4.1. Therapeutic indications

Orkambi granules are indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year 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 1 year and older

Age

Weight

Dose per sachet

Orkambi dose

(every 12 hours)

Morning

Evening

1 to <2 years

7 kg to <9 kg

lumacaftor 75 mg/ ivacaftor 94 mg

1 sachet

1 sachet

9 kg to <14 kg

lumacaftor 100 mg/ ivacaftor 125 mg

≥14 kg

lumacaftor 150 mg/ ivacaftor 188 mg

2 to 5 years

<14 kg

lumacaftor 100 mg/ivacaftor 125 mg

≥ 14 kg

lumacaftor 150 mg/ivacaftor 188 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 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. See Table 2.

Table 2: Orkambi treatment initiation in patients taking strong CYP3A inhibitors

Age

Weight

Dose per sachet

Week 1 of treatment

Week 2 onwards

1 to <2 years

7 kg to <9 kg

lumacaftor 75 mg/ ivacaftor 94 mg

1 sachet every other day i.e., day 1, 3, 5, 7.

On day 8 dosing should be at the recommended full daily dose

9 kg to <14 kg

lumacaftor 100 mg/ ivacaftor 125 mg

≥14 kg

lumacaftor 150 mg/ ivacaftor 188 mg

2 to 5 years

<14 kg

lumacaftor 100 mg/ ivacaftor 125 mg

≥ 14 kg

lumacaftor 150 mg/ ivacaftor 188 mg

6 years and older

See Orkambi tablets SmPC for further details

If treatment is interrupted for more than one week and then re-initiated while taking strong CYP3A inhibitors, reduce the dose to one sachet every other day for the first week of treatment re-initiation (see Table 2). 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 moderate or severe hepatic impairment see Table 3.

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

Age

Weight

Dose per sachet

Moderate

(Child-Pugh Class B)

Severe

(Child-Pugh Class C)

Morning

Evening

Morning

Evening

1 to <2 years

7 kg to <9 kg

lumacaftor 75 mg/ ivacaftor 94 mg

1 sachet of oral granules

1 sachet of oral granules every other day

1 sachet of oral granules or less frequently

No dose

9 kg to <14 kg

lumacaftor 100 mg/ ivacaftor 125 mg

≥14 kg

lumacaftor 150 mg/ ivacaftor 188 mg

2 to 5 years

<14 kg

lumacaftor 100 mg/ ivacaftor 125 mg

≥14 kg

lumacaftor 150 mg/ ivacaftor 188 mg

Paediatric population

The safety and efficacy of Orkambi in children aged less than 1 year 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 or liquids include puréed fruits or vegetables, flavoured yogurt, applesauce, water, milk, breast milk, infant food 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).

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 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. 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 less than 12 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).

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.

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

Table 4: 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.

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.

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.

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.

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.

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 Orkambi 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 Orkambi therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

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).

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

Table 5 reflects the adverse reactions reported with lumacaftor/ivacaftor and ivacaftor monotherapy from clinical trials, post-authorisation safety studies, and spontaneous reporting. Adverse reactions are listed by MedDRA system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (frequency cannot be estimated from the available data).

Table 5: 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 a 96-week rollover study (trial 3) were consistent with the safety data from the phase 3 studies (trials 1 and 2).

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 seven 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 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

The safety data of lumacaftor/ivacaftor were evaluated in 46 patients aged 1 to less than 2 years (trial 11), 60 patients aged 2 to 5 years (trial 8), 161 patients aged 6 to less than 12 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 three 96-week extension studies in 52, 57, and 239 patients aged 1 year and older (trial 12), 2 years and older (trial 10), and 6 years and older (trial 9), respectively, who were homozygous for the F508del mutation in the CFTR gene, were generally consistent with the 24-week parent studies. The parent studies were conducted in patients aged 1 to less than 2 years (trial 11, parent of trial 12), 2 to 5 years (trial 8, parent of trial 10), and 6 to less than 12 years (trials 6 and 7, parents of trial 9).

Description of selected adverse reactions for paediatric patients aged 1 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 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 one patient who discontinued treatment.

During the 24-week, placebo-controlled, phase 3 clinical study in 204 patients aged 6 to less than 12 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 due to transaminase elevations.

During the 24-week, open-label phase 3 clinical study in 60 patients aged 2 to 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 due to transaminase elevations.

During the 24-week, open-label phase 3 clinical study in 46 patients aged 1 to less than 2 years (trial 11), the incidence of maximum transaminase (ALT or AST) levels > 8, > 5, and > 3 x ULN was 2.2% (1/46), 4.3% (2/46), and 10.9% (5/46). No patients had total bilirubin levels > 2 x ULN. One patient discontinued lumacaftor/ivacaftor treatment 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 less than 12 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 less than 12 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:

Yellow Card Scheme

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

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.