Orkambi

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 events 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.

Shelf life

Orkambi 100 mg/125 mg film-coated tablets

3 years

Orkambi 200 mg/125 mg film-coated tablets

4 years

Orkambi price

Incompatibilities

Not applicable.

List of excipients

Tablet core

Cellulose, microcrystalline

Croscarmellose sodium

Hypromellose acetate succinate

Povidone (K30)

Sodium laurilsulfate

Magnesium stearate

Coating

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol 3350

Talc

Carmine (E120)

Brilliant blue FCF aluminum lake (E133)

Indigo carmine aluminum lake (E132)

Printing ink

Shellac

Iron oxide black (E172)

Propylene glycol

Ammonium hydroxide

Pharmaceutical form

Film-coated tablet (tablet)

Orkambi 100 mg/125 mg film-coated tablets

Pink, oval-shaped tablets (dimensions 14 × 7.6 × 4.9 mm) printed with “1V125” in black ink on one side.

Orkambi 200 mg/125 mg film-coated tablets

Pink, oval-shaped tablets (dimensions 14 × 8.4 × 6.8 mm) printed with “2V125” in black ink on one side.

Undesirable effects

Summary of the safety profile

The most common adverse reactions experienced by patients aged 12 years and older who received lumacaftor/ivacaftor in the pooled, placebo-controlled, Phase 3 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 occurring in at least 0.5% of patients included hepatobiliary events, e.g., transaminase elevations, cholestatic hepatitis and hepatic encephalopathy.

Tabulated list of adverse reactions

Adverse reactions identified from the 24-week, placebo-controlled, Phase 3 studies (Trials 1 and 2) in patients aged 12 years and older and from a 24-week, placebo-controlled study in patients aged 6 to 11 years (Trial 7), who are homozygous for the F508del mutation in the CFTR gene are presented in Table 4 and are listed by system organ class, frequency, and adverse reactions. Adverse reactions observed with ivacaftor alone are also provided in Table 4. Adverse reactions are ranked under the MedDRA frequency classification: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); and not known (frequency cannot be estimated using the available data).

*Adverse reactions and frequencies observed in patients in clinical studies with ivacaftor monotherapy (a component of Orkambi).

† 1 patient out of 738

‡ 2 patients out of 738

The safety data from 1029 patients aged 12 years and older who were homozygous for the F508del mutation in the CFTR gene treated with lumacaftor/ivacaftor for up to an additional 96 weeks in the long-term safety and efficacy rollover study (Trial 3) were similar to the 24-week, placebo-controlled studies.

Description of selected adverse reactions

Hepatobiliary events

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 events 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.

Among 7 patients with preexisting 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.

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.

Respiratory events

During Trials 1 and 2, the incidence of respiratory adverse reactions (e.g., chest discomfort, dyspnoea, and respiration abnormal) was 26.3% in lumacaftor/ivacaftor-treated patients compared to 17.0% in patients who received placebo. The incidence of these events was more common in patients with lower pre-treatment FEV1. Approximately three-quarters of the events began during the first week of treatment, and in most patients the events resolved without dosing interruption. The majority of events were mild or moderate in severity, non-serious and did not result in treatment discontinuation.

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 events 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 event, three patients subsequently had their dose reduced, and three patients discontinued treatment. No serious respiratory events, dose reductions or discontinuations were seen in patients who were initiated at the half dose.

Menstrual abnormalities

During Trials 1 and 2, the incidence of combined menstrual abnormality events (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%). 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.

Paediatric population

Safety data were evaluated in 161 paediatric patients aged 6 to 11 years (Trials 6 and 7) and in 194 paediatric 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. Additional adverse reactions from Trial 6 are included in Table 4.

Description of selected adverse reactions for patients aged 6 to 11 years

Hepatobiliary events

During the 24-week, open-label Phase 3 clinical study in 58 patients aged 6 to 11 years (Trial 6), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 5.3%, 8.8%, and 19.3%. No patients had total bilirubin levels > 2 x ULN. Lumacaftor/ivacaftor dosing was maintained or successfully resumed after interruption in all patients with transaminase elevations, except 1 patient who discontinued treatment permanently.

During the 24-week, placebo-controlled Phase 3 clinical study in 204 patients aged 6 to 11 years (Trial 7), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 1.0%, 4.9%, and 12.6% in the lumacaftor/ivacaftor patients, and 2.0%, 3.0%, and 7.9% in the placebo-treated patients. No patients had total bilirubin levels >2 x ULN. Two patients in the lumacaftor/ivacaftor group and two patients in the placebo group discontinued treatment permanently due to transaminase elevations.

Respiratory events

During the 24-week, open-label Phase 3 clinical study (Trial 6) in 58 patients aged 6 to 11 years (mean baseline ppFEV1 was 91.4), the incidence of respiratory adverse reactions was 6.9% (4/58).

During the 24-week, placebo-controlled Phase 3 clinical study (Trial 7) in patients aged 6 to 11 years (mean baseline ppFEV1 was 89.8), the incidence of respiratory adverse reactions was 18.4% in lumacaftor/ivacaftor patients and 12.9% in placebo patients. A decline in ppFEV1 at initiation of therapy was observed during serial post dose spirometry assessments. The absolute change from pre-dose at 4-6 hours post-dose was -7.7 on Day 1 and -1.3 on Day 15 in lumacaftor/ivacaftor patients. The post-dose decline was resolved by Week 16.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

Yellow Card Scheme

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

Preclinical safety data

Lumacaftor

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. Specific studies to evaluate the phototoxic potential of lumacaftor were not conducted; however, evaluation of the available non-clinical and clinical data suggests no phototoxic liability.

Ivacaftor

Effects in repeated dose studies were observed only at exposures considered sufficiently in excess (>25-, >45-, and >35-fold for mice, rats, and dogs, respectively) of the maximum human exposure of ivacaftor when administered as Orkambi, indicating little relevance to clinical use. Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity and carcinogenic potential.

Safety Pharmacology

Ivacaftor produced concentration-dependent inhibitory effect on hERG (human ether-à-go-go related gene) tail currents, with an IC15 of 5.5 µM, compared to the Cmax (1.5 µM) for ivacaftor at the therapeutic dose for lumacaftor/ivacaftor. However, no ivacaftor-induced QT prolongation was observed in a dog telemetry study at single doses up to 60 mg/kg or in ECG measurements from repeat-dose studies of up to 1 year duration at the 60 mg/kg/day dose level in dogs (Cmax after 365 days = 36.2 to 47.6 μM). Ivacaftor produced a dose-related but transient increase in the blood pressure parameters in dogs at single oral doses up to 60 mg/kg. No meaningful changes in QTc interval or blood pressure were observed in a thorough QT clinical study evaluating either lumacaftor 600 mg once daily/ivacaftor 250 mg q12h or lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h, demonstrating a lack of translation of these non-clinical findings to the clinic.

Pregnancy and Fertility

Ivacaftor was not teratogenic when dosed orally to pregnant rats and rabbits during the organogenesis stage of foetal development at doses approximately 7 times (ivacaftor and metabolite exposure) and 46 times the ivacaftor exposure in humans at the therapeutic lumacaftor/ivacaftor dose, respectively. At maternally toxic doses in rats, ivacaftor produced reductions in foetal body weight; an increase in the incidence of variations in cervical ribs, hypoplastic ribs, and wavy ribs; and sternal irregularities, including fusions. The significance of these findings for humans is unknown.

Ivacaftor impaired fertility and reproductive performance indices in male and female rats at 200 mg/kg/day (yielding exposures approximately 11 and 7 times, respectively, those obtained with the maximum recommended human dose of the ivacaftor component of Orkambi based on summed AUCs of ivacaftor and its metabolites extrapolated from Day 90 exposures at 150 mg/kg/day in the 6-month repeat-dose toxicity study and gestation Day 17 exposures in the pilot embryofetal development study in this species) when dams were dosed prior to and during early pregnancy. No effects on male or female fertility and reproductive performance indices were observed at ≤100 mg/kg/day (yielding exposures approximately 8 and 5 times, respectively, those obtained with the maximum recommended human dose of the ivacaftor component of Orkambi based on summed AUCs of ivacaftor and its metabolites extrapolated from Day 90 exposures at 100 mg/kg/day in the 6-month repeat-dose toxicity study and gestation Day 17 exposures in the embryofetal development study in this species).

Peri- and Post-Natal Development

Ivacaftor did not cause developmental defects in the offspring of pregnant rats dosed orally from pregnancy through parturition and weaning at 100 mg/kg/day. Doses above 100 mg/kg/day produced 92% and 98% reduction of survival and lactation indices, respectively, as well as reductions in pup body weights.

Juvenile Animals

Findings of cataracts were observed in juvenile rats dosed with ivacaftor at 0.32 times the maximum recommended human dose based on systemic exposure of ivacaftor and its metabolites when co-administered with lumacaftor as Orkambi. Cataracts were not observed in foetuses derived from rat dams treated during the organogenesis stage of foetal development, in rat pups exposed to a certain extent through milk ingestion prior to weaning, or in repeated dose toxicity studies with ivacaftor. The potential relevance of these findings in humans is unknown.

Lumacaftor and ivacaftor

Repeat-dose toxicity studies involving the co-administration of lumacaftor and ivacaftor revealed no special hazard for humans in terms of potential for additive and/or synergistic toxicities.

Therapeutic indications

Orkambi is indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who are homozygous for the F508del mutation in the CFTR gene.

Pharmacotherapeutic group

Pharmacodynamic properties

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

Mechanism of action

The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. The F508del mutation impacts the CFTR protein in multiple ways, primarily by causing a defect in cellular processing and trafficking that reduces the quantity of CFTR at the cell surface. The small amount of F508del-CFTR that reaches the cell surface has low channel-open probability (defective channel gating). Lumacaftor is a CFTR corrector that acts directly on F508del-CFTR to improve its cellular processing and trafficking, thereby increasing the quantity of functional CFTR at the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. The combined effect of lumacaftor and ivacaftor is increased quantity and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport. The exact mechanisms by which lumacaftor improves cellular processing and trafficking of F508del-CFTR and ivacaftor potentiates F508del-CFTR are not known.

Pharmacodynamic effects

Effects on Sweat Chloride

Changes in sweat chloride in response to lumacaftor alone or in combination with ivacaftor were evaluated in a double-blind, placebo-controlled, Phase 2 clinical trial in patients with CF age 18 years and older. In this trial, 10 patients (homozygous for F508del-CFTR mutation) completed dosing with lumacaftor alone 400 mg q12h for 28 days followed by the addition of ivacaftor 250 mg q12h for an additional 28 days, and 25 patients (homozygous or heterozygous for F508del) completed dosing with placebo. The treatment difference between lumacaftor 400 mg q12h alone and placebo evaluated as mean change in sweat chloride from baseline to Day 28 was statistically significant at -8.2 mmol/L (95% CI: -14, -2). The treatment difference between the combination of lumacaftor 400 mg/ivacaftor 250 mg q12h and placebo evaluated as mean change in sweat chloride from baseline to Day 56 was statistically significant at -11 mmol/L (95% CI: -18, -4).

Changes in sweat chloride in response to lumacaftor/ivacaftor were evaluated as part of a 24-week, placebo-controlled, Phase 3 clinical study (Trial 7) in 204 patients (103 received lumacaftor 200 mg/ivacaftor 250 mg every 12 hours and 101 received placebo) with CF aged 6 to 11 years old who were homozygous for the F508del mutation in the CFTR gene. Treatment with lumacaftor/ivacaftor demonstrated a statistically significant decrease in sweat chloride compared to placebo and sustained through 24 weeks of treatment. The treatment difference (LS mean) in sweat chloride for the average absolute change at Day 15 and at Week 4 as compared to placebo was -20.8 mmol/L (95% CI: -23.4, -18.2; P<0.0001). The treatment difference (LS mean) in sweat chloride for the absolute change at Week 24 as compared to placebo was -24.9 mmol/L (P<0.0001).

Changes in FEV1

Changes in ppFEV1 in response to lumacaftor alone or in combination with ivacaftor were also evaluated in the double-blind, placebo-controlled, Phase 2 trial in patients with CF age 18 years and older. The treatment difference between lumacaftor 400 mg q12h alone and placebo evaluated as mean absolute change in ppFEV1 was -4.6 percentage points (95% CI: -9.6, 0.4) from baseline to Day 28, 4.2 percentage points (95% CI: -1.3, 9.7) from baseline to Day 56, and 7.7 percentage points (95% CI: 2.6, 12.8; statistically significant) from Day 28 to Day 56 (following the addition of ivacaftor to lumacaftor monotherapy).

Decrease in Heart Rate

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

Clinical efficacy and safety

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

The efficacy of lumacaftor/ivacaftor in patients with CF who are homozygous for the F508del mutation in the CFTR gene was evaluated in two randomised, double-blind, placebo-controlled clinical trials of 1108 clinically stable patients with CF, in which 737 patients were randomised to and dosed with lumacaftor/ivacaftor. Patients in both trials were randomised 1:1:1 to receive lumacaftor 600 mg once daily/ivacaftor 250 mg q12h, lumacaftor 400 mg q12h/ivacaftor 250 mg q12h, or placebo. Patients took the study drug with fat-containing food for 24 weeks in addition to their prescribed CF therapies (e.g., bronchodilators, inhaled antibiotics, dornase alfa, and hypertonic saline). Patients from these trials were eligible to roll over into a blinded extension study.

Trial 1 evaluated 549 patients with CF who were aged 12 years and older (mean age 25.1 years) with percent predicted FEV1 (ppFEV1) at screening between 40-90 (mean ppFEV1 60.7 at baseline [range: 31.1 to 94.0]). Trial 2 evaluated 559 patients aged 12 years and older (mean age 25.0 years) with ppFEV1 at screening between 40-90 (mean ppFEV1 60.5 at baseline [range: 31.3 to 99.8]). Patients with a history of colonisation with organisms such as Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus or who had 3 or more abnormal liver function tests (ALT, AST, AP, GGT >3 times the ULN or total bilirubin >2 times the ULN) were excluded.

The primary efficacy endpoint in both studies was the absolute change from baseline in ppFEV1 at week 24. Other efficacy variables included relative change from baseline in ppFEV1, absolute change from baseline in BMI, absolute change from baseline in CFQ-R Respiratory Domain the proportion of patients achieving >5% relative change from baseline in ppFEV1 at week 24, and the number of pulmonary exacerbations (including those requiring hospitalisation or IV antibiotic therapy) through week 24.

In both trials, treatment with lumacaftor/ivacaftor resulted in a statistically significant improvement in ppFEV1 (Table 5). Mean improvement in ppFEV1 was rapid in onset (Day 15) and sustained throughout the 24-week treatment period. At Day 15, the treatment difference between lumacaftor 400 mg/ivacaftor 250 mg q12h and placebo for the mean absolute change (95% CI) in ppFEV1 from baseline was 2.51 percentage points in the pooled Trials 1 and 2 (P<0.0001). Improvements in ppFEV1 were observed regardless of age, disease severity, sex and geographic region. The Phase 3 trials of lumacaftor/ivacaftor included 81 patients with ppFEV1 <40 at baseline. The treatment difference in this subgroup was comparable to that observed in patients with ppFEV1 >40. At week 24, the treatment difference between lumacaftor 400 mg/ivacaftor 250 mg q12h and placebo for the mean absolute change (95% CI) in ppFEV1 from baseline in the pooled Trials 1 and 2 were 3.39 percentage points (P=0.0382) for patients with ppFEV1 <40 and 2.47 percentage points (P<0.0001) for patients with ppFEV1 >40.

At week 24, the proportion of patients who remained free from pulmonary exacerbations was significantly higher for patients treated with lumacaftor/ivacaftor compared with placebo. In the pooled analysis, the rate ratio of exacerbations through week 24 in subjects treated with lumacaftor/ivacaftor (lumacaftor 400 mg/ivacaftor 250 mg q12h; n=369) was 0.61 (P<0.0001), representing a reduction of 39% relative to placebo. The event rate per year, annualised to 48 weeks, was 0.70 in the lumacaftor/ivacaftor group and 1.14 in the placebo group. Treatment with lumacaftor/ivacaftor significantly decreased the risk for exacerbations requiring hospitalisation versus placebo by 61% (rate ratio=0.39, P<0.0001; event rate per 48 weeks 0.17 for lumacaftor/ivacaftor and 0.45 for placebo) and reduced exacerbations requiring treatment with intravenous antibiotics by 56% (rate ratio=0.44, P<0.0001; event rate per 48 weeks 0.25 for lumacaftor/ivacaftor and 0.58 for placebo). These results were not considered statistically significant within the framework of the testing hierarchy for the individual studies.

Long-term safety and efficacy rollover trial

Trial 3 was a Phase 3, parallel-group, multicentre, rollover extension study in patients with CF that included patients aged 12 years and older from Trial 1 and Trial 2. This extension trial was designed to evaluate the safety and efficacy of long-term treatment of lumacaftor/ivacaftor. Of the 1108 patients who received any treatment in Trial 1 or Trial 2, 1029 (93%) were dosed and received active treatment (lumacaftor 600 mg q12h/ivacaftor 250 mg q12h or lumacaftor 400 mg q12h/ivacaftor 250 mg q12h) in Trial 3 for up to an additional 96 weeks (i.e. up to a total of 120 weeks). The primary efficacy analysis of this extension study included data up to Week 72 of Trial 3 with a sensitivity analysis that included data up to Week 96 of Trial 3.

Patients treated with lumacaftor/ivacaftor in Trial 1 or Trial 2 showed an effect that was maintained with respect to baseline after an additional 96 weeks through Trial 3. For patients who transitioned from placebo to active treatment similar changes as those observed in patients treated with lumacaftor/ivacaftor in Trial 1 or Trial 2 were seen (see Table 5). Results from Trial 3 are presented in Figure 1 and Table 6.

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

† From Trials 1, 2 and 3.

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

Trial 4 was a multicentre, double-blind, randomised, placebo-controlled, Phase 2 trial in 125 patients with CF aged 18 years and older who had a ppFEV1 of 40 - 90, inclusive, and have the F508del mutation on one allele plus a second allele with a mutation predicted to result in the lack of CFTR production or a CFTR that is not responsive to ivacaftor in vitro.

Patients received either lumacaftor/ivacaftor (n=62) or placebo (n=63) in addition to their prescribed CF therapies. The primary endpoint was improvement in lung function as determined by the mean absolute change from baseline at Day 56 in ppFEV1. Treatment with lumacaftor/ivacaftor resulted in no significant improvement in ppFEV1 relative to placebo in patients with CF heterozygous for the F508del mutation in the CFTR gene (treatment difference 0.60 [P=0.5978]) and no meaningful improvements in BMI or weight.

Trials in patients with CF aged 6 to 11 years old who are homozygous for the F508del mutation in the CFTR gene

Trial 7 was a 24-week, placebo-controlled, Phase 3 clinical study in 204 patients with CF aged 6 to 11 years old (mean age 8.8 years). Trial 7 evaluated subjects with lung clearance index (LCI2.5) >7.5 at the initial screening visit (mean LCI2.5 10.28 at baseline [range: 6.55 to 16.38]) and ppFEV1 >70 at screening (mean ppFEV1 89.8 at baseline [range: 48.6 to 119.6]). Patients received either lumacaftor 200 mg/ivacaftor 250 mg every 12 hours (n=103) or placebo (n=101) in addition to their prescribed CF therapies. Patients who had 2 or more abnormal liver function tests (ALT, AST, AP, GGT >3 times the ULN), or ALT or AST >5 times ULN, or total bilirubin >2 times ULN were excluded.

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

Percent predicted FEV1 was also evaluated as a clinically meaningful other secondary endpoint. In the lumacaftor/ivacaftor patients, the treatment difference for absolute change in ppFEV1 from baseline through Week 24 was 2.4 (P=0.0182).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Orkambi in one or more subsets of the paediatric population in cystic fibrosis.

Pharmacokinetic properties

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

After oral administration of lumacaftor 400 mg q12h/ivacaftor 250 mg q12h in a fed state, the steady-state mean (±SD) for AUC0-12h and Cmax were 198 (64.8) μg∙hr/mL and 25.0 (7.96) μg/mL for lumacaftor, respectively, and 3.66 (2.25) μg∙hr/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∙hr/mL and 1.12 (0.319) μg/mL, respectively.

Absorption

Following multiple oral doses of lumacaftor, the exposure of lumacaftor generally increased proportional to dose over the range of 50 mg to 1000 mg every 24 hours. The exposure of lumacaftor increased approximately 2.0-fold when given with fat-containing food relative to fasted conditions. The median (range) tmax of lumacaftor is approximately 4.0 hours (2.0; 9.0) in the fed state.

Following multiple oral dose administration of ivacaftor in combination with lumacaftor, the exposure of ivacaftor generally increased with dose from 150 mg every 12 hours to 250 mg every 12 hours. The exposure of ivacaftor when given in combination with lumacaftor increased approximately 3-fold when given with fat-containing food in healthy volunteers. Therefore, lumacaftor/ivacaftor should be administered with fat-containing food. The median (range) tmax of ivacaftor is approximately 4.0 hours (2.0; 6.0) in the fed state.

Distribution

Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin. After oral administration of 400 mg every 12 hours in patients with CF in a fed state, the typical apparent volumes of distribution for the central and peripheral compartments (CV) were estimated to be 23.5 L (48.7%) and 33.3 L (30.5%), respectively.

Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. After oral administration of ivacaftor 250 mg every 12 hours in combination with lumacaftor, the typical apparent volumes of distribution for the central and peripheral compartments [coefficient of variation as a percentage (CV)] were estimated to be 95.0 L (53.9%) and 201 L (26.6%), respectively.

In vitro studies indicate that lumacaftor is a substrate of Breast Cancer Resistance Protein (BCRP).

Biotransformation

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

Ivacaftor is extensively metabolised in humans. In vitro and in vivo data indicate that ivacaftor is primarily metabolised by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active.

Elimination

Following oral administration of lumacaftor, the majority of lumacaftor (51%) is excreted unchanged in the faeces. There was negligible urinary excretion of lumacaftor as unchanged drug. The apparent terminal half-life is approximately 26 hours. The typical apparent clearance, CL/F (CV), of lumacaftor was estimated to be 2.38 L/hr (29.4%) for patients with CF.

Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the faeces after metabolic conversion. There was negligible urinary excretion of ivacaftor as unchanged drug. In healthy subjects, the half-life of ivacaftor when given with lumacaftor is approximately 9 hours. The typical CL/F (CV) of ivacaftor when given in combination with lumacaftor was estimated to be 25.1 L/hr (40.5%) for patients with CF.

Hepatic impairment

Following multiple doses of lumacaftor/ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had higher exposures (AUC0-12hr by approximately 50% and Cmax by approximately 30%) compared with healthy subjects matched for demographics. Therefore, the Orkambi dose should be reduced to two tablets in the morning and one tablet in the evening for patients with moderate hepatic impairment (Child-Pugh Class B). The impact of mild hepatic impairment (Child-Pugh Class A, score 5 to 6) on pharmacokinetics of lumacaftor given in combination with ivacaftor has not been studied, but the increase in exposure is expected to be less than 50%. Therefore, no dose adjustment is necessary for patients with mild hepatic impairment.

Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C, score 10 to 15), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, lumacaftor/ivacaftor should be used with caution at a maximum dose of one tablet in the morning and one tablet in the evening, or less, in patients with severe hepatic impairment after weighing the risks and benefits of treatment.

Renal impairment

Pharmacokinetic studies have not been performed with lumacaftor/ivacaftor in patients with renal impairment. In a human pharmacokinetic study with lumacaftor alone, there was minimal elimination of lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine with 0.18% as unchanged parent). In a human pharmacokinetic study with ivacaftor alone, there was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine). A population pharmacokinetic analysis of clearance versus creatinine clearance shows no trend for subjects with mild and moderate renal impairment. Therefore, no dose adjustment for lumacaftor/ivacaftor is recommended for mild or moderate renal impairment. However, caution is recommended when administering lumacaftor/ivacaftor to patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease.

Elderly people

The safety and efficacy of lumacaftor/ivacaftor in patients age 65 years or older have not been evaluated.

Gender

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

Paediatric population

The exposures are similar between adults and the paediatric population based on population (PK) analyses as presented in Table 8 below:

Date of revision of the text

02/2018

Name of the medicinal product

Orkambi 100 mg/125 mg film-coated tablets

Orkambi 200 mg/125 mg film-coated tablets

Marketing authorisation holder

Vertex Pharmaceuticals (Europe) Limited

2 Kingdom Street

London

W2 6BD

United Kingdom

Tel: +44 (0) 1923 437672

Special precautions for storage

Store below 30°C.

Nature and contents of container

Blister consisting of PolyChloroTriFluoroEthylene (PCTFE)/PolyVinyl Chloride (PVC) with a paper-backed aluminium foil lidding.

Orkambi 100 mg/125 mg film-coated tablets

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

Orkambi 200 mg/125 mg film-coated tablets

Pack containing 28 film-coated tablets.

Multipacks containing 56 film-coated tablets (2 packs of 28 film-coated tablets).

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

Not all pack sizes may be marketed.

Marketing authorisation number(s)

EU/1/15/1059/001

EU/1/15/1059/002

EU/1/15/1059/003

EU/1/15/1059/005

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. As a precautionary measure, it is preferable to avoid the use of lumacaftor/ivacaftor during pregnancy unless the clinical condition of the mother requires treatment with lumacaftor/ivacaftor.

Breast-feeding

It is unknown whether lumacaftor and/or ivacaftor and metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of both lumacaftor and ivacaftor into the milk of lactating female rats. As such, risks to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from lumacaftor/ ivacaftor therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.

Fertility

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. No effects on male or female fertility and reproductive performance indices were observed at ≤100 mg/kg/day.

Qualitative and quantitative composition

Orkambi 100 mg/125 mg film-coated tablets

Each film-coated tablet contains 100 mg of lumacaftor and 125 mg of ivacaftor.

Orkambi 200 mg/125 mg film-coated tablets

Each film-coated tablet contains 200 mg of lumacaftor and 125 mg of ivacaftor.

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.

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 events

Respiratory events (e.g., chest discomfort, dyspnoea, and respiration abnormal) were more common during initiation of lumacaftor/ivacaftor therapy. Serious respiratory events were seen more frequently in patients with percent predicted FEV1 (ppFEV1) <40, and may lead to drug discontinuation. Clinical experience in patients with ppFEV1 <40 is limited and additional monitoring of these patients is recommended during initiation of therapy. 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.

Patients with advanced liver disease

Abnormalities in liver function, including advanced liver disease, can be present in patients with CF., 4.8, and 5.2).

Hepatobiliary events

Elevated transaminases have been reported in patients with CF receiving lumacaftor/ivacaftor. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin.

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), dosing with lumacaftor/ivacaftor should be discontinued and laboratory tests closely followed until the abnormalities resolve. Following resolution of transaminase elevations, the benefits and risks of resuming dosing should be considered.

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.

Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with Orkambi.

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.

Renal impairment

Caution is recommended while using lumacaftor/ivacaftor in patients with severe renal impairment or end-stage renal disease.

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. 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.

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 or use machines. Ivacaftor may cause dizziness.

Patients experiencing dizziness while taking Orkambi should be advised not to drive or use machines until symptoms abate.

Dosage (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

For standard dosing recommendations see Table 1.

Orkambi should be taken with fat-containing food. A fat-containing meal or snack should be consumed just before or just after dosing.

Missed dose

If less than 6 hours have passed since the missed dose, the scheduled dose of Orkambi 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 Orkambi in patients taking strong CYP3A inhibitors, the dose should be reduced to one tablet daily (lumacaftor 100 mg/ivacaftor 125 mg total daily dose for patients aged 6 to 11 years; lumacaftor 200 mg/ivacaftor 125 mg total daily dose for patients aged 12 years and older) for the first week of treatment to allow for the steady state induction effect of lumacaftor. Following this period, the recommended daily dose should be continued.

If Orkambi is interrupted for more than one week and then re-initiated while taking strong CYP3A inhibitors, the Orkambi dose should be reduced to one tablet daily for the first week of treatment re-initiation. Following this period, the recommended daily dose should be continued.

Special populations

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 Orkambi 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 at a reduced dose.

For dose adjustments for patients with hepatic impairment see Table 2.

Renal impairment

No dose adjustment is necessary for patients with mild to moderate renal impairment. Caution is recommended while using Orkambi in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease.

Elderly people

The safety and efficacy of Orkambi in patients aged 65 years or older have not been evaluated.

Paediatric population

The safety and efficacy of Orkambi in children aged less than 6 years have not yet been established. No data are available.

Method of administration

For oral use. Patients should be instructed to swallow the tablets whole. Patients should not chew, break, or dissolve the tablets. Patients may start taking Orkambi on any day of the week.

Special precautions for disposal and other handling

No special requirements.

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

Date of first authorisation/renewal of the authorisation

Date of first authorisation: 19 November 2015

Interaction with other medicinal products and other forms of interaction

The drug interaction profile for lumacaftor 200 mg/ivacaftor 250 mg every 12 hours is considered to be the same as that for lumacaftor 400 mg/ivacaftor 250 mg every 12 hours, based on exposure at the indicated doses.

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.

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.

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.

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 drug interactions

Table 3 provides the established or predicted effect of lumacaftor/ivacaftor on other medicinal products or the effect of other medicinal products on lumacaftor/ivacaftor. The information reported in the Table mostly derives from in vitro studies. The recommendations provided under “Clinical comment” in Table 3 are based on drug interaction studies, clinical relevance, or predicted interactions due to elimination pathways. Drug interactions that have the most clinical relevance are listed first.

Paediatric population

Interaction studies have only been performed in adults.