Ivacaftor and Lumacaftor interacts in the following cases:
In vitro experiments show that lumacaftor is a substrate for Breast Cancer Resistance Protein (BCRP). Co-administration of lumacaftor/ivacaftor 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 lumacaftor/ivacaftor with medicinal products that are substrates for OAT1/3 and BCRP transport may increase plasma concentrations of such medicinal products. Ivacaftor is not an inhibitor of OAT1 and OAT3.
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.
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.
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.
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.
Caution is recommended in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease.
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, lumacaftor/ivacaftor should be used with caution in patients with severe hepatic impairment at a reduced dose.
Dose adjustment recommendations for patients with moderate or severe hepatic impairment in patients aged 1 to 5 years:
| Age | Weight | Strength | 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 per day | 1 sachet of oral granules every other day | 1 sachet of oral granules per day 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 | |||||
* Dosing interval should be modified according to clinical response and tolerability.
Dose adjustment recommendations for patients with moderate or severe hepatic impairment in patients aged 6 years and older:
| Age | Strength | Total Daily Dose | |||
|---|---|---|---|---|---|
| Moderate (Child-Pugh Class B) | Severe (Child-Pugh Class C) | ||||
| Morning | Evening | Morning | Evening | ||
| 6 to <12 years | lumacaftor 100 mg/ ivacaftor 125 mg | 2 tablets | 1 tablet | 1 tablet or less frequently* | 1 tablet or less frequently* |
| 12 years and older | lumacaftor 200 mg/ ivacaftor 125 mg | ||||
* Dosing interval should be modified according to clinical response and tolerability; the frequency may be reduced for both the morning dose and the evening dose.
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 preexisting 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.
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.
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.
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 woman.
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.
Ivacaftor has a minor influence on the ability to drive and use machines. Ivacaftor may cause dizziness.
Patients experiencing dizziness while taking lumacaftor/ivacaftor 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 and 809-104) in patients aged 12 years and older and from a 24-week, placebo-controlled study in patients aged 6 to less than 12 years (trial 809-109), who are homozygous for the F508del mutation in the CFTR gene are presented in the table below and are listed by system organ class and frequency. Adverse reactions observed with ivacaftor alone are also provided in the table. 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 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 73
The safety data from 1,029 patients aged 12 years and older who were homozygous for the F508del mutation in the CFTR gene treated with lumacaftor/ivacaftor for up to an additional 96 weeks in the long-term safety and efficacy rollover study (trial 809-105) were similar to the 24-week, placebo-controlled studies.
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/ivacaftorand 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.
Among 7 patients with pre-existing cirrhosis and/or portal hypertension who received lumacaftor/ivacaftor in the placebo-controlled, Phase 3 studies, worsening liver function with increased ALT, AST, bilirubin, and hepatic encephalopathy was observed in one patient. The event occurred within 5 days of the start of dosing and resolved following discontinuation of lumacaftor/ivacaftor.
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.
During trials 809-103 and 809-104, the incidence of respiratory adverse reactions (e.g., chest discomfort, dyspnoea, bronchospasm, and respiration abnormal) was 26.3% in lumacaftor/ivacaftor-treated patients compared to 17.0% in patients who received placebo. The incidence of these adverse reactions was more common in patients with lower pre-treatment FEV1. Approximately three-quarters of the events began during the first week of treatment, and in most patients the events resolved without dosing interruption. The majority of adverse reactions were mild or moderate in severity, non-serious and did not result in treatment discontinuation. During a 24-week, open-label, Phase 3b clinical study (trial 809-011 [Part B]) 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.
During trials 809-103 and 809-104, 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%). 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.
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 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.
The safety data of lumacaftor/ivacaftor were evaluated in 46 patients aged 1 to less than 2 years (trial 809-122), 60 patients aged 2 to 5 years (trial 809-115), 161 patients aged 6 to less than 12 years (trials 809-011 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 to 17 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 aged 2 years and older who were homozygous for the F508del mutation in the CFTR gene were generally consistent with the 24-week parent study in patients aged 2 to 5 years (trial 809-115) and safety data in patients 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 older who were homozygous for the F508del mutation in the CFTR gene (trial 809-110) were generally consistent with the 24-week parent studies in patients aged 6 to less than 12 years (trial 809-011 and trial 809-109).
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 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.
During the 24-week, placebo-controlled Phase 3 clinical study in 204 patients aged 6 to less than 12 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 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 (trial 809-011) 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 809-109) 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 to6 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.
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