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Orkambi

Generic Name: Lumacaftor and Ivacaftor
Class: Cystic Fibrosis Transmembrane Conductance Regulator Correctors
Chemical Name: 3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid
Molecular Formula: C24H18F2N2O5C24H28N2O3
CAS Number: 1220975-12-1

Introduction

Lumacaftor is a cystic fibrosis transmembrane conductance regulator corrector; ivacaftor is a cystic fibrosis transmembrane conductance regulator potentiator.

Uses for Orkambi

Lumacaftor and ivacaftor has the following uses:

Lumacaftor and ivacaftor is a combination of lumacaftor and ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, indicated for the treatment of cystic fibrosis (CF) in patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene. If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.1

Lumacaftor and ivacaftor has the following limitations of use:

The efficacy and safety of lumacaftor and ivacaftor have not been established in patients with CF other than those homozygous for the F508del mutation.1

Orkambi Dosage and Administration

General

The fixed combination of lumacaftor and ivacaftor is available in the following dosage form(s) and strength(s):

  • Tablets: lumacaftor 200 mg and ivacaftor 125 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Adults and pediatric patients age 12 years and older: two tablets (each containing lumacaftor 200 mg/ivacaftor 125 mg) taken orally every 12 hours.1

  • Reduce dose in patients with moderate or severe hepatic impairment.1

  • When initiating lumacaftor and ivacaftor in patients taking strong CYP3A inhibitors, reduce lumacaftor and ivacaftor dose for the first week of treatment.1

Cautions for Orkambi

Contraindications

  • None.1

Warnings/Precautions

Use in Patients with Advanced Liver Disease

Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported in some patients with CF while receiving lumacaftor and ivacaftor. Use lumacaftor and ivacaftor with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If lumacaftor and ivacaftor is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced.1

Liver-related Events

Serious adverse reactions related to elevated transaminases have been reported in patients with CF receiving lumacaftor and ivacaftor. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin.1

It is recommended that ALT, AST, and bilirubin be assessed prior to initiating lumacaftor and 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. Patients who develop increased ALT, AST, or bilirubin should be closely monitored until the abnormalities resolve.1

Dosing should be interrupted in patients with ALT or AST greater than 5 × upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations greater than 3 × ULN when associated with bilirubin elevations greater than 2 × ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing.1

Respiratory Events

Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of lumacaftor and ivacaftor compared to those who received placebo. Clinical experience in patients with percent predicted FEV1 (ppFEV1) <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy.1

Effect on Blood Pressure

Increased blood pressure has been observed in some patients treated with lumacaftor and ivacaftor. Blood pressure should be monitored periodically in all patients being treated with lumacaftor and ivacaftor.1

Drug Interactions

Substrates of CYP3A

Lumacaftor is a strong inducer of CYP3A. Administration of lumacaftor and ivacaftor may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended.1

Lumacaftor and ivacaftor may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular (27% in women using hormonal contraceptives compared with 3% in women not using hormonal contraceptives). Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with lumacaftor and ivacaftor.1

Strong CYP3A Inducers

Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of lumacaftor and ivacaftor with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of lumacaftor and ivacaftor. Therefore, co-administration with strong CYP3A inducers (e.g., rifampin, St. John's wort [Hypericum perforatum]) is not recommended.1

Cataracts

Cases of non-congenital lens opacities have been reported in pediatric patients treated with ivacaftor, a component of lumacaftor and ivacaftor. 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 pediatric patients initiating lumacaftor and ivacaftor treatment.1

Specific Populations

Pregnancy

Risk Summary: There are limited and incomplete human data from clinical trials and postmarketing reports on use of the fixed combination of lumacaftor and ivacaftor or its individual components, lumacaftor or ivacaftor, in pregnant women to inform a drug-associated risk. In animal reproduction studies, oral administration of lumacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse effects on fetal development at doses that produced maternal exposures up to approximately 8 (rats) and 5 (rabbits) times the exposure at the maximum recommended human dose (MRHD). Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse effects on fetal development at doses that produced maternal exposures up to approximately 7 (rats) and 45 (rabbits) times the exposure at the MRHD. No adverse developmental effects were observed after oral administration of either lumacaftor or ivacaftor to pregnant rats from organogenesis through lactation at doses that produced maternal exposures approximately 8 and 5 times the exposures at the MRHD, respectively. There are no animal reproduction studies with concomitant administration of lumacaftor and ivacaftor.1 The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

Lumacaftor Animal Data: In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 7-17, lumacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 8 times the MRHD (on an AUC basis at maternal oral doses up to 2000 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 7-19, lumacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 5 times the MRHD (on an AUC basis at maternal oral doses up to 200 mg/kg/day). In a pre- and postnatal development study in pregnant female rats dosed from gestation day 6 through lactation day 20, lumacaftor had no effects on delivery or growth and development of offspring at exposures up to 8 times the MRHD (on an AUC basis at maternal oral doses up to 1000 mg/kg/day). Placental transfer of lumacaftor was observed in pregnant rats and rabbits.1

Ivacaftor Animal Data: In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 7-17, ivacaftor was not teratogenic and did not affect fetal survival at exposures up to 7 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 200 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 7-19, ivacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 45 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day). In a pre- and postnatal development study in pregnant female rats dosed from gestation day 7 through lactation day 20, ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 5 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose that produced exposures 7 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at a maternal oral dose of 200 mg/kg/day). Placental transfer of ivacaftor was observed in pregnant rats and rabbits.1

Lactation

There is no information regarding the presence of lumacaftor or ivacaftor in human milk, the effects on the breast-fed infant, or the effects on milk production. Both lumacaftor and ivacaftor are excreted into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal lactation data may not reliably predict levels in human milk. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for lumacaftor and ivacaftor and any potential adverse effects on the breast-fed child from lumacaftor and ivacaftor or from the underlying maternal condition.1

Lacteal excretion of lumacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of 14C-lumacaftor administered 9 to 11 days postpartum to lactating mothers (dams). Exposure (AUC0-24h) values for lumacaftor in milk were approximately 40% of plasma levels.1

Lacteal excretion of ivacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of 14C-ivacaftor administered 9 to 10 days postpartum to lactating mothers (dams). Exposure (AUC0-24h) values for ivacaftor in milk were approximately 1.5 times higher than plasma levels.1

Females and Males of Reproductive Potential

Lumacaftor and ivacaftor may decrease hormonal contraceptive exposure, reducing the effectiveness. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with lumacaftor and ivacaftor.1

Pediatric Use

The safety and efficacy of lumacaftor and ivacaftor in patients with CF younger than age 12 years have not been established. Cases of non-congenital lens opacities have been reported in pediatric patients treated with ivacaftor, a component of the fixed combination of lumacaftor and ivacaftor. 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.1

In a juvenile toxicology study in which ivacaftor was administered to rats from postnatal days 7 to 35, cataracts were observed at all dose levels, ranging from 0.3 to 2 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at oral doses of 10-50 mg/kg/day). This finding has not been observed in older animals.1

Geriatric Use

CF is largely a disease of children and young adults. Clinical trials of lumacaftor and ivacaftor did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients.1

Hepatic Impairment

No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A dose reduction to 2 tablets in the morning and 1 tablet in the evening (lumacaftor 600 mg/ivacaftor 375 mg total daily dose) is recommended for patients with moderate hepatic impairment (Child-Pugh Class B).1

Studies have not been conducted 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, use with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening (lumacaftor 400 mg/ivacaftor 250 mg total daily dose), or less, in patients with severe hepatic impairment after weighing the risks and benefits of treatment.1

Renal Impairment

Lumacaftor and ivacaftor has not been studied in patients with mild, moderate, or severe renal impairment or in patients with end-stage renal disease. No dose adjustment is necessary for patients with mild and moderate renal impairment. Caution is recommended while using lumacaftor and ivacaftor in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease.1

Patients with Severe Lung Dysfunction

The Phase 3 trials included 29 patients receiving lumacaftor and ivacaftor with ppFEV1 <40 at baseline. The treatment effect in this subgroup was comparable to that observed in patients with ppFEV1 ≥40.1

Patients after Organ Transplantation

Lumacaftor and ivacaftor has not been studied in patients with CF who have undergone organ transplantation. Use in transplanted patients is not recommended due to potential drug-drug interactions.1

Common Adverse Effects

The most common adverse reactions to lumacaftor and ivacaftor (occurring in ≥5% of patients with CF homozygous for the F508del mutation in the CFTR gene) were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, influenza.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

See Full Prescribing Information for a complete list.1

Actions

Mechanism of Action

The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. The F508del mutation results in protein misfolding, causing a defect in cellular processing and trafficking that targets the protein for degradation and therefore reduces the quantity of CFTR at the cell surface. The small amount of F508del-CFTR that reaches the cell surface is less stable and has low channel-open probability (defective gating activity) compared to wild-type CFTR protein.1

Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to 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. In vitro studies have demonstrated that both lumacaftor and ivacaftor act directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport. In vitro responses do not necessarily correspond to in vivo pharmacodynamic response or clinical benefit.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Advanced Liver Disease

Inform patients that worsening of liver function in patients with advanced liver disease occurred in some patients treated with lumacaftor and ivacaftor. If lumacaftor and ivacaftor is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced.1

Abnormalities in Liver Function and Testing

Inform patients that abnormalities in liver function have occurred in patients treated with lumacaftor and ivacaftor. Blood tests to measure transaminases (ALT and AST) and bilirubin will be performed prior to initiating lumacaftor and ivacaftor, every 3 months during the first year of therapy, and annually thereafter.1

Respiratory Events

Inform patients that chest discomfort, dyspnea, and respiration abnormal were more common during initiation of lumacaftor and ivacaftor therapy. Additional monitoring of patients with ppFEV1<40 is recommended during initiation of therapy.1

Effect on Blood Pressure

Inform patients that increased blood pressure has been observed in some patients treated with lumacaftor and ivacaftor and that periodic monitoring of their blood pressure during treatment is recommended.1

Drug Interactions with CYP3A Inhibitors and Inducers and CYP Substrates

Ask patients to tell you all the medications they are taking, including any herbal supplements or vitamins. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended.1

Instruct patients on alternative methods of birth control because hormonal contraceptives should not be relied upon as an effective method of contraception and there is an increased incidence of menstruation-related adverse reactions when co-administered with lumacaftor and ivacaftor.1

When initiating lumacaftor and ivacaftor in patients taking strong CYP3A inhibitors (e.g., itraconazole), instruct the patient to reduce the dose of lumacaftor and ivacaftor to 1 tablet daily for the first week of treatment. Following this period, continue with the recommended daily dose.1

Patients should be instructed to tell their doctor if they stop lumacaftor and ivacaftor for more than 1 week while they are also taking a strong CYP3A inhibitor because the dose of lumacaftor and ivacaftor would need to be reduced upon re-initiation. The dose of lumacaftor and ivacaftor should be reduced to 1 tablet daily for the first week upon treatment re-initiation. Following this period, continue with the recommended daily dose.1

Use in Patients with Hepatic Impairment

Inform patients with moderate hepatic impairment (Child-Pugh Class B) to reduce the dose of lumacaftor and ivacaftor to 2 tablets in the morning and 1 tablet in the evening.1

If initiating lumacaftor and ivacaftor in a patient with severe hepatic impairment, after weighing the risks and benefits of treatment, instruct the patient to take a maximum dose of 1 tablet (lumacaftor 200 mg/ivacaftor 125 mg) every 12 hours, or less.1

Administration

Inform patients that lumacaftor and ivacaftor is best absorbed by the body when taken with fat-containing food. A typical CF diet will satisfy this requirement. Examples of fat-containing foods include eggs, avocados, nuts, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc.1

Inform patients that if a dose is missed and they remember the missed dose within 6 hours, the patients should take the dose with fat-containing food. If more than 6 hours elapsed after the usual dosing time, the patients should skip that dose and resume the normal schedule for the following dose. Patients should be informed not to take a double dose make up for the forgotten dose.1

Cataracts

Inform patients that abnormalities of the eye lens (cataract) have been noted in some children and adolescents receiving ivacaftor, a component of lumacaftor and ivacaftor. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating lumacaftor and ivacaftor treatment.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Lumacaftor and Ivacaftor

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, Film Coated

200 mg lumacaftor, 125 mg ivacaftor

Orkambi

Vertex Pharmaceuticals Incorporated

AHFS Drug Information. © Copyright 2016, Selected Revisions September 8, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Vertex Pharmaceuticals Incorporated. ORKAMBI (lumacaftor and ivacaftor) ORAL prescribing information. 2016 May.

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