Orkambi^® (Tablets, Granules) Instructions for Use

ATC Code

R07AX30 (Ivacaftor and Lumacaftor)

Active Substances

Ivacaftor (Rec.INN registered by WHO)

Lumacaftor (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Combination of a potentiator and a CFTR protein corrector. Drug for the treatment of cystic fibrosis

Pharmacotherapeutic Group

Other preparations for the treatment of respiratory system disorders

Pharmacological Action

Mechanism of action

The CFTR protein, a product of the CFTR gene (cystic fibrosis transmembrane conductance regulator), is a chloride channel present on the surface of epithelial cells in a large number of organs. The F508del mutation of the CFTR gene mainly causes a disruption in the CFTR protein folding process, leading to a defect in processing and transport and, as a result, a reduction in its quantity on the cell surface. The small amount of F508del-CFTR protein that reaches the cell surface is less stable and has a lower channel opening capacity compared to the wild-type CFTR protein.

Ivacaftor is a CFTR protein potentiator; it facilitates chloride transport by increasing the channel opening capacity of the CFTR protein on the cell surface.

Lumacaftor, a CFTR protein corrector, improves the conformational stability of the F508del-CFTR protein, leading to increased processing and transport of the mature protein to the cell surface.

The combined action of ivacaftor and lumacaftor results in an increased quantity and enhanced functional activity of the F508del-CFTR protein on the cell surface, promoting increased chloride ion transport.

Pharmacodynamics

Effect on sweat chloride

The change in sweat chloride content in response to the use of Ivacaftor + Lumacaftor was evaluated in a 24-week open-label phase III clinical study (study 8) in 60 cystic fibrosis patients aged 2-5 years (homozygous for the F508del mutation) who received Ivacaftor 125 mg + Lumacaftor 100 mg every 12 hours or a combination of Ivacaftor 188 mg + Lumacaftor 150 mg every 12 hours for 24 weeks. Treatment with Ivacaftor + Lumacaftor led to a reduction in sweat chloride content from week 4 to week 24. The mean absolute change in sweat chloride content at week 24 compared to baseline was -31.7 mmol/L (95% CI: 35.7, 27.6; P< 0.0001). Additionally, sweat chloride concentration was measured after a 2-week washout period to assess the response to drug discontinuation. The mean absolute change in sweat chloride from week 24 to week 26 after the 2-week washout period showed an increase in concentration of 33.0 mmol/L (95% CI: 28.9, 37.1; P< 0.0001). This change represents a return to baseline after the drug washout period.

Effect on the cardiovascular system

Decrease in heart rate During 24-week placebo-controlled phase III studies, a maximum decrease in heart rate of 6 beats per minute relative to baseline was recorded on day 1 and day 15. After week 4, among patients receiving the Ivacaftor + Lumacaftor combination, the mean decrease in heart rate varied from 1 to 2 beats compared to baseline. The percentage of patients with heart rate values < 50 beats per minute during treatment was 11% among those receiving the Ivacaftor + Lumacaftor combination compared to 4.9% among patients receiving placebo.

Effect on the QT interval The effect of multiple doses of ivacaftor 250 mg every 12 h/lumacaftor 600 mg once daily and ivacaftor 450 mg every 12 h/lumacaftor 1000 mg once daily on the QT_c interval was evaluated in a randomized, placebo- and active-controlled (400 mg moxifloxacin) thorough QT study conducted in parallel groups in 168 healthy volunteers. No significant changes in the QT_c interval were observed with the use of ivacaftor 250 mg every 12 h/lumacaftor 600 mg once daily and ivacaftor 450 mg every 12 h/lumacaftor 1000 mg once daily.

Pharmacokinetics

The area under the concentration-time pharmacokinetic curve (exposure, AUC) of lumacaftor is approximately 2 times higher in healthy adult volunteers compared to the exposure in cystic fibrosis patients. The AUC of ivacaftor is similar in healthy adult volunteers and cystic fibrosis patients. When taken twice daily, the steady-state plasma concentration of lumacaftor and ivacaftor in healthy volunteers was typically reached after approximately 7 days of treatment with an accumulation factor of about 1.9 for lumacaftor. The steady-state AUC of ivacaftor was lower than on day 1, due to the inducing effect of lumacaftor on the CYP3A isoenzyme.

After oral administration of ivacaftor 250 mg + lumacaftor 400 mg every 12 hours with food, the mean (standard deviation) pharmacokinetic parameters of lumacaftor and ivacaftor at steady state in cystic fibrosis patients were: AUC_0-12h and C_max – 198 (64.8) μg×h/mL and 25.0 (7.96) μg/mL for lumacaftor, respectively, and 3.66 (2.25) μg×h/mL and 0.602 (0.304) μg/mL for ivacaftor, respectively.

After oral administration of ivacaftor alone at a dose of 150 mg every 12 hours with food, the mean AUC_0-12h and C_max values at steady state were 9.08 (3.20) μg×h/mL and 1.12 (0.319) μg/mL, respectively.

Absorption

After multiple oral administrations of lumacaftor, exposure increased proportionally to the dose in the range from 50 mg to 1000 mg every 24 hours. Lumacaftor exposure increased approximately 2-fold when taken with a high-fat meal compared to taking the drug on an empty stomach. The median T_max of lumacaftor is approximately 4 hours (2.0; 9.0) when taken with food.

After multiple oral administrations of ivacaftor in combination with lumacaftor, ivacaftor exposure generally increased when taken in doses from 150 mg every 12 hours to 250 mg every 12 hours. Ivacaftor exposure when taken in combination with lumacaftor increased approximately 3-fold when taken with fat-containing food. Therefore, the Ivacaftor + Lumacaftor combination should be taken with fat-containing food. The median T_max of ivacaftor is approximately 4 hours (2.0; 6.0) when taken with food.

Distribution

Lumacaftor is approximately 99% bound to plasma proteins, primarily albumin. After oral administration with food of 400 mg every 12 hours in cystic fibrosis patients, the mean apparent V_d in the central and peripheral compartment (coefficient of variation, expressed in %) was 23.5 L (48.7%) and 33.3 L (30.5%), respectively.

Ivacaftor is approximately 99% bound to plasma proteins, primarily α₁-acid glycoprotein and albumin. After oral administration of ivacaftor 250 mg every 12 hours in combination with lumacaftor, the apparent V_d for the central and peripheral compartment was 95.0 L (53.9%) and 201 L (26.6%), respectively.

Metabolism

Ivacaftor is extensively metabolized. In vitro and in vivo data indicate that Ivacaftor is primarily metabolized by the CYP3A isoenzyme. Metabolites M1 and M6 are the two major metabolites of ivacaftor in humans. The activity of metabolite M1 is approximately 1/6 that of ivacaftor, and it is considered pharmacologically active. The activity of metabolite M6 is less than 1/50 that of ivacaftor, and it is not considered a pharmacologically active metabolite.

Lumacaftor is minimally metabolized and excreted from the human body through the intestine unchanged. In vitro and in vivo data demonstrate that Lumacaftor is primarily metabolized by oxidation and glucuronidation.

Excretion

After oral administration of lumacaftor, the majority (51%) is excreted from the body unchanged through the intestine. Renal excretion unchanged is negligible. The terminal T_1/2 is about 26 hours. The apparent clearance of lumacaftor (coefficient of variation %) was 2.38 L/h (29.4%) in cystic fibrosis patients.

After oral administration of ivacaftor alone, the majority (87.8%) is excreted through the intestine as metabolites. Renal excretion unchanged is negligible. In healthy volunteers, the T_1/2 of ivacaftor when taken in combination with lumacaftor is approximately 9 hours. The apparent clearance of ivacaftor (coefficient of variation %) when combined with lumacaftor was 25.1 L/h (40.5%) in cystic fibrosis patients.

Pharmacokinetics in special patient groups

Hepatic impairment. After multiple administrations of the Ivacaftor + Lumacaftor combination for 10 days, patients with moderate hepatic impairment (Child-Pugh class B, 7-9 points) had higher exposure (AUC_0-12h approximately 50% higher and C_max approximately 30% higher) compared to healthy volunteers with similar demographics. Therefore, the dosage of the Ivacaftor + Lumacaftor combination should be reduced to 1 sachet every morning and 1 sachet every other evening in patients with moderate hepatic impairment (Child-Pugh class B).

The effect of mild hepatic impairment (Child-Pugh class A, 5-6 points) on the pharmacokinetics of lumacaftor used in combination with ivacaftor has not been studied, but an increase in exposure of less than 50% is expected. Therefore, no dose adjustment is required in patients with mild hepatic impairment.

Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh class C, 10-15 points), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, in patients with severe hepatic impairment, the Ivacaftor + Lumacaftor combination should be used with caution at a maximum dose of 1 sachet or less per day after a thorough assessment of the risk-benefit ratio of treatment for patients with severe hepatic disorders.

Renal impairment. Pharmacokinetic studies of the Ivacaftor + Lumacaftor combination have not been conducted in patients with renal impairment. In a human pharmacokinetic study with lumacaftor alone, the renal excretion of lumacaftor and its metabolites was minimal (only 8.6% of total radioactivity was found in urine, with 0.18% unchanged). In a pharmacokinetic study of ivacaftor, minimal renal excretion of ivacaftor and its metabolites was observed (6.6% of total radioactivity). Therefore, no dose adjustment of the Ivacaftor + Lumacaftor combination is required in patients with mild and moderate renal impairment. However, caution should be exercised when using the combination in patients with severe renal impairment (CrCl ≤30 mL/min) or end-stage renal disease.

Gender. The effect of gender was evaluated using a population pharmacokinetic analysis of clinical trial data on the use of lumacaftor in combination with ivacaftor. The results indicate no clinically significant differences in the pharmacokinetic parameters of lumacaftor and ivacaftor between men and women. There is no need to adjust the dose of the Ivacaftor + Lumacaftor combination based on gender.

Pediatric age. Population pharmacokinetic analysis demonstrated exposure in children similar to adults. Information is presented in Table 1.

Table 1. Mean exposure (SD) of ivacaftor and lumacaftor by age group

Indications

• The combination Ivacaftor + Lumacaftor is indicated for the treatment of cystic fibrosis in patients aged 2 years and older, homozygous for the F508del mutation in the CFTR gene (the efficacy and safety of the Ivacaftor + Lumacaftor combination have been established only in cystic fibrosis patients homozygous for the F508del mutation in the CFTR gene).

ICD codes

Dosage Regimen

Tablets

Before starting treatment, if the patient’s genotype is unknown, the presence of the F508del mutation on both alleles of the CFTR gene should be confirmed by a reliable and validated genotyping method.

Orally, whole, without chewing, biting, or dissolving the tablets.

Treatment can be started on any day of the week.

It is necessary to consume fat-containing food immediately before or right after taking the drug. Food recommended for cystic fibrosis, as well as according to healthy eating standards in general, contains a sufficient amount of fat. Examples of fat-containing food dishes include dishes prepared with butter or olive oil, eggs, cheeses, nuts, whole milk, or meat.

Table 2. Recommended doses of Orkambi^® in patients aged 6 years and older

* recommended to be taken in the morning and evening

Missed dose

If less than 6 hours have passed since the missed dose, the missed dose of the Ivacaftor + Lumacaftor combination should be taken as usual with fat-containing food.

If more than 6 hours have passed since the missed dose, the patient should wait and take the drug at the scheduled time of the next dose. A double dose should not be taken to make up for a missed dose.

Special patient groups

Patients with hepatic impairment

• mild hepatic impairment (Child-Pugh class A) – no dose adjustment required;
• moderate hepatic impairment (Child-Pugh class B) – dose reduction is recommended;
• severe hepatic impairment (Child-Pugh class C) – studies in patients have not been conducted, but exposure in such patients is expected to be higher, therefore dose reduction is recommended.

Table 3. Recommendations for dose adjustment in patients with hepatic impairment

Patients with renal impairment

• mild and moderate renal impairment – no dose adjustment required;
• severe renal impairment (CrCl≤30 mL/min) or end-stage renal disease – it is recommended to use the drug with caution.

Pediatric age

The safety and efficacy of the Ivacaftor + Lumacaftor combination in children under 2 years of age have not been studied. The use of the drug in children under 6 years of age is contraindicated due to the lack of sufficient clinical experience.

Elderly patients (over 65 years)

The safety and efficacy of the Ivacaftor + Lumacaftor combination in patients aged 65 years and older have not been studied.

Concomitant use with CYP3A isoenzyme inhibitors

No dose adjustment is required if CYP3A isoenzyme inhibitors are initiated in patients already receiving the Ivacaftor + Lumacaftor combination. However, if the Ivacaftor + Lumacaftor combination is used in patients already receiving strong CYP3A isoenzyme inhibitors (including itraconazole), it is necessary to reduce the dose of the Ivacaftor + Lumacaftor combination to 1 tablet/day during the 1st week of taking the combination. Subsequently, the combination is used at the recommended daily dose.

If treatment with the Ivacaftor + Lumacaftor combination is interrupted for more than 1 week and then resumed while taking a strong CYP3A isoenzyme inhibitor, it is necessary to reduce the dose of the Ivacaftor + Lumacaftor combination to 1 tablet/day during the 1st week of resumed treatment. Subsequently, the combination is used at the recommended daily dose.

Granules

Before starting treatment, if the patient’s genotype is unknown, the presence of the F508del mutation on both alleles of the CFTR gene should be confirmed by a reliable and validated genotyping method.

The drug is intended for oral administration.

The entire contents of each sachet of granules should be mixed with one teaspoon (5 mL) of age-appropriate soft food or liquid, and the entire mixture should be taken orally.

Treatment can be started on any day of the week.

It is necessary to consume fat-containing food immediately before or right after taking the drug.

Some examples of soft food include fruit puree, flavored yogurt or pudding, and milk or juice. The food should be at room temperature or colder. Each sachet is for single use only. It has been shown that after mixing, the drug is stable for 1 hour, so it should be taken within this period.

Standard doses for patients aged 2 years and older are provided in Table 2.

Table 2. Recommended dosage of Orkambi^® in patients aged 2 years and older

Patients with renal impairment

• mild and moderate renal impairment – no dose adjustment required;
• severe renal impairment (CrCl ≤30 ml/min) or end-stage renal disease – it is recommended to use the drug with caution.

Pediatric population

The safety and efficacy of the Ivacaftor + Lumacaftor combination in children under 2 years of age have not been studied.

Elderly patients (over 65 years)

The safety and efficacy of the Ivacaftor + Lumacaftor combination in patients aged 65 years and older have not been studied.

Concomitant use with CYP3A isoenzyme inhibitors

No dose adjustment is required if CYP3A isoenzyme inhibitors are initiated in patients already receiving the Ivacaftor + Lumacaftor combination. However, if the Ivacaftor + Lumacaftor combination is used in patients already receiving potent CYP3A isoenzyme inhibitors (including itraconazole), the dose of the Ivacaftor + Lumacaftor combination should be reduced to 1 sachet every other day during the first week of treatment with the combination. Subsequently, the combination is used at the recommended daily dose.

If treatment with the Ivacaftor + Lumacaftor combination is interrupted for more than 1 week and then resumed while taking a potent CYP3A isoenzyme inhibitor, the dose of the Ivacaftor + Lumacaftor combination should be reduced to 1 sachet every other day during the first week of resumed treatment. Subsequently, the combination is used at the recommended daily dose.

Adverse Reactions

Summary of the safety profile

The most frequent adverse reactions observed in Phase III clinical trials were dyspnea (14.0% compared to 7.8% in the placebo group), diarrhea (11.0% compared to 8.4% in the placebo group), and nausea (10.2% compared to 7.6% in the placebo group).

Serious adverse reactions included hepatobiliary disorders, such as increased hepatic transaminase activity, cholestatic hepatitis, and hepatic encephalopathy.

The list of adverse reactions is presented in Table 4.

Adverse reactions are classified according to the MedDRA frequency classification: very common (≥1/10); common (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (frequency cannot be estimated from available data).

Table 4. Adverse reactions in patients receiving Ivacaftor + Lumacaftor

* 1 patient out of 738

** 2 patients out of 738

Additional information on selected adverse reactions obtained during studies is provided below.

Description of selected adverse reactions

Hepatobiliary system reactions

During the 24-week placebo-controlled Phase III studies (Studies 1 and 2), the frequency of maximum increases in ‘hepatic’ transaminase (ALT and AST) activity > 8, > 5 and > 3 × ULN was 0.8%, 2.0% and 5.2% in patients receiving the Ivacaftor + Lumacaftor combination, and 0.5%, 1.9% and 5.1% in patients receiving placebo. The frequency of adverse reactions associated with increased ‘hepatic’ transaminase activity was 5.1% and 4.6% in patients receiving the Ivacaftor + Lumacaftor combination and placebo, respectively. Seven patients receiving the Ivacaftor + Lumacaftor combination experienced serious hepatic adverse reactions with increased ‘hepatic’ transaminase activity, including 3 with concurrent increased total bilirubin. After discontinuation of the Ivacaftor + Lumacaftor combination, liver function tests returned to baseline or significantly improved in all patients. Despite the presence of other causes, the possibility of liver injury with the Ivacaftor + Lumacaftor combination cannot be completely ruled out (see section “Special Precautions”).

Of the 7 patients with a history of liver cirrhosis and/or portal hypertension receiving the Ivacaftor + Lumacaftor combination in a placebo-controlled Phase III study, worsening liver function with increased ALT, AST, bilirubin, and hepatic encephalopathy was observed in only one patient 5 days after starting the drug and resolved after discontinuation of the Ivacaftor + Lumacaftor combination (see section “Special Precautions”).

During a 24-week open-label Phase III clinical study in 58 patients aged 6-11 years (Study 5), the frequency of maximum increases in ‘hepatic’ transaminase (AST or ALT) activity >8, >5 and >3 × ULN was 5.3%, 8.8% and 19.3%. No patient had an increase in total bilirubin >2 × ULN.

Use of the Ivacaftor + Lumacaftor combination was not discontinued or was successfully resumed after an interruption in all patients with increased ‘hepatic’ transaminase activity, except for one patient who discontinued treatment.

During a 24-week placebo-controlled Phase III clinical study involving 204 patients aged 6-11 years (Study 7), the frequency of maximum increases in ‘hepatic’ transaminase (ALT or AST) activity >8, >5 and > 3 × ULN was 2.0%, 3.0% and 7.9% in patients taking placebo. No patient had an increase in total bilirubin > 2 × ULN. Two patients from the group taking the Ivacaftor+Lumacaftor combination and two patients from the placebo group discontinued treatment due to increased ‘hepatic’ transaminase activity.

During a 24-week open-label Phase III clinical study in 60 patients aged 2-5 years (Study 8), the frequency of maximum increases in ‘hepatic’ transaminase (ALT or AST) activity > 8, > 5 and > 3 × ULN was 8.3% (5/60), 11.7% (7/60) and 15.0% (9/60). No patient had an increase in total bilirubin >2 × ULN. Three patients completely discontinued treatment with the Ivacaftor/Lumacaftor combination due to increased ‘hepatic’ transaminase activity.

Respiratory disorders

During the 24-week placebo-controlled Phase III studies (Studies 1 and 2), the frequency of respiratory adverse reactions (including chest discomfort, dyspnea, and breathing difficulty) was 26.3% in the Ivacaftor + Lumacaftor group, and 17.0% in the placebo group. The frequency of these events was higher in patients with a lower forced expiratory volume in 1 second (FEV₁) prior to treatment initiation. Approximately 3/4 of events occurred during the first week of treatment and resolved in most patients without the need for treatment interruption or discontinuation. They were mostly non-serious and mild or moderate in severity (see section “Special Precautions”).

During a 24-week open-label Phase IIIb clinical study (Study 6) in 46 patients aged 12 years and older with severe lung impairment (percent predicted FEV₁<40) [mean baseline percent predicted FEV₁ 29.1 (range: from 18.3 to 42.0)], the frequency of respiratory adverse events was 65.2%. In the subgroup of 28 patients whose treatment was started with the full dose of the Ivacaftor + Lumacaftor combination (2 tablets every 12 hours), the frequency of respiratory disorders was 71.4%, and in the 18 patients whose treatment was started with a reduced dose (1 tablet every 12 hours for the first 2 weeks followed by an increase to the full dose), this frequency was 55.6%. Among patients started on the full dose of the Ivacaftor + Lumacaftor combination, only one patient experienced a serious respiratory adverse reaction, in 3 patients the dose was subsequently reduced, and 3 patients discontinued treatment. There were no cases of serious adverse reactions, dose reduction, or treatment discontinuation in patients when therapy was started with a half dose.

During a 24-week open-label Phase III clinical study (Study 5) in 58 patients aged 6-11 years (mean baseline ppFEV₁ was 91.4), the frequency of respiratory adverse reactions was 6.9% (4/58).

During a 24-week placebo-controlled Phase III clinical study (Study 7) in patients aged 6-11 years (mean baseline ppFEV₁ was 89.8), the frequency of respiratory adverse reactions was 18.4% in patients receiving the Ivacaftor + Lumacaftor combination and 12.9% in patients receiving placebo. A decrease in ppFEV₁ was observed at the start of therapy during a series of spirometry measurements. The absolute change from 4-6 hours before the first dose to the last dose was 7.7 on day 1 and 1.3 on day 15 in patients receiving the Ivacaftor + Lumacaftor combination. The post-dose decrease was resolved by week 16.

Menstrual cycle disorders

During the 24-week placebo-controlled Phase III studies (Studies 1 and 2), the frequency of combined menstrual cycle disorders (amenorrhea, dysmenorrhea, menorrhagia, menstrual disorder, metrorrhagia, oligomenorrhea, and polymenorrhea) was 9.9% in women receiving the Ivacaftor + Lumacaftor combination and 1.7% in women receiving placebo, and they were more common in the subgroup of patients who were taking hormonal contraceptives (25.0%) compared to patients not taking hormonal contraceptives (3.5%). Most of these reactions were non-serious and also mild or moderate in severity.

Increased blood pressure (BP)

During the 24-week placebo-controlled Phase III studies (Studies 1 and 2), adverse reactions associated with increased BP (including hypertension) were observed in 0.9% (7/738) of patients receiving the Ivacaftor + Lumacaftor combination, and in no patient in the placebo group.

In patients receiving the Ivacaftor + Lumacaftor combination, the maximum increase from baseline mean values (systolic BP [SBP] 114 mmHg and diastolic BP [DBP] 69 mmHg) was 3.1 mmHg and 1.8 mmHg, respectively. In patients receiving placebo, the maximum increase in mean SBP and DBP from baseline (SBP – 114 mmHg, DBP – 69 mmHg) was 0.9 mmHg and 0.9 mmHg, respectively.

The proportion of patients with SBP values >140 mmHg or DBP > 90 mmHg on at least two occasions was 3.4% and 1.5% in the group of patients receiving the Ivacaftor + Lumacaftor combination, respectively, compared to 1.6% and 0.5% in patients receiving placebo.

Post-marketing experience

Hepatic impairment

In the post-marketing period, cases of liver function decompensation, including liver failure leading to death, have been reported in patients with cystic fibrosis with pre-existing liver cirrhosis and portal hypertension who received the Ivacaftor + Lumacaftor combination. If the Ivacaftor + Lumacaftor combination is prescribed in this patient group, they should be properly monitored after initiation of therapy, and the dosage should be reduced.

Contraindications

• Hypersensitivity to the active substances or to any component of the drug;
• Children under 2 years of age.

With caution

• Severe renal impairment (CrCl ≤30 ml/min) or end-stage renal disease;
• Severe liver disorders;
• Severe hepatic impairment (Child-Pugh class C, 10-15 points) (see section “Special Precautions”);
• Patients with cystic fibrosis who are heterozygous for the F508del mutation in the CFTR gene (see section “Special Precautions”);
• Patients with cystic fibrosis who have class III mutations in the CFTR gene (see section “Special Precautions”);
• Pregnancy;
• Breastfeeding period.

Use in Pregnancy and Lactation

Pregnancy

Adequate and well-controlled studies of the Ivacaftor + Lumacaftor combination in pregnant women have not been conducted.

Since animal reproduction studies are not always predictive of human response, the Ivacaftor + Lumacaftor combination should be used during pregnancy only if clearly needed.

Lumacaftor toxicity studies in rats and rabbits using daily doses 20 times and 4 times, respectively, the recommended human daily dose of lumacaftor when used in the Ivacaftor + Lumacaftor combination revealed no evidence of toxic effects on the fetus.

Ivacaftor toxicity studies conducted in rats and rabbits at daily doses up to 3 times the recommended human daily dose of ivacaftor when used in the Ivacaftor + Lumacaftor combination revealed no evidence of toxic effects on the fetus.

Breastfeeding period

It is not known whether the Ivacaftor + Lumacaftor combination and their metabolites pass into breast milk. Both Lumacaftor and Ivacaftor were excreted in the milk of rats. The safety of the Ivacaftor + Lumacaftor combination during breastfeeding has not been established. The Ivacaftor + Lumacaftor combination should be used during breastfeeding only if the potential benefit to the mother outweighs the potential risk to the breastfed infant.

Fertility

Ivacaftor reduced fertility and reproductive performance indices in male and female rats at a dose of 200 mg/kg/day (approximately 11 and 7 times, respectively, the maximum recommended dose of the ivacaftor component of the Ivacaftor + Lumacaftor combination based on summed AUC values of ivacaftor and its metabolites, extrapolated from exposures on day 90 at 150 mg/kg/day for 6 months, a repeated-dose toxicity study in males and on day 17 of a pilot embryo-fetal development study in this species).

No effect on male or female fertility and reproductive performance indices was observed at doses ≤100 mg/kg/day (approximately 8 and 5 times, respectively, the maximum recommended dose of the ivacaftor component of the Ivacaftor + Lumacaftor combination based on summed AUC values of ivacaftor and its metabolites, extrapolated from exposures on day 90 at 100 mg/kg/day for 6 months, a repeated-dose toxicity study in this species).

Lumacaftor had no effect on fertility and reproductive performance indices in male and female rats at a dose of 1000 mg/kg/day (approximately 3 and 8 times, respectively, the maximum recommended human dose of the lumacaftor component of the Ivacaftor + Lumacaftor combination based on AUC values).

Use in Hepatic Impairment

Use with caution in severe liver diseases; in severe hepatic impairment (Child-Pugh class C, 10-15 points).

Use in Renal Impairment

Use with caution in severe renal impairment (CrCl ≤30 ml/min) or in end-stage renal disease.

Pediatric Use

Contraindicated for use in children under 2 years of age.

Geriatric Use

The safety and efficacy of the Ivacaftor + Lumacaftor combination in patients aged 65 years and older have not been studied.

Special Precautions

Patients with progressive liver disease

Patients with cystic fibrosis may have liver function disorders, including progressive liver disease.

Cases of liver function decompensation, including the development of liver failure leading to death, have been reported in patients with cystic fibrosis and a history of liver cirrhosis with portal hypertension receiving the Ivacaftor + Lumacaftor combination. The Ivacaftor + Lumacaftor combination should be used with caution in patients with progressive liver disease and only if the expected benefit outweighs the potential risk. When using the Ivacaftor + Lumacaftor combination, such patients should be under close clinical supervision, and the dosage must be reduced.

Hepatobiliary adverse events

Increased hepatic transaminase activity has been reported in patients with cystic fibrosis, including those receiving the Ivacaftor + Lumacaftor combination. In some cases, this was accompanied by an increase in total bilirubin in the blood serum.

Since a connection between the use of the combination and liver damage cannot be ruled out, measurement of functional hepatic transaminase parameters (ALT, AST and bilirubin) is recommended before starting treatment with the Ivacaftor + Lumacaftor combination, every 3 months during the first year of treatment and then annually. In patients with a history of increased ALT, AST and bilirubin activity, more frequent monitoring of their activity should be provided.

In case of a significant increase in ALT or AST activity with/without concurrent increased bilirubin (ALT or AST >5 ULN, or ALT or AST >3 x ULN with an increase in bilirubin >2 x ULN), the use of the Ivacaftor+Lumacaftor combination should be discontinued and careful monitoring of parameters should be carried out until the condition normalizes. After normalization of hepatic transaminase activity, resumption of treatment is possible only after a careful assessment of the benefits and risks of use.

Respiratory adverse events

Respiratory adverse events (including chest discomfort, dyspnea, and breathing difficulty) were observed more frequently in patients at the start of treatment with the Ivacaftor + Lumacaftor combination compared to those receiving placebo. These events led to drug discontinuation and can be serious, especially in patients with percent predicted FEV₁ (%) <40. Clinical experience with the combination in patients with percent predicted FEV₁ (%) <40 is limited, therefore additional monitoring of these patients at the start of therapy is recommended. A transient decrease in FEV₁ was also observed in some patients after starting the Ivacaftor + Lumacaftor combination. There is no experience with initiating treatment with the Ivacaftor + Lumacaftor combination in patients with a pulmonary exacerbation, and initiating treatment in patients with a pulmonary exacerbation is not recommended.

Effect on Blood Pressure

An increase in blood pressure was observed in some patients receiving the Ivacaftor + Lumacaftor combination. Blood pressure should be periodically monitored in all patients during treatment.

Drug Interactions

Based on exposure and the specified doses, the drug interaction profile is considered the same for all doses and dosage forms.

Ivacaftor is a weak inhibitor of the CYP3A isoenzyme when used as monotherapy. Lumacaftor is a potent inducer of the CYP3A isoenzyme. Concomitant use of lumacaftor with ivacaftor, which is a sensitive substrate of the CYP3A isoenzyme, reduces ivacaftor exposure by approximately 80%.

Potential Influence of Other Drugs on the Ivacaftor + Lumacaftor Combination

Substrates of the CYP3A isoenzyme. Lumacaftor is a potent inducer of the CYP3A isoenzyme. Use of the Ivacaftor + Lumacaftor combination may reduce the systemic exposure of drugs that are substrates of the CYP3A isoenzyme, thereby reducing their therapeutic effect. Concomitant use of the combination with sensitive substrates of the CYP3A isoenzyme or substrates of the CYP3A isoenzyme with a narrow therapeutic index is not recommended.

Use of the Ivacaftor + Lumacaftor combination may significantly reduce the exposure of hormonal contraceptives, thereby reducing their effectiveness. Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, should not be considered an effective method of contraception when used concomitantly with the Ivacaftor + Lumacaftor combination.

Potent Inducers of the CYP3A isoenzyme. Ivacaftor is a substrate of the CYP3A4 and CYP3A5 isoenzymes. Use of the Ivacaftor + Lumacaftor combination with potent inducers of the CYP3A isoenzyme, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic efficacy of the Ivacaftor + Lumacaftor combination; therefore, concomitant use with potent inducers of the CYP3A isoenzyme (including rifampin, St. John’s wort [Hypericum perforatum]) is not recommended.

Cataracts

Cases of acquired lens opacity without effect on vision have been reported in pediatric patients receiving ivacaftor monotherapy or the Ivacaftor + Lumacaftor combination. Although other risk factors were present in some cases (such as corticosteroid use and radiation), a possible risk of cataract development associated with ivacaftor use cannot be excluded. All children starting therapy with the Ivacaftor + Lumacaftor combination are recommended to have a baseline and periodic ophthalmological examination as part of routine care.

Renal Impairment

Caution is recommended when using the Ivacaftor + Lumacaftor combination in patients with severe renal impairment or end-stage renal disease (see subsections “Special Patient Groups” and “Pharmacokinetics in Special Patient Groups”).

Patients with Cystic Fibrosis Heterozygous for the F508del Mutation in the CFTR Gene

The Ivacaftor + Lumacaftor combination is not effective in patients with cystic fibrosis who have the F508del mutation on one allele and a mutation resulting in no CFTR production or non-responsive to Ivacaftor in vitro on the other allele (see subsection “Use with Caution”).

Patients with Cystic Fibrosis Having Class III Mutations in the CFTR Gene

The Ivacaftor + Lumacaftor combination has not been studied in patients with cystic fibrosis who have Class III mutations in the CFTR gene on one allele and with or without the F508del mutation on the other allele. Since ivacaftor exposure is very significantly reduced when dosed in combination with lumacaftor, these patients should not use the Ivacaftor + Lumacaftor combination (see subsection “Use with Caution”).

Patients Post-Organ Transplant

The use of the Ivacaftor + Lumacaftor combination has not been studied in patients with cystic fibrosis who have undergone organ transplantation; therefore, its use in patients with organ transplants is not recommended (see section “Drug Interactions” regarding interaction with immunosuppressants).

Effect on Ability to Drive and Operate Machinery

Data on the effect of the Ivacaftor + Lumacaftor combination on the ability to drive and operate machinery are not available.

Overdose

Treatment of overdose involves standard supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. There is no specific antidote for overdose of the Ivacaftor + Lumacaftor combination.

Drug Interactions

Based on exposure and the specified doses, the drug interaction profile is considered the same for all doses and dosage forms.

Ivacaftor is a weak inhibitor of the CYP3A isoenzyme when used as monotherapy.

Lumacaftor is a potent inducer of the CYP3A isoenzyme. Concomitant use of lumacaftor with ivacaftor, which is a sensitive substrate of the CYP3A isoenzyme, reduces ivacaftor exposure by approximately 80%.

Potential Influence of Other Drugs on the Ivacaftor + Lumacaftor Combination

Inhibitors of the CYP3A isoenzyme

Concomitant use of the Ivacaftor + Lumacaftor combination with itraconazole, a potent inhibitor of the CYP3A isoenzyme, did not affect lumacaftor exposure but increased ivacaftor exposure by 4.3-fold. Due to the inducing effect of lumacaftor on the CYP3A isoenzyme, the steady-state exposure of ivacaftor when used concomitantly with a CYP3A isoenzyme inhibitor is not expected to exceed that when used at the approved monotherapy dose of 150 mg every 12 hours in the absence of lumacaftor.

When CYP3A isoenzyme inhibitors are used concomitantly in patients currently taking the Ivacaftor + Lumacaftor combination, dose adjustment is not required. However, if treatment with the Ivacaftor + Lumacaftor combination is initiated in patients taking a potent CYP3A inhibitor, the dose should be reduced. Dose adjustment is not recommended for concomitant use with moderate or weak inhibitors of the CYP3A isoenzyme.

Inducers of the CYP3A isoenzyme

Concomitant use of the Ivacaftor + Lumacaftor combination with rifampin, a potent inducer of the CYP3A isoenzyme, had minimal effect on lumacaftor exposure but reduced ivacaftor exposure (AUC) by 57%; therefore, concomitant use of the Ivacaftor + Lumacaftor combination with potent inducers of the CYP3A isoenzyme is not recommended.

Dose adjustment is not required for concomitant use with moderate or weak inducers of the CYP3A isoenzyme.

Potential Influence of the Ivacaftor + Lumacaftor Combination on Other Drugs

Substrates of the CYP3A isoenzyme

Lumacaftor is a potent inducer of the CYP3A isoenzyme. Ivacaftor is a weak inhibitor of the CYP3A isoenzyme when used as monotherapy. The net effect of therapy with the Ivacaftor + Lumacaftor combination is expected to be potent induction of the CYP3A isoenzyme.

Thus, concomitant use of the Lumacaftor + Ivacaftor combination with substrates of the CYP3A isoenzyme may reduce the exposure of these substrates. Concomitant use of the Ivacaftor + Lumacaftor combination is not recommended with sensitive substrates of the CYP3A isoenzyme or substrates of the CYP3A isoenzyme with a narrow therapeutic range.

Substrates of P-glycoprotein

In vitro studies have shown that Lumacaftor has the potential to both inhibit and induce P-glycoprotein. Furthermore, a clinical study of ivacaftor monotherapy showed that Ivacaftor is a weak inhibitor of P-glycoprotein. Consequently, concomitant use of the Ivacaftor + Lumacaftor combination with P-glycoprotein substrates (e.g., digoxin) may alter the exposure of these substrates.

Substrates of the CYP2B6 and CYP2C isoenzymes

In vitro studies have shown that Lumacaftor has the potential to induce the CYP2B6, CYP2C8, CYP2C9, and CYP2C19 isoenzymes; however, inhibition of the CYP2C8 and CYP2C9 isoenzymes was also observed in vitro. Furthermore, in vitro studies suggest that Ivacaftor may inhibit the CYP2C9 isoenzyme. Consequently, concomitant use of the Ivacaftor + Lumacaftor combination may alter the exposure of substrates of the CYP2C8 and CYP2C9 isoenzymes and reduce the exposure of substrates of the CYP2B6 and CYP2C19 isoenzymes.

Interaction of the Ivacaftor + Lumacaftor Combination with Transporter Proteins

In vitro studies indicate that Lumacaftor is a substrate for the Breast Cancer Resistance Protein (BCRP). Concomitant use of Orkambi^® with drugs that inhibit BCRP may increase the plasma concentration of lumacaftor. Lumacaftor inhibits the Organic Anion Transporter (OAT) 1 and 3. Lumacaftor and Ivacaftor are inhibitors of BCRP. Concomitant use of Orkambi^® with drugs that are substrates for the OAT1/3 and BCRP transporter proteins may increase the plasma concentrations of such drugs. Lumacaftor and Ivacaftor are not inhibitors of OATP1B1, OATP1B3, and the Organic Cation Transporter (OCT) 1 and 2. Ivacaftor is not an inhibitor of OAT1 and OAT3.

Established and Other Potentially Significant Drug Interactions

Table 5 presents the established or predicted effect of the Ivacaftor + Lumacaftor combination on other drugs or the effect of other drugs on the Ivacaftor + Lumacaftor combination. Drug interaction studies were conducted in adult patients between the Ivacaftor + Lumacaftor combination and other drugs that may be used concomitantly or drugs typically used as pharmacological probes (metabolic marker, test substrate) in pharmacokinetic interaction studies.

The recommendations presented in the “Comment for Clinical Use” column in Table 5 are based on drug interaction studies, clinical significance, or predicted interactions in terms of elimination pathways. Drug interactions that have the greatest clinical significance are listed first.

Table 5. Established or Other Potentially Significant Drug Interaction – Dosing Recommendations for Use of the Ivacaftor + Lumacaftor Combination with Other Drugs

↑ – increase; ↓ – decrease; ↔ – no change

* – based on clinical interaction studies. All other listed interactions are not presumed.

False-Positive Urine Tetrahydrocannabinol Results

There have been reports of false-positive urine screening test results for tetrahydrocannabinol (THC) in patients receiving Orkambi^®. An alternative confirmatory method should be considered to verify the results.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life is 4 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.