ORKAMBI 100mg / 125mg tablets medication leaflet

Orkambi 100 mg/125 mg film-coated tablets

Orkambi 200 mg/125 mg film-coated tablets

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.

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 oneside.

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 oneside.

Orkambi tablets are indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years andolder who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductanceregulator (CFTR) gene (see sections 4.2, pct. 4.4, and 5.1).

Orkambi should only be prescribed by physicians with experience in the treatment of CF. If thepatient’s genotype is unknown, an accurate and validated genotyping method should be performed toconfirm the presence of the F508del mutation on both alleles of the CFTR gene.

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

Age Strength Dose (every 12 hours)

Morning Evening6 to < 12 years lumacaftor 100 mg/ivacaftor 125 mg 2 tablets 2 tablets12 years and older lumacaftor 200 mg/ivacaftor 125 mg 2 tablets 2 tablets

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 snackshould be consumed just before or just after dosing (see section 5.2).

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 thenext scheduled dose. A double dose should not be taken to make up for the forgotten dose.

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, the doseshould be reduced to one tablet daily for the first week of treatment to allow for the steady stateinduction effect of lumacaftor. Following this period, the recommended daily dose should becontinued (see Table 2).

Table 2: Treatment initiation in patients taking strong CYP3A inhibitors

Age Strength Week 1 oftreatment Week 2 onwards6 to lumacaftor 100 mg/ivacaftor 125 mg From day 8 and< 12 years 1 tablet per thereafter dosing should12 years andolder lumacaftor 200 mg/ivacaftor 125 mg day be at the recommendeddaily dose

If treatment is interrupted for more than one week and then re-initiated while taking strong CYP3Ainhibitors, the dose should be reduced to one tablet daily for the first week of treatment re-initiation(see Table 2). Following this period, the recommended daily dose should be continued (seesection 4.5).

No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution isrecommended in patients with severe renal impairment (creatinine clearance less than or equal to30 mL/min) or end-stage renal disease (see sections 4.4 and 5.2).

No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). Forpatients 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 hepaticimpairment. Therefore, after weighing the risks and benefits of treatment, Orkambi should be usedwith caution in patients with severe hepatic impairment, at a reduced dose (see sections 4.4, pct. 4.8, and5.2).

For dose adjustments for patients with moderate or severe hepatic impairment, (see Table 3).

Table 3: Dose adjustment recommendations for patients with moderate or severe hepaticimpairment

Total Daily Dose

Age Strength Moderate Severe(Child-Pugh Class B) (Child-Pugh Class C)

Morning Evening Morning Evening6 to lumacaftor< 12 years 100 mg/ivacaftor125 mg 2 tablets 1 tablet 1 tablet or less 1 tablet or lessfrequently * frequently *12 years lumacaftorand older 200 mg/ivacaftor125 mg

* Dosing interval should be modified according to clinical response and tolerability; the frequency may be reduced for boththe morning dose and the evening dose.

The safety and efficacy of Orkambi in children aged less than 1 year have not yet been established. Nodata are available.

For oral use.

Patients should be instructed to swallow the tablets whole. Patients should not chew, break, or dissolvethe tablets.

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

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 alleleplus a second allele with a mutation predicted to result in a lack of CFTR production or that is notresponsive 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) mutationin the CFTR gene on one allele, with or without the F508del mutation on the other allele. Since theexposure 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 respirationabnormal) were more common during initiation of lumacaftor/ivacaftor therapy. Serious respiratoryevents were seen more frequently in patients with percent predicted forced expiratory volume in1 second (ppFEV1) <40, and may lead to discontinuation of the medicinal product. Clinical experiencein patients with ppFEV1 < 40 is limited and additional monitoring of these patients is recommendedduring initiation of therapy (see section 4.8). A transient decline in FEV1 has also been observed insome patients following initiation of lumacaftor/ivacaftor. There is no experience of initiatingtreatment with lumacaftor/ivacaftor in patients having a pulmonary exacerbation and initiatingtreatment 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. Bloodpressure 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 functiondecompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension receiving lumacaftor/ivacaftor. Lumacaftor/ivacaftor shouldbe used with caution in patients with advanced liver disease and only if the benefits are expected tooutweigh the risks. If lumacaftor/ivacaftor is used in these patients, they should be closely monitoredafter the initiation of treatment and the dose should be reduced (see sections 4.2, pct. 4.8, and 5.2).

Hepatobiliary adverse reactions

Elevated transaminases have been commonly reported in patients with CF receivinglumacaftor/ivacaftor. In some instances, these elevations have been associated with concomitantelevations in total serum bilirubin. Transaminase elevations have been observed more frequently inpaediatric 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 thefirst year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubinelevations, 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 ULNand/or clinical jaundice), dosing with lumacaftor/ivacaftor should be discontinued and laboratory testsclosely followed until the abnormalities resolve. A thorough investigation of potential causes shouldbe conducted and patients should be followed closely for clinical progression. Following resolution oftransaminase elevations, the benefits and risks of resuming dosing should be considered (seesections 4.2, pct. 4.8, and 5.2).

Depression

Depression (including suicidal ideation and suicide attempt) has been reported in patients treated withlumacaftor/ivacaftor, usually occurring within three months of treatment initiation and in patients witha history of psychiatric disorders. In some cases, symptom improvement was reported after dosereduction or treatment discontinuation. Patients (and caregivers) should be alerted about the need tomonitor for depressed mood, suicidal thoughts, or unusual changes in behaviour and to seek medicaladvice immediately if these symptoms present.

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 reliedupon 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 CYP3Ainducers (e.g., rifampicin, St. John’s wort [Hypericum perforatum]) is not recommended (seesection 4.5).

Caution is recommended while using lumacaftor/ivacaftor in patients with severe renal impairment orend-stage renal disease (see sections 4.2 and 5.2).

Cases of non-congenital lens opacities without impact on vision have been reported in paediatricpatients treated with lumacaftor/ivacaftor and ivacaftor monotherapy. Although other risk factors werepresent in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributableto ivacaftor cannot be excluded (see section 5.3). Baseline and follow-up ophthalmologicalexaminations are recommended in paediatric patients initiating treatment with lumacaftor/ivacaftor.

Lumacaftor/ivacaftor has not been studied in patients with CF who have undergone organtransplantation. Therefore, use in transplanted patients is not recommended. See section 4.5 forinteractions with immunosuppressants.

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

Based on exposure and indicated doses, the interaction profile is considered to be the same for allstrengths and pharmaceutical forms.

Lumacaftor is a strong inducer of CYP3A and ivacaftor is a weak inhibitor of CYP3A when given asmonotherapy. There is potential for other medicinal products to affect lumacaftor/ivacaftor whenadministered 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 impactthe exposure of lumacaftor, but increased ivacaftor exposure by 4.3-fold. Due to the induction effect oflumacaftor 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 of150 mg every 12 hours, the approved dose of ivacaftor monotherapy.

No dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently takinglumacaftor/ivacaftor. However, when initiating lumacaftor/ivacaftor in patients taking strong CYP3Ainhibitors, 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 minimaleffect 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 (seesections 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

Lumacaftor is a strong inducer of CYP3A. Ivacaftor is a weak inhibitor of CYP3A when given asmonotherapy. The net effect of lumacaftor/ivacaftor therapy is expected to be strong CYP3Ainduction. Therefore, concomitant use of lumacaftor/ivacaftor with CYP3A substrates may decreasethe exposure of these substrates (see section 4.4).

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 alterthe exposure of these substrates.

CYP2B6 and CYP2C substrates

Interaction with CYP2B6 and CYP2C substrates has not been investigated in vivo. In vitro studiessuggest 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 vitrostudies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of lumacaftor/ivacaftormay alter (i.e., either increase or decrease) the exposure of CYP2C8 and CYP2C9 substrates, decreasethe 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 plasmalumacaftor concentration. Lumacaftor inhibits the organic anion transporter (OAT) 1 and 3.

Lumacaftor and ivacaftor are inhibitors of BCRP. Co-administration of Orkambi with medicinalproducts that are substrates for OAT1/3 and BCRP transport may increase plasma concentrations ofsuch medicinal products. Lumacaftor and ivacaftor are not inhibitors of OATP1B1, OATP1B3, andorganic cation transporter (OCT) 1 and 2. Ivacaftor is not an inhibitor of OAT1 and OAT3.

Established and other potentially significant interactions

Table 4 provides the established or predicted effect of lumacaftor/ivacaftor on other medicinalproducts or the effect of other medicinal products on lumacaftor/ivacaftor. The information reported in

Table 4 mostly derives from in vitro studies. The recommendations provided under “Clinicalcomment” in Table 4 are based on interaction studies, clinical relevance, or predicted interactions dueto elimination pathways. Interactions that have the most clinical relevance are listed first.

Table 4: Established and other potentially significant interactions - dose recommendations foruse of lumacaftor/ivacaftor with other medicinal products

Concomitant medicinalproduct class:

Active substance name Effect Clinical comment

Concomitant medicinal products of most clinical relevance

Anti-allergics:montelukast ↔ LUM, IVA↓ montelukast No dose adjustment for montelukast is

Due to the induction of recommended. Appropriate clinical

CYP3A/2C8/2C9 by monitoring should be employed, as is

LUM reasonable, when co-administered withlumacaftor/ivacaftor. Lumacaftor/ivacaftormay decrease the exposure of montelukast,which may reduce its efficacy.

fexofenadine ↔ LUM, IVA↑ or ↓ fexofenadine Dose adjustment of fexofenadine may be

Due to potential required to obtain the desired clinical effect.induction or inhibition Lumacaftor/ivacaftor may alter the exposureof P-gp of fexofenadine.

Antibiotics:clarithromycin, ↔ LUM No dose adjustment of lumacaftor/ivacaftortelithromycin ↑ IVA is recommended when clarithromycin or

Due to inhibition of telithromycin are initiated in patients

CYP3A by currently taking lumacaftor/ivacaftor.clarithromycin,telithromycin↓ clarithromycin, The dose of lumacaftor/ivacaftor should betelithromycin reduced to one tablet daily for the first week

Due to induction of of treatment when initiating lumacaftor/

CYP3A by LUM ivacaftor in patients currently takingclarithromycin or telithromycin.

An alternative to these antibiotics, such asazithromycin, should be considered.

Lumacaftor/ivacaftor may decrease theexposures of clarithromycin andtelithromycin, which may reduce theirefficacy.

erythromycin ↔ LUM No dose adjustment of lumacaftor/ivacaftor↑ IVA is recommended when co-administered with

Due to inhibition of erythromycin.

CYP3A byerythromycin

Concomitant medicinalproduct class:

Active substance name Effect Clinical comment↓ erythromycin An alternative to erythromycin, such as

Due to induction of azithromycin, should be considered.

CYP3A by LUM Lumacaftor/ivacaftor may decrease theexposure of erythromycin, which may reduceits efficacy.

Anticonvulsants:carbamazepine, ↔ LUMphenobarbital, phenytoin ↓ IVA

Due to induction of

CYP3A by theseanticonvulsants↓ carbamazepine, Concomitant use of lumacaftor/ivacaftor withphenobarbital, these anticonvulsants is not recommended.phenytoin The exposures of ivacaftor and the

Due to induction of anticonvulsant may be significantly

CYP3A by LUM decreased, which may reduce the efficacy ofboth active substances.

Antifungals:itraconazole*, ↔ LUM No dose adjustment of lumacaftor/ivacaftorketoconazole, ↑ IVA is recommended when these antifungals areposaconazole, Due to inhibition of initiated in patients currently takingvoriconazole CYP3A by these lumacaftor/ivacaftor.

antifungals↓ itraconazole, The dose of lumacaftor/ivacaftor should beketoconazole, reduced to one tablet daily for the first weekvoriconazole of treatment when initiating lumacaftor/

Due to induction of ivacaftor in patients currently taking these

CYP3A by LUM antifungals.

↓ Posaconazole Concomitant use of lumacaftor/ivacaftor with

Due to induction of these antifungals is not recommended.

UGT by LUM Patients should be monitored closely forbreakthrough fungal infections if suchmedicinal products are necessary.

Lumacaftor/ivacaftor may decrease theexposures of these antifungals, which mayreduce their efficacy.

fluconazole ↔ LUM No dose adjustment of lumacaftor/ivacaftor↑ IVA is recommended when co-administered with

Due to inhibition of fluconazole.

CYP3A by fluconazole↓ fluconazole A higher dose of fluconazole may be

Due to induction by required to obtain the desired clinical effect.

LUM; fluconazole is Lumacaftor/ivacaftor may decrease thecleared primarily by exposure of fluconazole, which may reducerenal excretion as its efficacy.unchanged drug;however, modestreduction influconazole exposurehas been observed withstrong inducers

Concomitant medicinalproduct class:

Active substance name Effect Clinical comment

Anti-inflammatories:ibuprofen ↔ LUM, IVA↓ ibuprofen A higher dose of ibuprofen may be required

Due to induction of to obtain the desired clinical effect.

CYP3A/2C8/2C9 by Lumacaftor/ivacaftor may decrease the

LUM exposure of ibuprofen, which may reduce itsefficacy.

Anti-mycobacterials:rifabutin, rifampicin*, ↔ LUMrifapentine ↓ IVA

Due to induction of

CYP3A by anti-mycobacterials↓ rifabutin Concomitant use of lumacaftor/ivacaftor with

Due to induction of these anti-mycobacterials is not

CYP3A by LUM recommended. The exposure of ivacaftor willbe decreased, which may reduce the efficacyof lumacaftor/ivacaftor.

A higher dose of rifabutin may be required toobtain the desired clinical effect.

Lumacaftor/ivacaftor may decrease theexposure of rifabutin, which may reduce itsefficacy.

↔ rifampicin,rifapentine

Benzodiazepines:midazolam, triazolam ↔ LUM, IVA↓ midazolam, triazolam Concomitant use of lumacaftor/ivacaftor with

Due to induction of these benzodiazepines is not recommended.

CYP3A by LUM Lumacaftor/ivacaftor will decrease theexposures of midazolam and triazolam,which will reduce their efficacy.

Hormonal contraceptives:ethinyl estradiol, ↓ ethinyl estradiol, Hormonal contraceptives, including oral,norethindrone, and other norethindrone, and injectable, transdermal, and implantable,progestogens other progestogens should not be relied upon as an effective

Due to induction of method of contraception when

CYP3A/UGT by LUM co-administered with lumacaftor/ivacaftor.

Lumacaftor/ivacaftor may decrease theexposure of hormonal contraceptives, whichmay reduce their efficacy.

Immunosuppressants:ciclosporin, everolimus, ↔ LUM, IVAsirolimus, tacrolimus

Concomitant medicinalproduct class:

Active substance name Effect Clinical comment(used after organ ↓ ciclosporin, Concomitant use of lumacaftor/ivacaftor withtransplant) everolimus, sirolimus, these immunosuppressants is nottacrolimus recommended. Lumacaftor/ivacaftor will

Due to induction of decrease the exposure of these

CYP3A by LUM immunosuppressants, which may reduce theefficacy of these immunosuppressants. Theuse of lumacaftor/ivacaftor in organtransplant patients has not been studied.

Proton pump inhibitors:esomeprazole, ↔ LUM, IVAlansoprazole, omeprazole↓ esomeprazole, A higher dose of these proton pumplansoprazole, inhibitors may be required to obtain theomeprazole desired clinical effect. Lumacaftor/ivacaftor

Due to induction of may decrease the exposures of these proton

CYP3A/2C19 by LUM pump inhibitors, which may reduce theirefficacy.

Herbals:

St. John’s wort ↔ LUM Concomitant use of lumacaftor/ivacaftor with(Hypericum perforatum) ↓ IVA St. John’s wort is not recommended. The

Due to induction of exposure of ivacaftor will be decreased,

CYP3A by St. John’s which may reduce the efficacy ofwort lumacaftor/ivacaftor.

Other concomitant medicinal products of clinical relevance

Antiarrhythmics:digoxin ↔ LUM, IVA↑ or ↓ digoxin The serum concentration of digoxin should

Due to potential be monitored and the dose should be titratedinduction or inhibition to obtain the desired clinical effect.of P-gp Lumacaftor/ivacaftor may alter the exposureof digoxin.

Anticoagulants:dabigatran ↔ LUM, IVA↑ or ↓ dabigatran Appropriate clinical monitoring should be

Due to potential employed when co-administered withinduction or inhibition lumacaftor/ivacaftor. Dose adjustment ofof P-gp dabigatran may be required to obtain thedesired clinical effect. Lumacaftor/ivacaftormay alter the exposure of dabigatran.

warfarin ↔ LUM, IVA↑ or ↓ warfarin The international normalised ratio (INR)

Due to potential should be monitored when warfarininduction or inhibition co-administration with lumacaftor/ivacaftorof CYP2C9 by LUM is required. Lumacaftor/ivacaftor may alterthe exposure of warfarin.

Concomitant medicinalproduct class:

Active substance name Effect Clinical comment

Antidepressants:citalopram, escitalopram, ↔ LUM, IVAsertraline↓ citalopram, A higher dose of these antidepressants mayescitalopram, sertraline be required to obtain the desired clinical

Due to induction of effect. Lumacaftor/ivacaftor may decrease

CYP3A/2C19 by LUM the exposures of these antidepressants, whichmay reduce their efficacy.bupropion ↔ LUM, IVA↓ bupropion A higher dose of bupropion may be required

Due to induction of to obtain the desired clinical effect.

CYP2B6 by LUM Lumacaftor/ivacaftor may decrease theexposure of bupropion, which may reduce itsefficacy.

Corticosteroids, systemic:methylprednisolone, ↔ LUM, IVAprednisone↓ methylprednisolone, A higher dose of these systemicprednisone corticosteroids may be required to obtain the

Due to induction of desired clinical effect. Lumacaftor/ivacaftor

CYP3A by LUM may decrease the exposures ofmethylprednisolone and prednisone, whichmay reduce their efficacy.

H2 blockers:ranitidine ↔ LUM, IVA↑ or ↓ ranitidine Dose adjustment of ranitidine may be

Due to potential required to obtain the desired clinical effect.induction or inhibition Lumacaftor/ivacaftor may alter the exposureof P-gp of ranitidine.

Oral hypoglycemics:repaglinide ↔ LUM, IVA↓ repaglinide A higher dose of repaglinide may be required

Due to induction of to obtain the desired clinical effect.

CYP3A/2C8 by LUM Lumacaftor/ivacaftor may decrease theexposure of repaglinide, which may reduceits 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) inpatients receiving Orkambi. An alternative confirmatory method should be considered to verify results.

Interaction studies have only been performed in adults.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use oflumacaftor/ivacaftor in pregnant women. Animal studies with lumacaftor and ivacaftor do not indicatedirect or indirect harmful effects with respect to developmental and reproductive toxicity, whereaseffects were noted with ivacaftor only at maternally toxic doses (see section 5.3). As a precautionarymeasure, it is preferable to avoid the use of lumacaftor/ivacaftor during pregnancy unless the clinicalcondition of the mother requires treatment with lumacaftor/ivacaftor.

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

No human data on the effects of lumacaftor and/or ivacaftor on fertility are available. Lumacaftor hadno effects on fertility and reproductive performance indices in male and female rats. Ivacaftor impairedfertility and reproductive performance indices in male and female rats (see section 5.3).

Ivacaftor, which is one of the active components of Orkambi, has a minor influence on the ability todrive and use machines. Ivacaftor may cause dizziness (see section 4.8). Patients experiencingdizziness while taking Orkambi should be advised not to drive or use machines until symptoms abate.

The most common adverse reactions are dyspnoea (14.0%), diarrhoea (11.0%), and nausea (10.2%).

Serious adverse reactions included hepatobiliary events, e.g., transaminase elevations (0.5%),cholestatic hepatitis (0.3%) and hepatic encephalopathy (0.1%).

Adverse reactions identified from the 24-week, placebo-controlled, Phase 3 studies (trials 809-103 and809-104) in patients aged 12 years and older and from a 24-week, placebo-controlled study in patientsaged 6 to less than 12 years (trial 809-109), who are homozygous for the F508del mutation in the

CFTR gene are presented in Table 5 and are listed by system organ class and frequency. Adversereactions observed with ivacaftor alone are also provided in Table 5. Adverse reactions are rankedunder 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 notknown (frequency cannot be estimated using the available data).

Table 5: Adverse reactions in lumacaftor/ivacaftor-treated patients and in patients treated withivacaftor alone

System organ class Frequency Adverse reactions

Infections and infestations very common Nasopharyngitis*common Upper respiratory tract infection, rhinitis

Psychiatric disorders not known Depression

Vascular disorders uncommon Hypertension

Nervous system disorders very common Headache, dizziness*uncommon Hepatic encephalopathy†

Ear and labyrinth disorders common Ear pain*, ear discomfort*, tinnitus*, tympanicmembrane hyperaemia*, vestibular disorder*uncommon Ear congestion*

Respiratory, thoracic and very common Nasal congestion, dyspnoea, productive cough,mediastinal disorders sputum increasedcommon Respiration abnormal, oropharyngeal pain, sinuscongestion*, rhinorrhoea, pharyngeal erythema*,bronchospasm

Gastrointestinal disorders very common Abdominal pain*, abdominal pain upper,diarrhoea, nauseacommon Flatulence, vomiting

Hepatobiliary disorders common Transaminase elevationsuncommon Cholestatic hepatitis‡

Skin and subcutaneous tissue common Rashdisorders

Reproductive system and common Menstruation irregular, dysmenorrhoea,breast disorders metrorrhagia, breast mass*uncommon Menorrhagia, amenorrhoea, polymenorrhoea,breast inflammation*, gynaecomastia*, nippledisorder*, nipple pain*, oligomenorrhoea

Investigations very common Bacteria in sputum*common Blood creatine phosphokinase increaseduncommon 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 F508delmutation in the CFTR gene treated with lumacaftor/ivacaftor for up to an additional 96 weeks in thelong-term safety and efficacy rollover study (trial 809-105) were similar to the 24-week,placebo-controlled studies (see section 5.1).

Hepatobiliary adverse reactions

During trials 809-103 and 809-104, 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 was5.1% 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 withelevated transaminases, including 3 with concurrent elevation in total bilirubin. Followingdiscontinuation of lumacaftor/ivacaftor, liver function tests returned to baseline or improvedsubstantially in all patients (see section 4.4).

Among 7 patients with pre-existing cirrhosis and/or portal hypertension who receivedlumacaftor/ivacaftor in the placebo-controlled, Phase 3 studies, worsening liver function withincreased ALT, AST, bilirubin, and hepatic encephalopathy was observed in one patient. The eventoccurred within 5 days of the start of dosing and resolved following discontinuation oflumacaftor/ivacaftor (see section 4.4).

Post-marketing cases of liver function decompensation including liver failure leading to death havebeen reported in CF patients with pre-existing cirrhosis with portal hypertension who were treated withlumacaftor/ivacaftor (see section 4.4).

Respiratory adverse reactions

During trials 809-103 and 809-104, the incidence of respiratory adverse reactions (e.g., chestdiscomfort, dyspnoea, bronchospasm, and respiration abnormal) was 26.3% inlumacaftor/ivacaftor-treated patients compared to 17.0% in patients who received placebo. Theincidence 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 mostpatients the events resolved without dosing interruption. The majority of adverse reactions were mildor 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 809-011 [Part B]) in 46 patients aged12 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 patientswho were initiated at the full dose of lumacaftor/ivacaftor (2 tablets every 12 hours), the incidence was71.4%, and in the 18 patients who were initiated at a reduced dose of lumacaftor/ivacaftor (1 tabletevery 12 hours for up to 2 weeks, and subsequently increased to the full dose), the incidence was55.6%. Of the patients who were initiated lumacaftor/ivacaftor at the full dose, one patient had aserious respiratory adverse reaction, three patients subsequently had their dose reduced, and threepatients discontinued treatment. No serious respiratory adverse reactions, dose reductions ordiscontinuations were seen in patients who were initiated at the half dose (see section 4.4).

Menstrual abnormalities

During trials 809-103 and 809-104, the incidence of combined menstrual abnormalities (amenorrhoea,dysmenorrhoea, menorrhagia, menstruation irregular, metrorrhagia, oligomenorrhoea, andpolymenorrhoea) was 9.9 % in lumacaftor/ivacaftor-treated female patients and 1.7% inplacebo-treated females. These menstrual events occurred more frequently in the subset of femalepatients who were taking hormonal contraceptives (25.0%) versus patients who were not takinghormonal contraceptives (3.5%) (see section 4.5). Most of these reactions were mild or moderate inseverity and non-serious. In lumacaftor/ivacaftor-treated patients, approximately two-thirds of thesereactions resolved, and the median duration was 10 days.

During trials 809-103 and 809-104, adverse reactions related to increased blood pressure (e.g.,hypertension, blood pressure increased) were reported in 0.9% (7/738) of patients treated withlumacaftor/ivacaftor and in no patients who received placebo.

In patients treated with lumacaftor/ivacaftor (mean baseline 114 mmHg systolic and 69 mmHgdiastolic), the maximum increase from baseline in mean systolic and diastolic blood pressure was3.1 mmHg and 1.8 mmHg, respectively. In patients who received placebo (mean baseline 114 mmHgsystolic and 69 mmHg diastolic), the maximum increase from baseline in mean systolic and diastolicblood 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 diastolicblood pressure > 90 mmHg on at least two occasions was 3.4% and 1.5% in patients treated withlumacaftor/ivacaftor, respectively, compared with 1.6% and 0.5% in patients who received placebo(see section 4.4).

The safety data of lumacaftor/ivacaftor were evaluated in 46 patients aged 1 to less than 2 years (trial809-122), 60 patients aged 2 to 5 years (trial 809-115), 161 patients aged 6 to less than 12 years (trials809-011 and 809-109) 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 to17 years were included in trials 809-103 and 809-104.

The overall safety profile in these paediatric patients is generally consistent with that in adult patients.

Few selected adverse reactions are specifically reported in the paediatric population.

Long-term safety data from a 96-week rollover extension study (trial 809-116) in 57 patients aged2 years and older who were homozygous for the F508del mutation in the CFTR gene were generallyconsistent with the 24-week parent study in patients aged 2 to 5 years (trial 809-115) and safety data inpatients aged 6 to less than 12 years.

Long-term safety data from a 96-week rollover extension study in 239 patients aged 6 years and olderwho were homozygous for the F508del mutation in the CFTR gene (trial 809-110) were generallyconsistent with the 24-week parent studies in patients aged 6 to less than 12 years (trial 809-011 andtrial 809-109).

Description of selected adverse reactions for patients aged 6 to less than 12 years

Hepatobiliary adverse reactions

During the 24-week, open-label Phase 3 clinical study in 58 patients aged 6 to less than 12 years(trial 809-011), the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and >3 x ULNwas 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 patientswith transaminase elevations, except 1 patient who discontinued treatment.

During the 24-week, placebo-controlled Phase 3 clinical study in 204 patients aged 6 to less than12 years (trial 809-109), 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 thelumacaftor/ivacaftor group and two patients in the placebo group discontinued treatment due totransaminase elevations.

Respiratory adverse reactions

During the 24-week, open-label Phase 3 clinical study (trial 809-011) in 58 patients aged 6 to less than12 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 809-109) in patients aged 6 to lessthan 12 years (mean baseline ppFEV1 was 89.8), the incidence of respiratory adverse reactions was18.4% in lumacaftor/ivacaftor patients and 12.9% in placebo patients. A decline in ppFEV1 atinitiation of therapy was observed during serial post dose spirometry assessments. The absolute changefrom pre-dose at 4 to 6 hours post-dose was -7.7 on day 1 and -1.3 on day 15 in lumacaftor/ivacaftorpatients. The post-dose decline was resolved by week 16.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No specific antidote is available for overdose with lumacaftor/ivacaftor. Treatment of overdoseconsists of general supportive measures including monitoring of vital signs and observation of theclinical status of the patient.

Adverse reactions that occurred at an increased incidence of ≥ 5% in the supratherapeutic dose periodcompared with the therapeutic dose period were headache, generalised rash, and increasedtransaminase.

Pharmacotherapeutic group: Other respiratory system products; ATC code: R07AX30

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 incellular processing and trafficking that reduces the quantity of CFTR at the cell surface. The smallamount of F508del-CFTR that reaches the cell surface has low channel-open probability (defectivechannel gating). Lumacaftor is a CFTR corrector that acts directly on F508del-CFTR to improve itscellular processing and trafficking, thereby increasing the quantity of functional CFTR at the cellsurface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating thechannel-open probability (or gating) of the CFTR protein at the cell surface. The combined effect oflumacaftor 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 improvescellular processing and trafficking of F508del-CFTR and ivacaftor potentiates F508del-CFTR are notknown.

Changes in sweat chloride in response to lumacaftor alone or in combination with ivacaftor wereevaluated in a double-blind, placebo-controlled, Phase 2 clinical trial in patients with CF aged 18 yearsand older. In this trial, 10 patients (homozygous for F508del-CFTR mutation) completed dosing withlumacaftor alone 400 mg q12h for 28 days followed by the addition of ivacaftor 250 mg q12h for anadditional 28 days, and 25 patients (homozygous or heterozygous for F508del) completed dosing withplacebo. The treatment difference between lumacaftor 400 mg q12h alone and placebo evaluated asmean 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/ivacaftor250 mg q12h and placebo evaluated as mean change in sweat chloride from baseline to day 56 wasstatistically significant at -11 mmol/L (95% CI: -18, -4).

In trial 809-109 (see Clinical efficacy and safety) in patients homozygous for the F508del-CFTRmutation aged 6 to less than 12 years, the treatment difference (LS mean) in sweat chloride for theabsolute change at week 24 as compared to placebo was -24.9 mmol/L (nominal P < 0.0001). Thetreatment difference (LS mean) in sweat chloride for the average absolute change at day 15 and atweek 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 alsoevaluated in the double-blind, placebo-controlled, Phase 2 trial in patients with CF aged 18 years andolder. The treatment difference between lumacaftor 400 mg q12h alone and placebo evaluated as meanabsolute change in ppFEV1 was -4.6 percentage points (95% CI: -9.6, 0.4) from baseline to day 28, 4.2percentage 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 lumacaftormonotherapy).

Decrease in heart rate

During the 24-week, placebo-controlled, Phase 3 studies, a maximum decrease in mean heart rate of6 beats per minute (bpm) from baseline was observed on day 1 and day 15 around 4 to 6 hours afterdosing. After day 15, heart rate was not monitored in the period after dosing in these studies. Fromweek 4, the change in mean heart rate at pre-dose ranged from 1 to 2 bpm below baseline amongpatients treated with lumacaftor/ivacaftor. The percentage of patients with heart rate values < 50 bpmon treatment was 11% for patients who received lumacaftor/ivacaftor, compared to 4.9% for patientswho received placebo.

No meaningful changes in QTc interval or blood pressure were observed in a thorough QT clinicalstudy evaluating lumacaftor 600 mg once daily/ivacaftor 250 mg q12h and lumacaftor 1000 mg oncedaily/ivacaftor 450 mg q12h.

Trials in patients with CF aged 12 years and above who are homozygous for the F508del mutation inthe CFTR gene

The efficacy of lumacaftor/ivacaftor in patients with CF who are homozygous for the F508delmutation in the CFTR gene was evaluated in two randomised, double-blind, placebo-controlled clinicaltrials of 1,108 clinically stable patients with CF, in which 737 patients were randomised to and dosedwith lumacaftor/ivacaftor. Patients in both trials were randomised 1:1:1 to receive lumacaftor 600 mgonce 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 CFtherapies (e.g., bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). Patients fromthese trials were eligible to roll over into a blinded extension study.

Trial 809-103 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 809-104 evaluated 559 patients aged 12 years and older (mean age 25.0years) 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 atweek 24. Other efficacy variables included relative change from baseline in ppFEV1, absolute changefrom baseline in BMI, absolute change from baseline in CFQ-R Respiratory Domain, the proportion ofpatients achieving ≥ 5% relative change from baseline in ppFEV1 at week 24, and the number ofpulmonary exacerbations (including those requiring hospitalisation or IV antibiotic therapy) throughweek 24.

In both trials, treatment with lumacaftor/ivacaftor resulted in a statistically significant improvement inppFEV1 (see Table 6). Mean improvement in ppFEV1 was rapid in onset (day 15) and sustainedthroughout the 24-week treatment period. At day 15, the treatment difference between lumacaftor400 mg/ivacaftor 250 mg q12h and placebo for the mean absolute change (95% CI) in ppFEV1 frombaseline was 2.51 percentage points in the pooled trials 809-103 and 809-104 (P < 0.0001).

Improvements in ppFEV1 were observed regardless of age, disease severity, sex and geographicregion. 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 withppFEV1 ≥ 40. At week 24, the treatment difference between lumacaftor 400 mg/ivacaftor 250 mg q12hand placebo for the mean absolute change (95% CI) in ppFEV1 from baseline in the pooled trials 809-103 and 809-104 were 3.39 percentage points (P = 0.0382) for patients with ppFEV1 < 40 and 2.47percentage points (P < 0.0001) for patients with ppFEV1 ≥ 40.

Table 6: Summary of primary and key secondary outcomes in trial 809-103 and trial 809-104*

Trial 809-103 Trial 809-104 Pooled (trial 809-103and trial 809-104)

LUM

LUM LUM 400 mg400 mg 400 mg q12h/IVAq12h/ IVA q12h/IVA 250 mg

Placebo 250 mg q12h Placebo 250 mg q12h Placebo q12h(n = 184) (n = 182) (n = 187) (n = 187) (n = 371) (n = 369)

Absolute Treatmentchange in difference - 2.41 2.65 2.55(P = 0.0003)† - (P = 0.0011)† - (P < 0.0001)ppFEV1 atweek 24 Within-group -0.73 1.68 -0.02 2.63 -0.39 2.16(percentage change (P = 0.2168) (P = 0.0051) (P = 0.9730) (P < 0.0001) (P < 0.3494) (P < 0.0001)points)

Relative Treatment - 4.15difference (P = 0.0028)† - 4.69 4.4change in (P = 0.0009)† - (P < 0.0001)ppFEV1 at Within-group -0.85 3.3 0.16 4.85 -0.34 4.1week 24 (%) change (P = 0.3934) (P = 0.0011) (P = 0.8793) (P < 0.0001) (P = 0.6375) (P < 0.0001)

Absolute Treatment 0.13 0.36 0.24change in difference - (P = 0.1938) - (P < 0.0001)† - (P = 0.0004)

BMI atweek 24 Within-group 0.19 0.32 0.07 0.43 0.13 0.37(kg/m2) change (P = 0.0065) (P < 0.0001) (P = 0.2892) (P < 0.0001) (P = 0.0066) (P < 0.0001)

Absolute Treatment 1.5 2.9 2.2change in difference - (P = 0.3569) - (P = 0.0736) - (P = 0.0512)

CFQ-R

Respiratory

Domain Within-group 1.1 2.6 2.8 5.7 1.9 4.1

Score at change (P = 0.3423) (P = 0.0295) (P = 0.0152) (P < 0.0001) (P = 0.0213) (P < 0.0001)week 24(points)

Proportion of % 25% 32% 26% 41% 26% 37%patients with≥5% relativechange in Odds ratio - 1.43 1.90 1.66ppFEV1 at (P = 0.1208) - (P = 0.0032) - (P = 0.0013)week 24

Number of # of eventspulmonary (rate per 48 112 (1.07) 73 (0.71) 139 (1.18) 79 (0.67) 251 (1.14) 152 (0.70)exacerbations weeks)throughweek 24 Rate ratio - 0.66 - 0.57 0.61(P = 0.0169) (P = 0.0002) - (P < 0.0001)

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

† Indicates statistical significance confirmed in the hierarchical testing procedure.

At week 24, the proportion of patients who remained free from pulmonary exacerbations wassignificantly higher for patients treated with lumacaftor/ivacaftor compared with placebo. In thepooled analysis, the rate ratio of exacerbations through week 24 in subjects treated withlumacaftor/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 withlumacaftor/ivacaftor significantly decreased the risk for exacerbations requiring hospitalisation versusplacebo by 61% (rate ratio=0.39, P < 0.0001; event rate per 48 weeks 0.17 for lumacaftor/ivacaftor and0.45 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 forplacebo). These results were not considered statistically significant within the framework of the testinghierarchy for the individual studies.

Long-term safety and efficacy rollover trial

Trial 809-105 was a Phase 3, parallel-group, multicentre, rollover extension study in patients with CFthat included patients aged 12 years and older from trial 809-103 and trial 809-104. This extension trialwas designed to evaluate the safety and efficacy of long-term treatment of lumacaftor/ivacaftor. Of the1,108 patients who received any treatment in trial 809-103 or trial 809-104, 1,029 (93%) were dosedand received active treatment (lumacaftor 600 mg once daily/ivacaftor 250 mg q12h or lumacaftor400 mg q12h/ivacaftor 250 mg q12h) in trial 809-105 for up to an additional 96 weeks (i.e., up to atotal of 120 weeks). The primary efficacy analysis of this extension study included data up to week 72of trial 809-105 with a sensitivity analysis that included data up to week 96 of trial 809-105.

Patients treated with lumacaftor/ivacaftor in trial 809-103 or trial 809-104 showed an effect that wasmaintained with respect to baseline after an additional 96 weeks through trial 809-105. For patientswho transitioned from placebo to active treatment similar changes as those observed in patients treatedwith lumacaftor/ivacaftor in trial 809-103 or trial 809-104 were seen (see Table 6). Results from trial809-105 are presented in Figure 1 and Table 7.

Figure 1. Absolute change from baseline in percent predicted FEV at each visit†† From trials 809-103, 809-104 and 809-105.

Table 7: Long-term effect of lumacaftor/ivacaftor in trial 809-105*

Placebo transitioned tolumacaftor 400 mg q12h/ lumacaftor 400 mg q12h/ivacaftor 250 mg q12h ivacaftor 250 mg q12h(n = 176)** (n = 369)†

Mean LS Means Mean LS Means

Baseline and endpoint (SD) (95% CI) P value (SD) (95% CI) P value

Baseline ppFEV ‡ 60.2 60.51 (14.7) (14.1)

Absolute change from baseline ppFEV1 (percentage points)(n = 134) (n = 273)

Extension week 72 1.5 0.0254 0.5 0.2806(0.2, 2.9) (-0.4, 1.5)(n = 75) (n = 147)

Extension week 96 0.8 0.3495 0.5 0.4231(-0.8, 2.3) (-0.7, 1.6)

Relative change from baseline ppFEV1 (%)(n = 134) (n = 273)

Extension week 72 2.6 0.0332 1.4 0.1074(0.2, 5.0) (-0.3, 3.2)(n = 75) (n = 147)

Extension week 96 1.1 0.4415 1.2 0.2372(-1.7, 3.9) (-0.8, 3.3)

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

Absolute change from baseline in BMI (kg/m2)(n = 145) (n = 289)

Extension week 72 0.62 < 0.0001 0.69 < 0.0001(0.45, 0.79) (0.56, 0.81)(n = 80) (n = 155)

Extension week 96 0.76 < 0.0001 0.96 < 0.0001(0.56, 0.97) (0.81, 1.11)

Baseline CFQ-R 70.4 68.3

Respiratory Domain (18.5) (18.0)

Score (points)‡

Absolute change in CFQ-R Respiratory Domain Score (points)(n = 135) (n = 269)

Extension week 72 3.3 0.0124 5.7 < 0.0001(0.7, 5.9) (3.8, 7.5)(n = 81) (n = 165)

Extension week 96 0.5 0.7665 3.5 0.0018(-2.7, 3.6) (1.3, 5.8)

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

Number of events perpatient- year (95% CI) 0.69 0.65(rate per 48 weeks) (0.56, 0.85) (0.56, 0.75)

Number of eventsrequiringhospitalization per 0.30 0.24patient-year (95% CI) (0.22, 0.40) (0.19, 0.29)(rate per 48 weeks)

Placebo transitioned tolumacaftor 400 mg q12h/ lumacaftor 400 mg q12h/ivacaftor 250 mg q12h ivacaftor 250 mg q12h(n = 176)** (n = 369)†

Mean LS Means Mean LS Means

Baseline and endpoint (SD) (95% CI) P value (SD) (95% CI) P value

Number of eventsrequiring intravenousantibiotics per patient- 0.37 0.32year (95% CI) (rate per (0.29, 0.49) (0.26, 0.38)48 weeks)

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

** For patients rolled over from trials 809-103 and 809-104 (placebo-to-lumacaftor/ivacaftor group) total exposure was up to96 weeks. Presentation of the lumacaftor 400 mg q12h/ivacaftor 250 mg q12h dose group is consistent withrecommended posology.

*** The event rate per patient-year was annualised to 48 weeks.† For patients rolled over from trials 809-103 and 809-104 (lumacaftor/ivacaftor-to-lumacaftor/ivacaftor group) totalexposure was up to 120 weeks. Presentation of the lumacaftor 400 mg q12h/ivacaftor 250 mg q12h dose group isconsistent with recommended posology.

‡ Baseline for the placebo transitioned to lumacaftor 400 mg q12h/ivacaftor 250 mg q12h group was the trial 809-105baseline. Baseline for the lumacaftor 400 mg q12h/ivacaftor 250 mg q12h group was the trial 809-103 and 809-104baseline.

Trial in patients with CF who are heterozygous for the F508del mutation in the CFTR gene

Trial 809-102 was a multicentre, double-blind, randomised, placebo-controlled, Phase 2 trial in125 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 meanabsolute change from baseline at day 56 in ppFEV1. Treatment with lumacaftor/ivacaftor resulted in nosignificant 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 meaningfulimprovements in BMI or weight (see section 4.4).

Trials in patients with CF aged 6 to less than 12 years old who are homozygous for the F508delmutation in the CFTR gene

Trial 809-109 was a 24-week, placebo-controlled, Phase 3 clinical study in 204 patients with CF aged6 to less than 12 years old (mean age 8.8 years). Trial 809-109 evaluated subjects with lung clearanceindex (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 receivedeither lumacaftor 200 mg/ivacaftor 250 mg every 12 hours (n = 103) or placebo (n = 101) in additionto 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 wereexcluded.

The primary efficacy endpoint was absolute change in LCI2.5 from baseline through week 24. Keysecondary endpoints included average absolute change from baseline in sweat chloride at day 15 andweek 4 and at week 24 (see Pharmacodynamic effects), absolute change from baseline in BMI atweek 24, absolute change from baseline in CFQ-R Respiratory Domain through week 24. Theseresults are presented in Table 8 below:

Table 8: Summary of primary and key secondary outcomes in trial 809-109

LUM 200 mg/IVA

Placebo 250 mg q12h(n = 101) (n = 103)

Primary endpoint

- 1.09

Absolute change in lung Treatment difference - (P < 0.0001)clearance index (LCI2.5) frombaseline through week 24 0.08

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

Key Secondary Endpoints*

Treatment difference - 0.11

Absolute change in BMI at (P = 0.2522)week 24 (kg/m2)

Within-group change 0.27 0.38(P = 0.0002) (P < 0.0001)2.5

Absolute change in CFQ-R Treatment difference - (P = 0.0628)

Respiratory Domain Scorethrough week 24 (points) Within-group change 3.0 5.5(P = 0.0035) (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 thelumacaftor/ivacaftor patients, the treatment difference for absolute change in ppFEV1 from baselinethrough week 24 was 2.4 (P = 0.0182).

Patients with CF aged 6 years and older from trial 809-011 and trial 809-109 were included in aphase 3, multicentre, rollover extension study (trial -809-110). This extension trial was designed toevaluate the safety and efficacy of long-term treatment of lumacaftor/ivacaftor. Of the 262 patientswho received any treatment in trial 809-011 or trial 809-109, 239 (91%) were dosed and receivedactive treatment (patients 6 to <12 years of age received lumacaftor 200 mg q12h/ivacaftor 250 mgq12h; patients ≥12 years of age received lumacaftor 400 mg q12h/ivacaftor 250 mg q12h) in theextension 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 9.

Table 9: Long-term effect of lumacaftor/ivacaftor in trial 809-110

Placebo transitioned to lumacaftor/ivacaftor -lumacaftor/ivacaftor lumacaftor/ivacaftor(P-L/I) (L/I-L/I)(n = 96)* (n = 143)*

LS Mean LS Mean

Baseline and endpoint Mean (SD) (95% CI) Mean (SD) (95% CI)n = 101 n = 128

Baseline LCI ‡**2.5 10.26 (2.24) 10.24 (2.42)

Absolute change from baseline in LCI2.5(n = 69) (n = 88)

Extension week 96 -0.86 -0.85(-1.33, -0.38) (-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)(n = 83) (n =130)

Extension week 96 2.04 1.78(1.77, 2.31) (1.56, 1.99)n = 78 n = 135

Baseline CFQ-R‡ 77.1 78.5

Respiratory Domain (15.5) (14.3)

Score (points)

Absolute change in CFQ-R Respiratory Domain Score (points)(n = 65) (n = 108)

Extension week 96 6.6 7.4(3.1, 10.0) (4.8, 10.0)

Number of pulmonary exacerbations (events) (trial 809-109 FAS and ROS)†

Number of events per n = 96 n = 103patient- year (95% CI) 0.30 0.45(0.21, 0.43) (0.33, 0.61)

* Subjects treated with placebo in trial 809-109 (n=96) and transitioned onto active LUM/IVA treatment in the extensionstudy (P-L/I). Subjects treated with LUM/IVA in either parent study [trial 809-011 (n=49) or trial 809-109 (n=94)] andcontinued 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 809-011 and trial 809-109 (parent study) baseline and thecorresponding 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 809-109 and in trial 809-110, assessed over thecumulative study period for L/I; ROS = Rollover Set (n=96) includes subjects who received placebo in trial 809-109 and

L/I in trial 809-110, assessed over the current study period for trial 809-110.

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 forinformation on paediatric use).

The exposure (AUC) of lumacaftor is approximately 2-fold higher in healthy adult volunteerscompared to exposure in patients with CF. The exposure of ivacaftor is similar between healthy adultvolunteers and patients with CF. After twice-daily dosing, steady-state plasma concentrations oflumacaftor and ivacaftor in healthy subjects were generally reached after approximately 7 days oftreatment, with an accumulation ratio of approximately 1.9 for lumacaftor. The steady-state exposureof ivacaftor is lower than that of day 1 due to the CYP3A induction effect of lumacaftor (seesection 4.5).

After oral administration of lumacaftor 400 mg q12h/ivacaftor 250 mg q12h in a fed state, thesteady-state mean (± SD) for AUC0-12h and Cmax were 198 (64.8) µg∙h/mL and 25.0 (7.96) µg/mL forlumacaftor, 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.

Following multiple oral doses of lumacaftor, the exposure of lumacaftor generally increasedproportional to dose over the range of 50 mg to 1000 mg every 24 hours. The exposure of lumacaftorincreased 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 exposureof ivacaftor generally increased with dose from 150 mg every 12 hours to 250 mg every 12 hours. Theexposure of ivacaftor when given in combination with lumacaftor increased approximately 3-foldwhen given with fat-containing food in healthy volunteers. Therefore, lumacaftor/ivacaftor should beadministered with fat-containing food. The median (range) Tmax of ivacaftor is approximately 4.0 hours(2.0; 6.0) in the fed state.

Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin. After oraladministration of 400 mg every 12 hours in patients with CF in a fed state, the typical apparentvolumes of distribution for the central and peripheral compartments [coefficient of variation as apercentage (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 andalbumin. 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) wereestimated 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).

Lumacaftor is not extensively metabolised in humans, with the majority of lumacaftor excretedunchanged in the faeces. In vitro and in vivo data indicate that lumacaftor is mainly metabolised viaoxidation and glucuronidation.

Ivacaftor is extensively metabolised in humans. In vitro and in vivo data indicate that ivacaftor isprimarily 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.

Following oral administration of lumacaftor, the majority of lumacaftor (51%) is excreted unchangedin the faeces. There was negligible urinary excretion of lumacaftor as unchanged drug. The apparentterminal half-life is approximately 26 hours. The typical apparent clearance, CL/F (CV), of lumacaftorwas 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 thefaeces after metabolic conversion. There was negligible urinary excretion of ivacaftor as unchangeddrug. In healthy subjects, the half-life of ivacaftor when given with lumacaftor is approximately 9hours. The typical CL/F (CV) of ivacaftor when given in combination with lumacaftor was estimatedto be 25.1 L/h (40.5%) for patients with CF.

Following multiple doses of lumacaftor/ivacaftor for 10 days, subjects with moderately impairedhepatic function (Child-Pugh Class B, score 7 to 9) had higher exposures (AUC0-12h by approximately50% and Cmax by approximately 30%) compared with healthy subjects matched for demographics. Theimpact of mild hepatic impairment (Child-Pugh Class A, score 5 to 6) on pharmacokinetics oflumacaftor given in combination with ivacaftor has not been studied, but the increase in exposure isexpected 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 hepaticimpairment (see sections 4.2, pct. 4.4, and 4.8).

Pharmacokinetic studies have not been performed with lumacaftor/ivacaftor in patients with renalimpairment. In a human pharmacokinetic study with lumacaftor alone, there was minimal eliminationof lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urinewith 0.18% as unchanged parent). In a human pharmacokinetic study with ivacaftor alone, there wasminimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity wasrecovered in the urine). A population pharmacokinetic analysis of clearance versus creatinineclearance shows no trend for subjects with mild and moderate renal impairment (see section 4.2).

The safety and efficacy of lumacaftor/ivacaftor in patients aged 65 years or older have not beenevaluated.

The effect of gender on lumacaftor pharmacokinetics was evaluated using a populationpharmacokinetics analysis of data from clinical studies of lumacaftor given in combination withivacaftor. Results indicate no clinically relevant difference in pharmacokinetic parameters forlumacaftor or ivacaftor between males and females. No dose adjustments are necessary based ongender.

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

Mean

Age group Dose lumacaftor (SD) Mean ivacaftor (SD)

AUCss AUCss(μg∙h/mL) (μg∙h/mL)

Patients aged 6 to lumacaftor 200 mg/ivacaftor<12 years 250 mg every 12 hours 203 (57.4) 5.26 (3.08)

Patients aged 12 to lumacaftor 400 mg/ivacaftor<18 years 250 mg every 12 hours 241 (61.4) 3.90 (1.56)

Patients aged 18 years lumacaftor 400 mg/ivacaftorand older 250 mg every 12 hours 198 (64.8) 3.66 (2.25)

Lumacaftor

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity toreproduction and development. Specific studies to evaluate the phototoxic potential of lumacaftor werenot conducted; however, evaluation of the available non-clinical and clinical data suggests nophototoxic liability.

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 ofivacaftor when administered as Orkambi, indicating little relevance to clinical use. Non-clinical datareveal no special hazard for humans based on conventional studies of genotoxicity and carcinogenicpotential.

Safety pharmacology

Ivacaftor produced concentration-dependent inhibitory effect on hERG (human ether-à-go-go relatedgene) tail currents, with an IC15 of 5.5 µM, compared to the Cmax (1.5 µM) for ivacaftor at thetherapeutic dose for lumacaftor/ivacaftor. However, no ivacaftor-induced QT prolongation wasobserved in a dog telemetry study at single doses up to 60 mg/kg or in ECG measurements fromrepeat-dose studies of up to 1 year duration at the 60 mg/kg/day dose level in dogs (Cmax after365 days = 36.2 to 47.6 μM). Ivacaftor produced a dose-related but transient increase in the bloodpressure parameters in dogs at single oral doses up to 60 mg/kg (see section 5.1).

Ivacaftor was not teratogenic when dosed orally to pregnant rats and rabbits during the organogenesisstage of foetal development at doses approximately 7 times (ivacaftor and metabolite exposure) and 46times the ivacaftor exposure in humans at the therapeutic lumacaftor/ivacaftor dose, respectively. Atmaternally toxic doses in rats, ivacaftor produced reductions in foetal body weight; an increase in theincidence 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 at200 mg/kg/day (yielding exposures approximately 11 and 7 times, respectively, those obtained withthe 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 the6-month repeat-dose toxicity study and gestation day 17 exposures in the pilot embryofoetaldevelopment study in this species) when dams were dosed prior to and during early pregnancy. Noeffects 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 withthe 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 the6-month repeat-dose toxicity study and gestation day 17 exposures in the embryofoetal developmentstudy in this species). Placental transfer of ivacaftor was observed in pregnant rats and rabbits.

Ivacaftor did not cause developmental defects in the offspring of pregnant rats dosed orally frompregnancy through parturition and weaning at 100 mg/kg/day (yielding exposures that wereapproximately 4 times those obtained with the maximum recommended human dose of the ivacaftorcomponent of Orkambi based on summed AUCs of ivacaftor and its metabolites). Doses above100 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 maximumrecommended human dose based on systemic exposure of ivacaftor and its metabolites whenco-administered with lumacaftor as Orkambi. Cataracts were not observed in foetuses derived from ratdams treated during the organogenesis stage of foetal development, in rat pups exposed to a certainextent through milk ingestion prior to weaning, or in repeated dose toxicity studies with ivacaftor. Thepotential relevance of these findings in humans is unknown.

Lumacaftor and ivacaftor

Repeat-dose toxicity studies involving the co-administration of lumacaftor and ivacaftor revealed nospecial hazard for humans in terms of potential for additive and/or synergistic toxicities.

Cellulose, microcrystalline

Croscarmellose sodium

Hypromellose acetate succinate

Povidone (K30)

Sodium laurilsulfate

Magnesium stearate

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol (3350)

Talc

Carmine (E120)

Brilliant blue FCF aluminium lake (E133)

Indigo carmine aluminium lake (E132)

Shellac

Iron oxide black (E172)

Ammonia solution, concentrated

Not applicable.

Orkambi 100 mg/125 mg film-coated tablets3 years

Orkambi 200 mg/125 mg film-coated tablets4 years

This medicinal product does not require any special storage conditions.

Blister consisting of PolyChloroTriFluoroEthylene (PCTFE)/PolyVinyl Chloride (PVC) with apaper-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

Multipacks containing 112 (4 packs of 28) film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Vertex Pharmaceuticals (Ireland) Limited

Unit 49, Block 5, Northwood Court, Northwood Crescent,

Dublin 9, D09 T665,

Ireland

EU/1/15/1059/001

EU/1/15/1059/005

Date of first authorisation: 19 November 2015

Date of latest renewal: 18 November 2020

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

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