg q12h/ivacaftor 250 mg q12h) in the extension study for up to an additional 
96 weeks (i.e., up to a total of 120 weeks) (see section 4.8). Secondary efficacy results and pulmonary 
exacerbation event rate per patient year are presented in Table 8. 
 



52 

 
Trial 8: Safety and tolerability study in paediatric patients with CF aged 2 to 5 years homozygous for 
the F508del mutation in the CFTR gene 
Trial 8 evaluated 60 patients aged 2 to 5 years at screening (mean age at baseline 3.7 years). According 
to their weight at screening, patients were administered granules mixed with food every 12 hours, at a 
dose of lumacaftor 100 mg/ivacaftor 125 mg granules for patients weighing less than14 kg (n = 19) or 
lumacaftor 150 mg/ivacaftor 188 mg for patients weighing 14 kg or greater (n = 41), for 24 weeks in 
addition to their prescribed CF therapies. In order to evaluate off drug effects, patients had a safety 
follow-up visit following a 2-week washout period. 
 
Secondary endpoints included absolute change from baseline in sweat chloride at week 24 and 
absolute change in sweat chloride from week 24 at week 26 (see Pharmacodynamic effects) as well as 
the endpoints listed in Table 9. The clinical relevance of the magnitude of these changes in children 2 
to 5 years with cystic fibrosis has not been clearly ascertained in longer-term treatment. 
 

Table 8: Long-term effect of lumacaftor/ivacaftor in trial 9 
 
 Placebo transitioned to  

lumacaftor / ivacaftor  
(P-L/I) 

(n = 96)* 

Lumacaftor / ivacaftor –  
lumacaftor / ivacaftor   

(L/I-L/I) 
(n = 143)* 

Baseline and endpoint Mean (SD) 
LS Mean 
(95% CI) Mean (SD) 

LS Mean 
(95% CI) 

 n = 101  n = 128  
Baseline LCI2.5‡** 10.26 (2.24)  10.24 (2.42)  
Absolute change from baseline in LCI2.5  

 
Extension week 96 

 (n = 69) 
-0.86 

(-1.33, -0.38) 
 

 (n = 88) 
-0.85 

(-1.25, -0.45) 
  

 n = 101  n = 161  
Baseline BMI (kg/m2)‡ 16.55 (1.96)  16.56 (1.77)  
Absolute change from baseline in BMI (kg/m2) 

 
Extension week 96  

 (n = 83) 
2.04  

(1.77, 2.31)  
 

 (n =130) 
1.78  

(1.56, 1.99) 
 

 n = 78  n = 135  
Baseline CFQ-R‡ 
Respiratory Domain Score 
(points) 

77.1  
(15.5) 

 78.5  
(14.3) 

 

Absolute change in CFQ-R Respiratory Domain Score (points) 

 
Extension week 96  

 (n = 65) 
6.6  

(3.1, 10.0) 
 

 (n = 108) 
7.4 

(4.8, 10.0) 
 

Number of pulmonary exacerbations (events) (trial 7 FAS and ROS)† 

 
Number of events per 
patient- year (95% CI)  
 

 n = 96 
0.30 

(0.21, 0.43) 
 

 n = 103 
0.45 

(0.33, 0.61) 
 

*Subjects treated with placebo in trial 7 (n=96) and transitioned onto active LUM/IVA treatment in the extension study 
(P-L/I). Subjects treated with LUM/IVA in either parent study [trial 6 (n=49) or trial 7 (n=94)] and continued active 
LUM/IVA treatment in the extension (L/I-L/I).  
‡Baseline for both groups (P-L/I and L/I-L/I) was the trial 6 and trial 7 (parent study) baseline and the corresponding n 
refers to the analysis set in the parent study. 
**The LCI sub-study included 117 subjects in the L/I-L/I group and 96 subjects in the P-L/I group. 
†FAS = full analysis set (n=103) includes subjects who received L/I in trial 7 and in trial 9, assessed over the 
cumulative study period for L/I; ROS = rollover set (n=96) includes subjects who received placebo in trial 7 and L/I in 
trial 9, assessed over the current study period in for trial 9. 



53 

Table 9: Summary of secondary outcomes in Trial 8 

Secondary endpoints* LUM/IVA 

Absolute change from baseline in body mass index (BMI) 
n = 57 
0.27 

95% CI: 0.07, 0.47; P = 0.0091 

Absolute change from baseline in BMI-for-age-z-score  
n = 57 
0.29 

95% CI: 0.14, 0.45; P = 0.0003 

Absolute change from baseline in weight (kg) 
n = 57 

1.4 
95% CI: 1.2, 1.7; P < 0.0001 

Absolute change from baseline in weight-for-age z-score  
n = 57 
0.26 

95% CI: 0.15, 0.38; P < 0.0001 

Absolute change from baseline in stature (cm) 
n = 57 

3.6 
95% CI: 3.3, 3.9; P < 0.0001 

Absolute change from baseline in stature-for-age z-score 
n = 57 
0.09 

95% CI: 0.02, 0.15; P = 0.0104 

Absolute change from baseline in faecal elastase-1 (FE-1) 
levels (µg/g)** 

n = 35 
52.6 

95% CI: 22.5, 82.7; P = 0.0012 

LCI 2.5 
n = 17 
-0.58 

95% CI: -1.17, 0.02; P = 0.0559 
Note: P values in the table are nominal. 
* For the endpoints listed, absolute change from baseline is the mean absolute change from baseline at 

week 24.  
** All patients had pancreatic insufficiency at baseline. Three of the 48 patients who had faecal elastase-1 values < 100 µg/g 

at baseline achieved a level of ≥ 200 µg/g at week 24. 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Orkambi in one or more subsets of the paediatric population in cystic fibrosis (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The exposure (AUC) of lumacaftor is approximately 2-fold higher in healthy adult volunteers 
compared to exposure in patients with CF. The exposure of ivacaftor is similar between healthy adult 
volunteers and patients with CF. After twice-daily dosing, steady-state plasma concentrations of 
lumacaftor and ivacaftor in healthy subjects were generally reached after approximately 7 days of 
treatment, with an accumulation ratio of approximately 1.9 for lumacaftor. The steady-state exposure 
of ivacaftor is lower than that of day 1 due to the CYP3A induction effect of lumacaftor (see 
section 4.5). 
 
After oral administration of lumacaftor 400 mg q12h/ivacaftor 250 mg q12h in a fed state, the 
steady-state mean (± SD) for AUC0-12h and Cmax were 198 (64.8) µg∙h/mL and 25.0 (7.96) µg/mL for 
lumacaftor, respectively, and 3.66 (2.25) µg∙h/mL and 0.602 (0.304) µg/mL for ivacaftor, respectively. 
After oral administration of ivacaftor alone as 150 mg q12h in a fed state, the steady-state mean (± SD) 
for AUC0-12h and Cmax were 9.08 (3.20) µg∙h/mL and 1.12 (0.319) µg/mL, respectively. 
 



54 

Absorption 
 
Following multiple oral doses of lumacaftor, the exposure of lumacaftor generally increased 
proportional to dose over the range of 50 mg to 1000 mg every 24 hours. The exposure of lumacaftor 
increased approximately 2.0-fold when given with fat-containing food relative to fasted conditions. 
The median (range) tmax of lumacaftor is approximately 4.0 hours (2.0; 9.0) in the fed state. 
 
Following multiple oral dose administration of ivacaftor in combination with lumacaftor, the exposure 
of ivacaftor generally increased with dose from 150 mg every 12 hours to 250 mg every 12 hours. The 
exposure of ivacaftor when given in combination with lumacaftor increased approximately 3-fold 
when given with fat-containing food in healthy volunteers. Therefore, lumacaftor/ivacaftor should be 
administered with fat-containing food. The median (range) tmax of ivacaftor is approximately 4.0 hours 
(2.0; 6.0) in the fed state. 
 
Distribution 
 
Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin. After oral 
administration of 400 mg every 12 hours in patients with CF in a fed state, the typical apparent 
volumes of distribution for the central and peripheral compartments [coefficient of variation as a 
percentage (CV)] were estimated to be 23.5 L (48.7%) and 33.3 L (30.5%), respectively. 
 
Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and 
albumin. After oral administration of ivacaftor 250 mg every 12 hours in combination with lumacaftor, 
the typical apparent volumes of distribution for the central and peripheral compartments (CV) were 
estimated to be 95.0 L (53.9%) and 201 L (26.6%), respectively. 
 
In vitro studies indicate that lumacaftor is a substrate of Breast Cancer Resistance Protein (BCRP). 
 
Biotransformation 
 
Lumacaftor is not extensively metabolised in humans, with the majority of lumacaftor excreted 
unchanged in the faeces. In vitro and in vivo data indicate that lumacaftor is mainly metabolised via 
oxidation and glucuronidation. 
 
Ivacaftor is extensively metabolised in humans. In vitro and in vivo data indicate that ivacaftor is 
primarily metabolised by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. 
M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. 
M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active. 
 
Elimination 
 
Following oral administration of lumacaftor, the majority of lumacaftor (51%) is excreted unchanged 
in the faeces. There was negligible urinary excretion of lumacaftor as unchanged drug. The apparent 
terminal half-life is approximately 26 hours. The typical apparent clearance, CL/F (CV), of lumacaftor 
was estimated to be 2.38 L/h (29.4%) for patients with CF. 
 
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. In healthy subjects, the half-life of ivacaftor when given with lumacaftor is approximately 
9 hours. The typical CL/F (CV) of ivacaftor when given in combination with lumacaftor was estimated 
to be 25.1 L/h (40.5%) for patients with CF. 
 
Special populations 
 
Hepatic impairment 
Following multiple doses of lumacaftor/ivacaftor for 10 days, subjects with moderately impaired 
hepatic function (Child-Pugh Class B, score 7 to 9) had higher exposures (AUC0-12h by approximately 



55 

50% and Cmax by approximately 30%) compared with healthy subjects matched for demographics. The 
impact of mild hepatic impairment (Child-Pugh Class A, score 5 to 6) on pharmacokinetics of 
lumacaftor given in combination with ivacaftor has not been studied, but the increase in exposure is 
expected to be less than 50%. 
 
Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C, 
score 10 to 15), but exposure is expected to be higher than in patients with moderate hepatic 
impairment (see sections 4.2, 4.4, and 4.8). 
 
Renal impairment 
Pharmacokinetic studies have not been performed with lumacaftor/ivacaftor in patients with renal 
impairment. In a human pharmacokinetic study with lumacaftor alone, there was minimal elimination 
of lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine 
with 0.18% as unchanged parent). 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). A population pharmacokinetic analysis of clearance versus creatinine 
clearance shows no trend for subjects with mild and moderate renal impairment (see section 4.2).  
 
Elderly 
The safety and efficacy of lumacaftor/ivacaftor in patients aged 65 years or older have not been 
evaluated. 
 
Gender 
The effect of gender on lumacaftor pharmacokinetics was evaluated using a population 
pharmacokinetics analysis of data from clinical studies of lumacaftor given in combination with 
ivacaftor. Results indicate no clinically relevant difference in pharmacokinetic parameters for 
lumacaftor or ivacaftor between males and females. No dose adjustments are necessary based on 
gender. 
 
Paediatric population 
The exposures are similar between adults and the paediatric population based on population (PK) 
analyses as presented in Table 10. 
 
Table 10: Mean (SD) lumacaftor and ivacaftor exposure by age group 

Age group Dose 

Mean 
lumacaftor 

(SD) 
AUCss 

(μg/mL*h) 

Mean ivacaftor 
(SD) 

AUCss 
(μg/mL*h) 

Patients aged 2 to 5 years 
and weighing and less than 
14 kg 

lumacaftor 100 mg/ivacaftor 
125 mg sachet every 12 hours 

180 (45.5) 5.92 (4.61) 
Patients aged 2 to 5 years 
and weighing 14 kg or 
greater 

lumacaftor 150 mg/ivacaftor 
188 mg sachet every 12 hours 

217 (48.6) 5.90 (1.93) 
Patients aged 6 to 11 years lumacaftor 200 mg/ivacaftor 

250 mg every 12 hours  203 (57.4) 5.26 (3.08) 
Patients aged 12 to less than 
18 years  

lumacaftor 400 mg/ivacaftor 
250 mg every 12 hours  241 (61.4) 3.90 (1.56) 

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



56 

reproduction and development. Specific studies to evaluate the phototoxic potential of lumacaftor were 
not conducted; however, evaluation of the available non-clinical and clinical data suggests no 
phototoxic liability. 
 
Ivacaftor 
 
Effects in repeated dose studies were observed only at exposures considered sufficiently in excess 
(> 25-, > 45-, and > 35-fold for mice, rats, and dogs, respectively) of the maximum human exposure of 
ivacaftor when administered as Orkambi, indicating little relevance to clinical use. Non-clinical data 
reveal no special hazard for humans based on conventional studies of genotoxicity and carcinogenic 
potential. 
 
Safety pharmacology 
Ivacaftor produced concentration-dependent inhibitory effect on hERG (human ether-à-go-go related 
gene) tail currents, with an IC15 of 5.5 µM, compared to the Cmax (1.5 µM) for ivacaftor at the 
therapeutic dose for lumacaftor/ivacaftor. However, no ivacaftor-induced QT prolongation was 
observed in a dog telemetry study at single doses up to 60 mg/kg or in ECG measurements from 
repeat-dose studies of up to 1 year duration at the 60 mg/kg/day dose level in dogs (Cmax after 
365 days = 36.2 to 47.6 μM). Ivacaftor produced a dose-related but transient increase in the blood 
pressure parameters in dogs at single oral doses up to 60 mg/kg (see section 5.1).  
 
Pregnancy and fertility 
Ivacaftor was not teratogenic when dosed orally to pregnant rats and rabbits during the organogenesis 
stage of foetal development at doses approximately 7 times (ivacaftor and metabolite exposure) and 
46 times the ivacaftor exposure in humans at the therapeutic lumacaftor/ivacaftor dose, respectively. 
At maternally toxic doses in rats, ivacaftor produced reductions in foetal body weight; an increase in 
the incidence of variations in cervical ribs, hypoplastic ribs, and wavy ribs; and sternal irregularities, 
including fusions. The significance of these findings for humans is unknown. 
 
Ivacaftor impaired fertility and reproductive performance indices in male and female rats at 
200 mg/kg/day (yielding exposures approximately 11 and 7 times, respectively, those obtained with 
the maximum recommended human dose of the ivacaftor component of Orkambi based on summed 
AUCs of ivacaftor and its metabolites extrapolated from day 90 exposures at 150 mg/kg/day in the 
6-month repeat-dose toxicity study and gestation day 17 exposures in the pilot embryofoetal 
development study in this species) when dams were dosed prior to and during early pregnancy. No 
effects on male or female fertility and reproductive performance indices were observed at 
≤ 100 mg/kg/day (yielding exposures approximately 8 and 5 times, respectively, those obtained with 
the maximum recommended human dose of the ivacaftor component of Orkambi based on summed 
AUCs of ivacaftor and its metabolites extrapolated from day 90 exposures at 100 mg/kg/day in the 
6-month repeat-dose toxicity study and gestation day 17 exposures in the embryofoetal development 
study in this species). Placental transfer of ivacaftor was observed in pregnant rats and rabbits. 
 
Peri- and post-natal development 
Ivacaftor did not cause developmental defects in the offspring of pregnant rats dosed orally from 
pregnancy through parturition and weaning at 100 mg/kg/day (yielding exposures that were 
approximately 4 times those obtained with the maximum recommended human dose of the ivacaftor 
component of Orkambi based on summed AUCs of ivacaftor and its metabolites). Doses above 
100 mg/kg/day resulted in survival and lactation indices that were 92% and 98% of control values, 
respectively, as well as reductions in pup body weights. 
 
Juvenile animals 
Findings of cataracts were observed in juvenile rats dosed with ivacaftor at 0.32 times the maximum 
recommended human dose based on systemic exposure of ivacaftor and its metabolites when 
co-administered with lumacaftor as Orkambi. Cataracts were not observed in foetuses derived from rat 
dams treated during the organogenesis stage of foetal development, in rat pups exposed to a certain 
extent through milk ingestion prior to weaning, or in repeated dose toxicity studies with ivacaftor. The 
potential relevance of these findings in humans is unknown. 



57 

 
Lumacaftor and ivacaftor 
 
Repeat-dose toxicity studies involving the co-administration of lumacaftor and ivacaftor revealed no 
special hazard for humans in terms of potential for additive and/or synergistic toxicities. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Cellulose, microcrystalline 
Croscarmellose sodium 
Hypromellose acetate succinate 
Povidone (K30) 
Sodium laurilsulfate 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
 
Once mixed, the mixture has been shown to be stable for one hour. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Orkambi granules are packaged in a foil laminate [biaxially-oriented polyethylene 
terephthalate/polyethylene/foil/polyethylene (BOPET/PE/Foil/PE)] sachet.  
 
Pack size of 56 (4 wallets with 14 sachets per wallet) sachets. 
 
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/1/15/1059/006 
EU/1/15/1059/007 
 



58 

 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 November 2015 
Date of latest renewal: 
 
 
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. 

  

http://www.ema.europa.eu/


59 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
 

 



60 

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 Limited 
Seagoe Industrial Estate 
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; 
• 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. 

 
• Obligation to conduct post-authorisation measures: 



61 

 
The MAH shall complete, within the stated timeframe, the below measures: 
 

Description Due Date 
Post-Authorisation Safety Study (PASS) 
The applicant should conduct a 5-year long-term observational study with 
lumacaftor/ivacaftor in patients with cystic fibrosis, including also 
microbiological and clinical endpoints (e.g. exacerbations) according to an 
approved protocol. The Applicant should submit yearly analyses from 
December 2017 to 2020 and the final CSR by December 2021. 

Final CSR 
December 2021 

 
Post-Authorisation Efficacy Study (PAES) 
Based on an agreed protocol, the Applicant should conduct a long-term 
effectiveness study to compare disease progression among children with CF 
homozygous for F508del-CFTR and are aged 2 through 5 years at the time 
of Orkambi treatment initiation versus disease progression among concurrent 
matched cohort of children with CF who have never received Orkambi 
treatment, in addition to a longitudinal historical cohort. 

 
Interim Analysis: 
December 2022 
 
Final Report: 
December 2025 

  



62 

 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



63 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
A. LABELLING 

 



64 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orkambi 100 mg/125 mg film-coated tablets 
lumacaftor/ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 100 mg of lumacaftor and 125 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
112 film-coated tablets (4 packs of 28 tablets). 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
 
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 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



65 

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/1/15/1059/005 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Orkambi 100/125 tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 



66 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
INNER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orkambi 100 mg/125 mg film-coated tablets 
lumacaftor/ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 100 mg of lumacaftor and 125 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 
 
Mon. Tue. Wed. Thu. Fri. Sat. Sun. 
 
 
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 
 
 



67 

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/1/15/1059/005 
 
 
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 
 
 
  



68 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orkambi 100 mg/125 mg tablets 
lumacaftor/ivacaftor 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Vertex Pharmaceuticals (Ireland) Limited 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Morning 
 
Evening 
 
  



69 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON – SINGLE PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orkambi 200 mg/125 mg film-coated tablets 
lumacaftor/ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 200 mg of lumacaftor and 125 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 
 
Mon. Tue. Wed. Thu. Fri. Sat. Sun. 
 
 
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 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 



70 

 
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/1/15/1059/003 28 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Orkambi 200/125 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
  



71 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON - MULTIPACK - WITH BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orkambi 200 mg/125 mg film-coated tablets 
lumacaftor/ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 200 mg of lumacaftor and 125 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack: 112 (4 packs of 28) film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 

 
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 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 



72 

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/1/15/1059/001 112 film-coated tablets (4 packs of 28 tablets) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Orkambi 200/125 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 
  



73 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
INNER CARTON FOR MULTIPACK 
 
NO BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orkambi 200 mg/125 mg film-coated tablets 
lumacaftor/ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 200 mg of lumacaftor and 125 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets 
Component of a multipack, can’t be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
Mon. Tue. Wed. Thu. Fri. Sat. Sun. 
 
 
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 
 
 



74 

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/1/15/1059/001 112 film-coated tablets 
 
 
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 
 
 
 
  



75 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orkambi 200 mg/125 mg tablets 
lumacaftor/ivacaftor 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Vertex Pharmaceuticals (Ireland) Limited 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Morning 
 
Evening 



76 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR SACHET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orkambi 100 mg/125 mg granules in sachet 
lumacaftor/ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet of granules contains 100 mg of lumacaftor and 125 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
granules 
 
56 sachets 
 
4 individual wallets with 14 sachets per wallet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
 
Read the package leaflet before use. 
 
Oral use 
 
Lift here to open 
 
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 
 
 



77 

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/1/15/1059/006 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Orkambi 100/125 granules 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



78 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
WALLET FOR SACHET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orkambi 100 mg/125 mg granules in sachet 
lumacaftor/ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet of granules contains 100 mg of lumacaftor and 125 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
granules  
 
14 sachets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Instructions for Use 
 

• Usual dose: Take one sachet of ORKAMBI granules every 12 hours.  
• Mix entire content of sachet with 5 mL of age-appropriate soft food or liquid that is at or 

below room temperature. Consume it completely. Use within one hour after mixing, just 
before or after a fat-containing meal or snack. 

 
Read the package leaflet before use. 
 
Oral use 
 
Morning 
Evening 
 
Use all 7 days’ doses before starting a new wallet. 
 
Mon. Tue. Wed. Thu. Fri. Sat. Sun. 
 
 
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 
 



79 

 
8. EXPIRY DATE 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1059/006 
 
 
13. BATCH NUMBER 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
 
  



80 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Orkambi 100 mg/125 mg granules 
lumacaftor/ivacaftor 
 
Oral use 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Vertex Pharmaceuticals (Ireland) Limited 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 
  



81 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR SACHET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orkambi 150 mg/188 mg granules in sachet 
lumacaftor/ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet of granules contains 150 mg of lumacaftor and 188 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
granules 
 
56 sachets 
 
4 individual wallets with 14 sachets per wallet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
Lift here to open 
 
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 
 
 



82 

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/1/15/1059/007 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Orkambi 150/188 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



83 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
WALLET FOR SACHET 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Orkambi 150 mg/188 mg granules in sachet  
lumacaftor/ivacaftor 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet of granules contains 150 mg of lumacaftor and 188 mg of ivacaftor. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
granules  
 
14 sachets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Instructions for Use 
 

• Usual dose: Take one sachet of ORKAMBI granules every 12 hours.  
• Mix entire content of sachet with 5 mL of age-appropriate soft food or liquid that is at or 

below room temperature. Consume it completely. Use within one hour after mixing, just 
before or after a fat-containing meal or snack. 
 

Read the package leaflet before use. 
 
Oral use 
 
Morning 
Evening 
 
Use all 7 days’ doses before starting a new wallet. 
 
Mon. Tue. Wed. Thu. Fri. Sat. Sun. 
 
 
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 
 



84 

 
8. EXPIRY DATE 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1059/007 
 
 
13. BATCH NUMBER 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
 
  



85 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
SACHETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Orkambi 150 mg/188 mg granules 
lumacaftor/ivacaftor 
 
Oral use 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Vertex Pharmaceuticals (Ireland) Limited 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
  



86 

 

B. PACKAGE LEAFLET 



87 

Package leaflet: Information for the patient 
 

Orkambi 100 mg/125 mg film-coated tablets 
Orkambi 200 mg/125 mg film-coated tablets 

lumacaftor/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 Orkambi is and what it is used for 
2. What you need to know before you take Orkambi 
3. How to take Orkambi 
4. Possible side effects 
5. How to store Orkambi 
6. Contents of the pack and other information 
 
 
1. What Orkambi is and what it is used for 
 
Orkambi contains two active substances, lumacaftor and ivacaftor. It is a medicine used for long-term 
treatment of cystic fibrosis (CF) in patients aged 6 years and older who have a specific change (called 
F508del mutation) affecting the gene for a protein called cystic fibrosis transmembrane conductance 
regulator (CFTR), which plays an important role in regulating the flow of mucus in the lungs. People 
with the mutation will produce an abnormal CFTR protein. Cells contain two copies of the CFTR 
gene; Orkambi is used in patients in whom both copies are affected by the F508del mutation 
(homozygotes). 
 
Lumacaftor and ivacaftor work together to improve the function of the abnormal CFTR protein. 
Lumacaftor increases the amount of CFTR available and ivacaftor helps the abnormal protein to work 
more normally.  
 
Orkambi may help your breathing by improving your lung function. You may also notice  that it is 
easier to gain weight. 
. 
 
2. What you need to know before you take Orkambi 
 
Do not take Orkambi 
• if you are allergic to lumacaftor, ivacaftor, or any of the other ingredients of this medicine 

(listed in section 6). 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Orkambi. 
 



88 

Orkambi should not be used in patients other than those who have two copies of the F508del 
mutation in their CFTR gene. 
 
Talk to your doctor before taking Orkambi if you have been told you have liver or kidney disease as 
your doctor may need to adjust the dose of Orkambi. 
 
Abnormal blood tests of the liver have been commonly seen in some people receiving Orkambi. Tell 
your doctor straight away if you have any of these symptoms, which may be a sign of liver problems: 
• Pain or discomfort in the upper right stomach (abdominal) area 
• Yellowing of your skin or the white part of your eyes 
• Loss of appetite 
• Nausea or vomiting 
• Dark urine 
• Confusion 
 
Your doctor should do some blood tests to check your liver before and while you are taking Orkambi, 
particularly during the first year. 
 
Respiratory events such as shortness of breath or chest tightness or narrowing of the airways were 
seen in patients when starting Orkambi, especially in patients who have poor lung function. If you 
have poor lung function your doctor may monitor you more closely when you start Orkambi. 
 
An increase in blood pressure has been seen in some patients treated with Orkambi. Your doctor may 
monitor your blood pressure during treatment with Orkambi. 
 
Abnormality of the lens of the eye (cataract) without any effect on vision has been noted in some 
children and adolescents treated with Orkambi and ivacaftor alone (one of the components of 
Orkambi).Your doctor may perform some eye examinations prior to and during treatment with 
Orkambi.  
 
Orkambi is not recommended in patients who have undergone an organ transplant. 
 
Children under 6 years old 
Orkambi tablets should not be used in children under the age of 6 years. Other forms of this medicine 
(granules in a sachet) are more suitable for children under 6 years of age, ask your doctor or 
pharmacist. 
 
Other medicines and Orkambi 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Especially tell your doctor if you take any of the following medicines: 
 
• Antibiotic medicines (used for the treatment of bacterial infections) for example: 

telithromycin, clarithromycin, rifampicin, rifabutin, rifapentine, erythromycin 
 
• Anticonvulsant medicines (used for the treatment of fits [epileptic seizures]) for example: 

phenobarbital, carbamazepine, phenytoin 
 
• Benzodiazepines (used for the treatment of anxiety or sleeplessness [insomnia], agitation, etc.) 

for example:midazolam, triazolam 
 
• Antifungal medicines (used for the treatment of fungal infections) for example: 

fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole 
 



89 

• Immunosuppressants (used after an organ transplantation) for example: 
ciclosporin, everolimus, sirolimus, tacrolimus 

 
• Herbal medicines, for example: 

St. John’s wort (Hypericum perforatum) 
 
• Anti-allergic medicines (used for the treatment of allergies and/or asthma) for example: 

montelukast, fexofenadine 
 
• Antidepressant medicines (used for the treatment of depression) for example: 

citalopram, escitalopram, sertraline, bupropion 
 
• Anti-inflammatory medicines (used for the treatment of inflammation) for example: 

ibuprofen 
 
• H2 Antagonist medicines (used to reduce stomach acid) for example: 

ranitidine 
 
• Cardiac glycosides (used for the treatment of mild to moderate congestive heart failure and an 

abnormal heart rhythm called atrial fibrillation) for example: 
digoxin 

 
• Anticoagulants (used to prevent blood clots from forming or growing larger in blood and blood 

vessels) for example: 
warfarin, dabigatran 

 
• Contraceptive medicines (used for the prevention of pregnancy): 

oral, injectable, and implantable contraceptives as well as contraceptive skin patches; that may 
include ethinyl estradiol, norethindrone, and other progestogens. These should not be relied 
upon as an effective method of birth control when given with Orkambi 

 
• Corticosteroid medicines (used to treat inflammation): 

methylprednisolone, prednisone 
 
• Proton pump inhibitor medicines (used to treat acid reflux disease and ulcers): 

omeprazole, esomeprazole, lansoprazole 
 
• Oral hypoglycaemics (used for the management of type 2 diabetes):  

repaglinide 
 
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC - an 
active component in cannabis) in patients receiving Orkambi. Your doctor may request another test to 
verify results. 
 
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. It may be better to avoid using Orkambi during 
pregnancy, if possible, and your doctor will help you decide what is best for you and your child. 
 
It is unknown if lumacaftor or ivacaftor are found in human milk. If you plan to breast-feed, ask your 
doctor for advice before taking Orkambi. Your doctor will decide whether to recommend that you stop 
breast-feeding or for you to stop lumacaftor/ivacaftor therapy. Your doctor will take into account the 
benefit of breast-feeding for the child and the benefit of therapy for you. 
 



90 

Driving and using machines 
Dizziness has been reported in patients receiving ivacaftor, a component of Orkambi, which could 
influence the ability to drive or use machines. If you experience dizziness, you should not drive or use 
machines until these symptoms disappear. 
 
If a child experiences dizziness while taking Orkambi, it is advised that the child does not ride a 
bike or do anything else that needs their full attention, until their symptoms disappear. 
 
Orkambi contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-
free’. 
 
 
3. How to take Orkambi 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
Recommended dose 
The recommended dose for patients aged 6 years and over is two tablets in the morning, and two 
tablets in the evening (12 hours apart). That is a total of four tablets per day, to be taken with food 
containing fat. 
 
There are different strengths of Orkambi tablet for different age groups. Check you have been given 
the right tablet (below). 
 

Age Tablets Dose 
6 to 11 years 
 

Orkambi 100 mg/125 mg 
 

2 tablets in the morning 
2 tablets in the evening 
 

12 years and older 
 

Orkambi 200 mg/125 mg 
 

2 tablets in the morning 
2 tablets in the evening 

 
You may start taking Orkambi on any day of the week. 
 
If you have moderate or severe problems with liver function, your doctor may need to reduce the 
dose of Orkambi as your liver will not clear Orkambi as fast as in people who have normal liver 
function. 
• Moderate liver problems: the dose may be reduced to two tablets in the morning and one tablet 

in the evening.  
• Severe liver problems: the dose may be reduced to one tablet in the morning and one tablet in the 

evening. 
 
Method of administration 
Orkambi is for oral use. Swallow the tablets whole. Do not chew, break, or dissolve the tablets.  
 
Taking Orkambi with fat-containing food is important to get the right levels of medicine in your 
body. A fat-containing meal or snack should be consumed just before or just after taking Orkambi. 
Meals and snacks recommended in CF guidelines or meals recommended in standard nutritional 
guidelines contain adequate amounts of fat. Examples of meals or snacks that contain fat are those 
prepared with butter or oils or those containing eggs. Examples of other fat-containing foods are: 
• Cheese, whole milk, whole-milk dairy products 
• Meats, oily fish 
• Avocados, hummus, soy-based products (tofu) 
• Nutritional bars or drinks 
 



91 

If you take more Orkambi than you should 
Contact your doctor or pharmacist for advice. If possible, have your medicine and this leaflet with you. 
You may experience side effects, including those mentioned in section 4 below. 
 
If you forget to take Orkambi 
Take the missed dose with fat-containing food if less than 6 hours have passed since the time you 
missed the dose. Otherwise, wait until your next scheduled dose as you normally would. Do not take a 
double dose to make up for the forgotten tablets. 
 
If you stop taking Orkambi 
You should keep taking the medicine as your doctor directs even if you feel well. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects although not everybody gets them. The side 
effects reported with Orkambi and ivacaftor alone (one of the active substances of Orkambi) are listed 
below and may occur with the use of Orkambi. 
 
Serious side effects for Orkambi include raised levels of liver enzymes in the blood, liver injury,  and 
worsening of pre-existing severe liver disease. The worsening of liver function can be fatal. These 
serious side effects are uncommon (may affect up to 1 in 100 people).  
 
Tell your doctor straight away if you have any of the following symptoms: 
• Pain or discomfort in the upper right stomach (abdominal) area 
• Yellowing of your skin or the white part of your eyes 
• Loss of appetite 
• Nausea or vomiting 
• Confusion 
• Dark urine 
 
Other side effects 
Very common (may affect more than 1 in 10 people) 
• Cough with sputum 
• Nasal congestion  
• Shortness of breath 
• Headache 
• Abdominal pain (stomach ache)  
• Diarrhoea 
• Increase in sputum 
• Nausea 
• Common cold* 
• Dizziness* 
• Changes in the type of bacteria in mucus* 
 
Common (may affect up to 1 in 10 people) 
• Chest tightness 
• Narrowing of the airways 
• Sinus congestion* 
• Stuffy or runny nose 
• Upper respiratory tract infection  
• Sore throat 
• Redness in the throat* 
• Rash 



92 

• Passing gas 
• Vomiting  
• Increase of an enzyme in your blood (blood creatine phosphokinase) 
•  high levels of liver enzymes, shown by blood test 
• Irregular periods (menses) or pain with menses 
• Ear pain, ear discomfort* 
• Ringing in the ears* 
• Redness inside the ear* 
• Inner ear disorder (feeling dizzy or spinning)* 
• Breast mass* 
 
Uncommon (may affect up to 1 in 100 people) 
• Abnormal periods, including the absence or infrequent menses, or more frequent or heavier 

menstrual bleeding 
• Increase in blood pressure 
• Ear congestion* 
• Breast inflammation* 
• Enlargement of the breast in males* 
• Nipple changes or pain* 
 
*Side effects seen for ivacaftor alone. 
 
Side effects in children 
Side effects seen in children are similar to those seen in adults and adolescents. However, increased 
liver enzymes in the blood have been seen more frequently in younger children than 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 Orkambi 
 
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 carton/blister 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 protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Orkambi contains 
The active substances are lumacaftor and ivacaftor.  
 
Orkambi 100 mg/125 mg film-coated tablets: 
Each film-coated tablet contains 100 mg of lumacaftor and 125 mg of ivacaftor. 
 

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


93 

Orkambi 200 mg/125 mg film-coated tablets: 
Each film-coated tablet contains 200 mg of lumacaftor and 125 mg of ivacaftor. 
 
Orkambi 100 mg/125 mg film-coated tablets and Orkambi 200 mg/125 mg film-coated tablets: 
The other ingredients are: 
• Tablet core: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate succinate; 

povidone (K30); sodium laurilsulfate; and magnesium stearate (see section 2 “Orkambi contains 
sodium”). 

• Tablet coating: polyvinyl alcohol; titanium dioxide (E171); macrogol 3350; talc; carmine 
(E120); brilliant blue FCF aluminium lake (E133); and indigo carmine aluminium lake (E132). 

• Printing ink: shellac; iron oxide black (E172); propylene glycol; and ammonium hydroxide. 
 
What Orkambi looks like and contents of the pack 
 
Orkambi 100 mg/125 mg film-coated tablets 
 
Orkambi 100 mg/125 mg film-coated tablets (tablets) are pink, oval-shaped tablets (dimensions 14 × 
7.6 × 4.9 mm) printed with “1V125” in black ink on one side. 
Orkambi 100 mg/125 mg is available in packs containing 112 film-coated tablets (4 packs of 28 film-
coated tablets).  
 
Orkambi 200 mg/125 mg film-coated tablets 
 
Orkambi 200 mg/125 mg film-coated tablets (tablets) are pink, oval-shaped tablets (dimensions 14 × 
8.4 × 6.8 mm) printed with “2V125” in black ink on one side. 
Orkambi 200 mg/125 mg is available in packs containing 28 film-coated tablets and in multipacks 
containing 112 film-coated tablets (4 packs of 28 film-coated tablets). 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Vertex Pharmaceuticals (Ireland) Limited 
28-32 Pembroke Street Upper 
Dublin 2, D02 EK84 
Ireland 
Tel: +353 (0)1 761 7299 
 
Manufacturer 
Almac Pharma Services (Ireland) Limited 
Finnabair Industrial Estate 
Dundalk 
Co. Louth 
A91 P9KD 
Ireland 
 
Almac Pharma Services Limited 
Seagoe Industrial Estate 
Craigavon 
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 web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 

http://www.ema.europa.eu/


94 

Package leaflet: Information for the patient 
 

Orkambi 100 mg/125 mg granules in sachet 
Orkambi 150 mg/188 mg granules in sachet 

lumacaftor/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 your child may get. See the end of 
section 4 for how to report side effects. 
 
Read all of this leaflet carefully before your child starts 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 child’s doctor or pharmacist. 
• This medicine has been prescribed for your child only. Do not pass it on to others. It may harm 

them even if their signs of illness are the same as your child’s. 
• If your child gets any side effects, talk to your child’s doctor or pharmacist. This includes any 

possible side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Orkambi is and what it is used for 
2. What you need to know before your child takes Orkambi 
3. How to take Orkambi 
4. Possible side effects 
5. How to store Orkambi 
6. Contents of the pack and other information 
 
 
1. What Orkambi is and what it is used for 
 
Orkambi contains two active substances, lumacaftor and ivacaftor. It is a medicine used for long-term 
treatment of cystic fibrosis (CF) in patients aged 2 years and older who have a specific change (called 
F508del mutation) affecting the gene for a protein called cystic fibrosis transmembrane conductance 
regulator (CFTR), which plays an important role in regulating the flow of mucus in the lungs. People 
with the mutation will produce an abnormal CFTR protein. Cells contain two copies of the CFTR 
gene; Orkambi is used in patients in whom both copies are affected by the F508del mutation 
(homozygotes). 
 
Lumacaftor and ivacaftor work together to improve the function of the abnormal CFTR protein. 
Lumacaftor increases the amount of CFTR available and ivacaftor helps the abnormal protein to work 
more normally.  
 
 
2. What you need to know before your child takes Orkambi 
 
Do not use Orkambi 
• if your child is allergic to lumacaftor, ivacaftor, or any of the other ingredients of this medicine 

(listed in section 6). 
 
Warnings and precautions 
Talk to your child’s doctor or pharmacist before taking Orkambi. 
 
Orkambi should not be used in patients other than those who have two copies of the F508del 
mutation in their CFTR gene. 
 



95 

Talk to your child’s doctor before taking Orkambi if you have been told your child has liver or kidney 
disease as the doctor may need to adjust the dose of Orkambi. 
 
Abnormal blood tests of the liver have been commonly seen in some people receiving Orkambi. Tell 
your child’s doctor straight away if your child has any of these symptoms, which may be a sign of 
liver problems: 
• Pain or discomfort in the upper right stomach (abdominal) area 
• Yellowing of the skin or the white part of the eyes 
• Loss of appetite 
• Nausea or vomiting 
• Dark urine 
• Confusion 
 
Your child’s doctor should do some blood tests to check your child’s liver before and while she/he is 
taking Orkambi, particularly during the first year. 
 
Respiratory events such as shortness of breath or chest tightness or narrowing of the airways were 
seen in patients when starting Orkambi, especially in patients who have poor lung function. If your 
child has poor lung function your child’s doctor may monitor your child more closely when she/he 
starts Orkambi. 
 
An increase in blood pressure has been seen in some patients treated with Orkambi. Your child’s 
doctor may monitor your child’s blood pressure during treatment with Orkambi. 
 
Abnormality of the lens of the eye (cataract) without any effect on vision has been noted in some 
children and adolescents treated with Orkambi and ivacaftor alone (one of the components of 
Orkambi). Your child’s doctor may perform some eye examinations prior to and during treatment with 
Orkambi. 
 
Orkambi is not recommended in patients who have undergone an organ transplant. 
 
Children under 2 years old 
It is not known if Orkambi is safe and effective in children under 2 years of age. Therefore, Orkambi 
should not be used in children under the age of 2 years. 
 
Other medicines and Orkambi 
Tell your child’s doctor or pharmacist if your child is taking, has recently taken or might take any 
other medicines. 
 
Especially tell the doctor if your child takes any of the following medicines: 
 
• Antibiotic medicines (used for the treatment of bacterial infections) for example: 

telithromycin, clarithromycin, rifampicin, rifabutin, rifapentine, erythromycin 
 
• Anticonvulsant medicines (used for the treatment of fits [epileptic seizures]) for example: 

phenobarbital, carbamazepine, phenytoin 
 
• Benzodiazepines (used for the treatment of anxiety or sleeplessness [insomnia], agitation, etc.) 

for example: 
midazolam, triazolam 

 
• Antifungal medicines (used for the treatment of fungal infections) for example: 

fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole 
 
• Immunosuppressants (used after an organ transplantation) for example: 

ciclosporin, everolimus, sirolimus, tacrolimus 



96 

 
• Herbal medicines, for example: 

St. John’s wort (Hypericum perforatum) 
 
• Anti-allergic medicines (used for the treatment of allergies and/or asthma) for example: 

montelukast, fexofenadine 
 
• Antidepressant medicines (used for the treatment of depression) for example: 

citalopram, escitalopram, sertraline, bupropion 
 
• Anti-inflammatory medicines (used for the treatment of inflammation) for example: 

ibuprofen 
 
• H2 Antagonist medicines (used to reduce stomach acid) for example: 

ranitidine 
 
• Cardiac glycosides (used for the treatment of mild to moderate congestive heart failure and an 

abnormal heart rhythm called atrial fibrillation) for example: 
digoxin 

 
• Anticoagulants (used to prevent blood clots from forming or growing larger in blood and blood 

vessels) for example: 
warfarin, dabigatran 

 
• Contraceptive medicines (used for the prevention of pregnancy): 

oral, injectable, and implantable contraceptives as well as contraceptive skin patches; that may 
include ethinyl estradiol, norethindrone, and other progestogens. These should not be relied 
upon as an effective method of birth control when given with Orkambi 

 
• Corticosteroid medicines (used to treat inflammation): 

methylprednisolone, prednisone 
 
• Proton pump inhibitor medicines (used to treat acid reflux disease and ulcers): 

omeprazole, esomeprazole, lansoprazole 
 
• Oral hypoglycaemics (used for the management of type 2 diabetes):  

repaglinide 
 
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC - an 
active component in cannabis) in patients receiving Orkambi. Your child’s doctor may request another 
test to verify results. 
 
Driving and using machines 
Dizziness has been reported in patients receiving ivacaftor, a component of Orkambi, which could 
influence the ability to drive or use machines.  
 
If a child experiences dizziness while taking Orkambi, it is advised that the child does not ride a 
bike or do anything else that needs their full attention, until their symptoms disappear. 
 
IOrkambi contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-
free’. 
 
 



97 

3. How to take Orkambi 
 
Always give your child this medicine exactly as your child’s doctor has told you. Check with the 
doctor if you are not sure. 
 
Your child’s doctor will determine the correct dose for your child. Your child must keep using all 
other medicines, unless your child’s doctor tells you to stop using any. 
 
Recommended dose 
The recommended dose for patients aged 2 years and over is indicated in the table below. Orkambi has 
to be taken in the morning and in the evening (12 hours apart) with food containing fat. 
 
There are different strengths of Orkambi according to a child’s age and weight. Check your child has 
been given the right dose (below). 
 

Age, weight Product Dose 
2 to 5 years and 
weighing less than 
14 kg 

Orkambi 100 mg/125 mg granules in 
sachet 

One sachet in the morning; 
One sachet in the evening 

2 to 5 years and 
weighing 14 kg or 
greater  

Orkambi 150 mg/188 mg granules in 
sachet 

One sachet in the morning; 
One sachet in the evening 

 
If your child has moderate or severe problems with liver function, your child’s doctor may need to 
reduce the dose of Orkambi as your child’s liver will not clear Orkambi as fast as in children who have 
normal liver function. 
• Moderate liver problems: the dose may be reduced on alternate days: two sachets on one day 

(morning and evening), one sachet the next (morning only). 
• Severe liver problems: the dose may be reduced to one sachet per day, or less often. 
 
Method of administration 
Orkambi is for oral use.  
 
Each sachet is for single use only. 
 
You may start giving your child Orkambi on any day of the week. 
 
Giving Orkambi granules to your child: 
• Hold sachet of granules with cut line on top. 
• Shake sachet gently to settle contents. 
• Tear or cut sachet open along the line. 
• Mix the entire contents of a sachet with one teaspoon (5 mL) of age-appropriate soft food or 

liquid. Food or liquid should be at room temperature or below. Some examples of age-
appropriate soft foods and liquids include puréed fruits, flavoured yogurt, and milk or juice. 

• Once mixed, give the product to your child immediately. If this is not possible, give it within the 
hour after mixing. Make sure that the mixture is consumed immediately and completely. 

• Food containing fat should be given to your child just before or just after dosing (some 
examples are provided below). 

 
Taking Orkambi with fat-containing food is important to get the right levels of medicine in the 
body. Meals and snacks recommended in CF guidelines or meals recommended in standard nutritional 
guidelines contain adequate amounts of fat. Examples of meals or snacks that contain fat are those 
prepared with butter or oils or those containing eggs. Examples of other fat-containing foods are: 
• Cheese, whole milk, whole-milk dairy products 
• Meats, oily fish 
• Avocados, hummus, soy-based products (tofu) 



98 

• Nutritional bars or drinks 
 
If your child takes more Orkambi than he/she should 
Contact your child’s doctor or pharmacist for advice. If possible, have your child’s medicine and this 
leaflet with you. Your child may experience side effects, including those mentioned in section 4 
below. 
 
If you forget to give your child Orkambi 
Give the missed dose with fat-containing food if less than 6 hours have passed since the time your 
child missed the dose. Otherwise, wait until your child’s next scheduled dose as you normally would. 
Do not give your child a double dose to make up for the forgotten dose. 
 
If you stop giving your child Orkambi 
Give Orkambi to your child for as long as your child’s doctor recommends. Do not stop unless your 
child’s doctor advises you to. You should keep giving the medicine as the doctor directs even if the 
child feels well. 
 
If you have any further questions on the use of this medicine, ask your child’s doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects although not everybody gets them. The side 
effects reported with Orkambi and ivacaftor alone (one of the active substances of Orkambi) are listed 
below and may occur with the use of Orkambi. 
 
Serious side effects for Orkambi include raised levels of liver enzymes in the blood, liver injury and 
worsening of pre-existing severe liver disease. The worsening of liver function can be fatal. These 
serious side effects are uncommon (may affect up to 1 in 100 people).  
 
Tell your child’s doctor straight away if he/she gets any of these: 
• Pain or discomfort in the upper right stomach (abdominal) area 
• Yellowing of the skin or the white part of the eyes 
• Loss of appetite 
• Nausea or vomiting 
• Confusion 
• Dark urine 
 
Other side effects 
Very common (may affect more than 1 in 10 people) 
• Cough with sputum 
• Nasal congestion  
• Shortness of breath 
• Headache 
• Abdominal pain (stomach ache)  
• Diarrhoea 
• Increase in sputum 
• Nausea 
• Common cold* 
• Dizziness* 
• Changes in the type of bacteria in mucus* 
 
Common (may affect up to 1 in 10 people) 
• Chest tightness 
• Narrowing of the airways 
• Sinus congestion* 



99 

• Stuffy or runny nose 
• Upper respiratory tract infection  
• Sore throat 
• Redness in the throat* 
• Rash 
• Passing gas 
• Vomiting 
• Increase of an enzyme in the blood (blood creatine phosphokinase) 
• High levels of liver enzymes, shown by blood test 
• Irregular periods (menses) or pain with menses 
• Ear pain, ear discomfort* 
• Ringing in the ears* 
• Redness inside the ear* 
• Inner ear disorder (feeling dizzy or spinning)* 
• Breast mass* 
 
Uncommon (may affect up to 1 in 100 people) 
• Abnormal periods, including the absence or infrequent menses, or more frequent or heavier 

menstrual bleeding 
• Increase in blood pressure 
• Ear congestion* 
• Breast inflammation* 
• Enlargement of the breast in males* 
• Nipple changes or pain* 
 
*Side effects seen for ivacaftor alone. 
 
Side effects in children 
Side effects seen in children are similar to those seen in adults and adolescents. However, increased 
liver enzymes in the blood have been seen more frequently in younger children than in adults.  
 
Reporting of side effects 
If your child gets any side effects, talk to your child’s 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 Orkambi 
 
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 carton/sachet 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 child’s pharmacist 
how to throw away medicines your child no longer uses. These measures will help protect the 
environment. 
 
 
6. Contents of the pack and other information 
 
What Orkambi contains 
The active substances are lumacaftor and ivacaftor.  

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100 

 
Orkambi 100 mg/125 mg granules in sachet:  
Each sachet contains 100 mg of lumacaftor and 125 mg of ivacaftor. 
 
Orkambi 150 mg/188 mg granules in sachet:  
Each sachet contains 150 mg of lumacaftor and 188 mg of ivacaftor. 
 
The other ingredients are: cellulose, microcrystalline; croscarmellose sodium; hypromellose acetate 
succinate; povidone (K30); and sodium laurilsulfate (see section 2 “Orkambi contains sodium”). 
 
What Orkambi looks like and contents of the pack 
Orkambi 100 mg/125 mg granules in sachet are white to off-white granules. 
 
Orkambi 150 mg/188 mg granules in sachet are white to off-white granules. 
 
The granules are supplied in sachets. 
• Pack size of 56 sachets (contains 4 individual wallets with 14 sachets per wallet) 
 
Marketing Authorisation Holder 
Vertex Pharmaceuticals (Ireland) Limited 
28-32 Pembroke Street Upper 
Dublin 2, D02 EK84 
Ireland 
Tel: +353 (0)1 761 7299 
 
Manufacturer 
Almac Pharma Services (Ireland) Limited 
Finnabair Industrial Estate 
Dundalk 
Co. Louth 
A91 P9KD 
Ireland 
 
Almac Pharma Services Limited 
Seagoe Industrial Estate 
Craigavon 
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 web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 

  

http://www.ema.europa.eu/


101 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Annex IV 
Grounds for one additional renewal 

 



102 

Grounds for one additional renewal 
 
Based upon the data that have become available since the granting of the initial Marketing 
authorisation, the CHMP considers that the benefit-risk balance of Orkambi remains positive, but 
considers that its safety profile is to be closely monitored for the following reasons: 
 
• There is an ongoing PASS for Orkambi which aims to evaluate the long-term safety of 

lumacaftor/ivacaftor (LUM/IVA) therapy in patients with cystic fibrosis (CF). Given that this 
study is categorised as a category 1 and the results are considered key to benefit risk it is 
considered appropriate to have a second renewal of the marketing authorisation. 

• There is limited exposure and post-marketing data available for the recent approvals in 
paediatric patients (6-12 years and 2-5 years of age). 

• There is a planned PAES study to compare disease progression among children with CF 
homozygous for F508del-CFTR and aged 2 through 5 years at the time of Orkambi treatment 
initiation versus disease progression among concurrent matched cohort of children with CF 
who have never received Orkambi treatment, in addition to a longitudinal historical cohort. 
This study is expected to provide verification of the impact of Orkambi treatment on clinical 
outcomes (including long term safety) and disease progression and to confirm current efficacy 
and safety assumptions.  

•  
Therefore, based upon the limited safety profile of Orkambi, the CHMP concluded that the MAH 
should submit one additional renewal application in 5 years’ time. 
 


	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
	Grounds for one additional renewal