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IVACAFTOR AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ivacaftor potentiates the cystic fibrosis transmembrane conductance protein (CFTR), specifically G551D-CFTR, resulting in increased chloride transport on the surface of epithelial cells in multiple organs. Lumacaftor/ivacaftor is a combination drug that improves the functionality and stability of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel proteins with F508del mutations.

Specific Substances

    A) IVACAFTOR
    1) VX-770
    2) N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
    3) CAS 873054-44-5
    LUMACAFTOR
    1) VX-809
    2) CAS 936727-05-8

    1.2.1) MOLECULAR FORMULA
    1) IVACAFTOR: C24H28N2O3
    2) LUMACAFTOR: C24H18F2N2O5

Available Forms Sources

    A) FORMS
    1) Ivacaftor is available as 150 mg tablets and 50 mg and 75 mg oral granules (unit-dose packets) (Prod Info KALYDECO(R) oral tablets oral granules, 2015).
    2) The combination product, lumacaftor 200 mg and ivacaftor 125 mg, is also available as tablets (Prod Info ORKAMBI(TM) oral tablets, 2015).
    B) USES
    1) Ivacaftor is indicated for the treatment of cystic fibrosis (CF) in patients 2 years of age and older who have a G551D mutation in the CF transmembrane conductance regulator (CFTR) gene (Prod Info KALYDECO(R) oral tablets oral granules, 2015).
    2) Lumacaftor and ivacaftor combination is 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 (Prod Info ORKAMBI(TM) oral tablets, 2015).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Ivacaftor is indicated for the treatment of cystic fibrosis (CF) in patients 2 years of age and older who have a G551D mutation in the CF transmembrane conductance regulator (CFTR) gene. Lumacaftor and ivacaftor combination is 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.
    B) PHARMACOLOGY: Ivacaftor potentiates the cystic fibrosis transmembrane conductance protein (CFTR), specifically G551D-CFTR, resulting in increased chloride transport on the surface of epithelial cells in multiple organs. Lumacaftor/ivacaftor is a combination drug that improves the functionality and stability of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel proteins with F508del mutations.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (8% or greater): Headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, and dizziness. OTHER EFFECTS: Acne, elevated liver enzymes, myalgia, arthralgia, rhinitis, pharyngeal erythema, pleuritic pain, sinus congestion, and wheezing. LUMACAFTOR/IVACAFTOR: MOST COMMON: Dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, increased creatine phosphokinase, rash, flatulence, and rhinorrhea.
    E) WITH POISONING/EXPOSURE
    1) In a study evaluating the effect of ivacaftor on ECGs of healthy subjects, more patients developed dizziness and diarrhea after receiving repeated doses of ivacaftor (450 mg tablets every 12 hours for 4.5 days (9 doses)) compared with placebo.
    0.2.20) REPRODUCTIVE
    A) Ivacaftor is classified as FDA pregnancy category B. There are no adequate and well-controlled studies of ivacaftor or ivacaftor/lumacaftor combination use in pregnant women. In animal studies, ivacaftor was not teratogenic. Ivacaftor is excreted in the milk of lactating rats and excretion in human breast milk is probable. Lumacaftor is excreted in the milk of lactating animals.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of ivacaftor or lumacaftor.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea. Monitor hepatic enzymes in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with vomiting and/or diarrhea.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENTS
    1) Airway management is very unlikely to be necessary. Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory symptoms.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, should be referred to a healthcare facility to be monitored for several hours to assess electrolyte and fluid balance and gastrointestinal function. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, hepatotoxicity, dehydration, and electrolyte abnormalities.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) IVACAFTOR: Tmax: Oral, single-dose, 150 mg: 4 hours. A 2- to 4-fold increase in exposure occurred when ivacaftor was administered with food containing fat. Protein binding: 99% (primarily alpha 1-acid glycoprotein and albumin). Vd: 353 L. Metabolism: Primarily metabolized by CYP3A to 2 major metabolites, M1 (active) and M6 (inactive). Urinary excretion of ivacaftor as unchanged parent was negligible. After metabolism, 87.8% of ivacaftor is eliminated in the feces. Elimination half-life: 12 hours. LUMACAFTOR: Tmax: Oral, 4 hours. Protein binding: 99%, primarily to albumin. Vd: 86 L. Metabolism: Extensively metabolized, via oxidation and glucuronidation. Excretion: renal: Recovery of lumacaftor and its metabolites in the urine was 8.6% of the administered dose, with 0.18% recovered as. Fecal: 51% excreted in the feces as unchanged drug. Elimination half-life: 26 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause elevated liver enzymes.

Range Of Toxicity

    A) TOXICITY: In a clinical study, the highest single dose of ivacaftor 800 mg solution did not cause any adverse events. In a study evaluating the effect of ivacaftor on ECGs of healthy subjects, more patients developed dizziness and diarrhea after receiving repeated doses of ivacaftor (450 mg tablets every 12 hours for 4.5 days (9 doses)) compared with placebo. THERAPEUTIC DOSES: ADULT: IVACAFTOR: 150 mg orally every 12 hours. LUMACAFTOR/IVACAFTOR: Lumacaftor 400 mg/ivacaftor 250 mg (2 tablets) orally every 12 hours with fat-containing food. PEDIATRIC: IVACAFTOR: The safety and efficacy of ivacaftor in children less than 2 years of age have not been established. 6 YEARS AND OLDER: 150 mg orally every 12 hours. 2 TO LESS THAN 6 YEARS: LESS THAN 14 KG: 50 mg oral granules every 12 hours; MAX: 100 mg/day. 14 KG OR GREATER: 75 mg oral granules every 12 hours; MAX: 150 mg/day. LUMACAFTOR/IVACAFTOR: UNDER 12 YEARS: The safety and efficacy of ivacaftor/lumacaftor in children less than 12 years have not been established. 12 YEARS OF AGE AND OLDER: Lumacaftor 400 mg/ivacaftor 250 mg (2 tablets) orally every 12 hours with fat-containing food.
    B) 2 TO LESS THAN 6 YEARS
    1) LESS THAN 14 KG: 50 mg oral granules every 12 hours; MAX: 100 mg/day (Prod Info KALYDECO(R) oral tablets oral granules, 2015)
    2) 14 KG OR GREATER: 75 mg oral granules every 12 hours; MAX: 150 mg/day (Prod Info KALYDECO(R) oral tablets oral granules, 2015)
    C) 6 YEARS AND OLDER
    1) 150 mg orally every 12 hours (Prod Info KALYDECO(TM) oral tablets, 2012)

Clinical Effects

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH THERAPEUTIC USE
    a) Rhinitis, pharyngeal erythema, pleuritic pain, sinus congestion, and wheezing occurred in 4% to 7% of patients receiving ivacaftor in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).
    B) NASOPHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) Nasopharyngitis occurred in 15% (n=16/109) of patients receiving ivacaftor, compared with 12% (n=12/104) of patients receiving placebo, in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).
    b) LUMACAFTOR/IVACAFTOR: In 2 double-blind, placebo-controlled, phase 3 clinical trials of patients with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene, 13% of 369 patients (age, 12 years and older) developed nasopharyngitis after receiving at least one dose of lumacaftor/ivacaftor as compared with 11% of 370 of patients after receiving placebo (Prod Info ORKAMBI(TM) oral tablets, 2015).
    C) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) Upper respiratory tract infections occurred in 22% (n=24/109) of patients receiving ivacaftor, compared with 14% (n=14/104) of patients receiving placebo, in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).
    b) LUMACAFTOR/IVACAFTOR: In 2 double-blind, placebo-controlled, phase 3 clinical trials of patients with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene, 10% of 369 patients (age, 12 years and older) developed upper respiratory tract infection after receiving at least one dose of lumacaftor/ivacaftor as compared with 5% of 370 of patients after receiving placebo (Prod Info ORKAMBI(TM) oral tablets, 2015).
    D) NASAL CONGESTION
    1) WITH THERAPEUTIC USE
    a) Nasal congestion occurred in 20% (n=22/109) of patients receiving ivacaftor, compared with 15% (n=16/104) of patients receiving placebo, in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).
    E) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) LUMACAFTOR/IVACAFTOR: In 2 double-blind, placebo-controlled, phase 3 clinical trials of patients with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene, 13% of 369 patients (age, 12 years and older) developed dyspnea after receiving at least one dose of lumacaftor/ivacaftor as compared with 8% of 370 of patients after receiving placebo (Prod Info ORKAMBI(TM) oral tablets, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache occurred in 24% (n=26/109) of patients receiving ivacaftor, compared with 16% (n=17/104) of patients receiving placebo, in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness occurred in 9% (n=10/109) of patients receiving ivacaftor, compared with 1% (n=1/104) of patients receiving placebo, in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) In a study evaluating the effect of ivacaftor on ECGs of healthy subjects, more patients developed dizziness and diarrhea after receiving repeated doses of ivacaftor (450 mg tablets every 12 hours for 4.5 days (9 doses)) compared with placebo (Prod Info KALYDECO(TM) oral tablets, 2012).
    C) FATIGUE
    1) WITH THERAPEUTIC USE
    a) LUMACAFTOR/IVACAFTOR: In 2 double-blind, placebo-controlled, phase 3 clinical trials of patients with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene, 9% of 369 patients (age, 12 years and older) developed fatigue after receiving at least one dose of lumacaftor/ivacaftor as compared with 8% of 370 of patients after receiving placebo (Prod Info ORKAMBI(TM) oral tablets, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain occurred in 16% (n=17/109) of patients receiving ivacaftor, compared with 13% (n=13/104) of patients receiving placebo, in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea occurred in 12% (n=13/109) of patients receiving ivacaftor, compared with 11% (n=11/104) of patients receiving placebo, in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).
    b) LUMACAFTOR/IVACAFTOR: In 2 double-blind, placebo-controlled, phase 3 clinical trials of patients with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene, 13% of 369 patients (age, 12 years and older) developed nausea after receiving at least one dose of lumacaftor/ivacaftor as compared with 8% of 370 of patients after receiving placebo (Prod Info ORKAMBI(TM) oral tablets, 2015).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea occurred in 13% (n=14/109) of patients receiving ivacaftor, compared with 10% (n=10/104) of patients receiving placebo, in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).
    b) LUMACAFTOR/IVACAFTOR: In 2 double-blind, placebo-controlled, phase 3 clinical trials of patients with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene, 12% of 369 patients (age, 12 years and older) developed diarrhea after receiving at least one dose of lumacaftor/ivacaftor as compared with 8% of 370 of patients after receiving placebo (Prod Info ORKAMBI(TM) oral tablets, 2015).
    2) WITH POISONING/EXPOSURE
    a) In a study evaluating the effect of ivacaftor on ECGs of healthy subjects, more patients developed dizziness and diarrhea after receiving repeated doses of ivacaftor (450 mg tablets every 12 hours for 4.5 days (9 doses)) compared with placebo (Prod Info KALYDECO(TM) oral tablets, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) Hepatic enzyme elevations occurred in 4% to 7% of patients receiving ivacaftor in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).
    b) Transaminase elevations greater than 3, greater than 5, and greater than 8 times the ULN occurred in 6%, 3%, and 2% of patients receiving ivacaftor in 48-week placebo-controlled trials, respectively (Prod Info KALYDECO(TM) oral tablets, 2012).
    c) LUMACAFTOR/IVACAFTOR: Serious adverse effects have occurred in patients with cystic fibrosis in association with elevated transaminase levels. The events sometimes occurred along with elevations in total serum bilirubin (Prod Info ORKAMBI(TM) oral tablets, 2015).
    B) HEPATIC ENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) LUMACAFTOR/IVACAFTOR: Hepatic encephalopathy and other worsening of liver function has been reported in patients with advanced liver disease while receiving lumacaftor/ivacaftor (Prod Info ORKAMBI(TM) oral tablets, 2015).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ACNE
    1) WITH THERAPEUTIC USE
    a) Acne occurred in 4% to 7% of patients receiving ivacaftor in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash occurred in 13% (n=14/109) of patients receiving ivacaftor, compared with 7% (n=7/104) of patients receiving placebo, in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).
    b) LUMACAFTOR/IVACAFTOR: In 2 double-blind, placebo-controlled, phase 3 clinical trials of patients with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene, 7% of 369 patients (age, 12 years and older) developed rash after receiving at least one dose of lumacaftor/ivacaftor as compared with 2% of 370 of patients after receiving placebo (Prod Info ORKAMBI(TM) oral tablets, 2015).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia occurred in 4% to 7% of patients receiving ivacaftor in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia occurred in 4% to 7% of patients receiving ivacaftor in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).
    C) MUSCULOSKELETAL CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) Musculoskeletal chest pain occurred in 4% to 7% of patients receiving ivacaftor in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).
    D) INCREASED CREATINE KINASE LEVEL
    1) WITH THERAPEUTIC USE
    a) LUMACAFTOR/IVACAFTOR: In 2 double-blind, placebo-controlled, phase 3 clinical trials of patients with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene, 7% of 369 patients (age, 12 years and older) developed increased creatine phosphokinase levels after receiving at least one dose of lumacaftor/ivacaftor as compared with 5% of 370 of patients after receiving placebo (Prod Info ORKAMBI(TM) oral tablets, 2015).

Summary Of Exposure

    A) USES: Ivacaftor is indicated for the treatment of cystic fibrosis (CF) in patients 2 years of age and older who have a G551D mutation in the CF transmembrane conductance regulator (CFTR) gene. Lumacaftor and ivacaftor combination is 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.
    B) PHARMACOLOGY: Ivacaftor potentiates the cystic fibrosis transmembrane conductance protein (CFTR), specifically G551D-CFTR, resulting in increased chloride transport on the surface of epithelial cells in multiple organs. Lumacaftor/ivacaftor is a combination drug that improves the functionality and stability of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel proteins with F508del mutations.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (8% or greater): Headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, and dizziness. OTHER EFFECTS: Acne, elevated liver enzymes, myalgia, arthralgia, rhinitis, pharyngeal erythema, pleuritic pain, sinus congestion, and wheezing. LUMACAFTOR/IVACAFTOR: MOST COMMON: Dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, increased creatine phosphokinase, rash, flatulence, and rhinorrhea.
    E) WITH POISONING/EXPOSURE
    1) In a study evaluating the effect of ivacaftor on ECGs of healthy subjects, more patients developed dizziness and diarrhea after receiving repeated doses of ivacaftor (450 mg tablets every 12 hours for 4.5 days (9 doses)) compared with placebo.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Bilateral cataract has been reported in patients receiving ivacaftor (Prod Info ORKAMBI(TM) oral tablets, 2015)
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) LUMACAFTOR/IVACAFTOR: In 2 double-blind, placebo-controlled, phase 3 clinical trials of patients with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene, 6% of 369 patients (age, 12 years and older) developed rhinorrhea after receiving at least one dose of lumacaftor/ivacaftor as compared with 4% of 370 of patients after receiving placebo (Prod Info ORKAMBI(TM) oral tablets, 2015).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) Oropharyngeal pain occurred in 22% (n=24/109) of patients receiving ivacaftor, compared with 18% (n=19/104) of patients receiving placebo, in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HIGH GLUCOSE LEVEL IN BLOOD
    1) WITH THERAPEUTIC USE
    a) Increased blood glucose levels occurred in 4% to 7% of patients receiving ivacaftor in 2 double-blind, placebo-controlled, 48-week trials of 213 patients 6 to 53 years of age with cystic fibrosis and a G551D mutation in the CFTR gene (Prod Info KALYDECO(TM) oral tablets, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Ivacaftor is classified as FDA pregnancy category B. There are no adequate and well-controlled studies of ivacaftor or ivacaftor/lumacaftor combination use in pregnant women. In animal studies, ivacaftor was not teratogenic. Ivacaftor is excreted in the milk of lactating rats and excretion in human breast milk is probable. Lumacaftor is excreted in the milk of lactating animals.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) IVACAFTOR
    a) Placental transfer of ivacaftor was observed in animal studies, but there was no evidence of teratogenicity in animals administered ivacaftor at doses approximately 6 times and 12 times the maximum recommended human dose (Prod Info KALYDECO(R) oral tablets, 2015).
    2) IVACAFTOR/LUMACAFTOR
    a) Placental transfer has been reported during animal studies, however, teratogenic effects were not reported with administration of lumacaftor at doses approximately 5 to 8 times the maximum recommended human dose (MRHD). There were also no reports of teratogenicity with ivacaftor at doses approximately 7 and 45 times the MRHD (Prod Info ORKAMBI(R) oral tablets, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Ivacaftor is classified as FDA pregnancy category B. There are no adequate and well-controlled studies of ivacaftor use in pregnant women. Although no evidence of teratogenicity was found in animal studies, only use ivacaftor in pregnancy if clearly needed (Prod Info KALYDECO(R) oral tablets, 2015).
    2) There are no adequate and well-controlled studies of ivacaftor/lumacaftor use in pregnant women. Although no evidence of teratogenicity was found in animal studies, use caution when administering ivacaftor/lumacaftor to a pregnant woman (Prod Info ORKAMBI(R) oral tablets, 2016).
    B) CONTRACEPTION
    1) Concomitant use of ivacaftor/lumacaftor combination with hormonal contraceptives may reduce the efficacy of hormonal contraceptives (including oral, injectable, transdermal, and implantable). Do not rely on hormonal contraceptives as an effective method of contraception when used concomitantly with ivacaftor/lumacaftor (Prod Info ORKAMBI(R) oral tablets, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) IVACAFTOR
    a) Ivacaftor is excreted in the milk of lactating rats and excretion in human breast milk is probable. Until human studies have been conducted on the effects of ivacaftor in a nursing infant, caution is recommended with ivacaftor use in lactating women (Prod Info KALYDECO(R) oral tablets, 2015).
    2) IVACAFTOR/LUMACAFTOR
    a) Both ivacaftor and lumacaftor are known to be excreted into the milk of lactating rats. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for ivacaftor/lumacaftor and any potential adverse effects on the nursing infant from the drug combination or the mother's underlying condition before administering the combination to a lactating woman (Prod Info ORKAMBI(R) oral tablets, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) IVACAFTOR
    a) Fertility and reproductive performance indices were impaired after male and female animals were administered ivacaftor at doses approximately 5 and 6 times the maximum recommended human dose (MRHD). In females, increases in prolonged diestrus were noted with ivacaftor at doses approximately 15 times the MRHD. Administration of the same dose of ivacaftor before and during early pregnancy increased the number of all nonviable embryos while decreasing the number of corpora lutea, implantations, and viable embryos. No effects on male or female fertility and reproductive indices were seen with doses up to 8 times the MRHD (Prod Info ORKAMBI(TM) oral tablets, 2015; Prod Info KALYDECO(R) oral tablets, 2015).
    2) IVACAFTOR/LUMACAFTOR
    a) During animal studies, no adverse effects on fertility or reproductive performance were reported with lumacaftor at doses up to 8 times the maximum recommended human dose (MRHD). In contrast, both fertility and reproductive performance were impaired with administration of ivacaftor at doses approximately 7 times the MRHD; increases in prolonged diestrus were observed in females at this dose. The number of females with all nonviable embryos also increased and corpora lutea, implantations, and viable embryos decreased when dams were exposed to this dose prior to and during early pregnancy (Prod Info ORKAMBI(R) oral tablets, 2016).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of ivacaftor or lumacaftor.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) IVACAFTOR
    a) In 2-year animal studies, no tumorigenicity was noted in mice or rats following ivacaftor oral doses up to 200 mg/kg and 50 mg/kg, respectively (about equivalent to and 3 to 10 times the MRHD) (Prod Info ORKAMBI(TM) oral tablets, 2015; Prod Info KALYDECO(TM) oral tablets, 2012).
    2) LUMACAFTOR
    a) During a 26-week animal study in transgenic Tg.rasH2 mice, there was no evidence of tumorigenicity at doses up to 2000 mg/kg/day (Prod Info ORKAMBI(TM) oral tablets, 2015).

Genotoxicity

    A) IVACAFTOR
    1) There was no evidence of genotoxicity in the following tests: Ames test for bacterial gene mutation, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus test (Prod Info ORKAMBI(TM) oral tablets, 2015; Prod Info KALYDECO(TM) oral tablets, 2012).
    B) LUMACAFTOR
    1) There was no evidence of genotoxicity in the following tests: Ames test for bacterial gene mutation, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus test (Prod Info ORKAMBI(TM) oral tablets, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea. Monitor hepatic enzymes in symptomatic patients.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, hepatotoxicity, dehydration, and electrolyte abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, should be referred to a healthcare facility to be monitored for several hours to assess electrolyte and fluid balance and gastrointestinal function. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor vital signs and mental status.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea. Monitor hepatic enzymes in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signa and mental status.
    2) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4) Monitor hepatic enzymes in symptomatic patients.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.

Range Of Toxicity

Summary

    A) TOXICITY: In a clinical study, the highest single dose of ivacaftor 800 mg solution did not cause any adverse events. In a study evaluating the effect of ivacaftor on ECGs of healthy subjects, more patients developed dizziness and diarrhea after receiving repeated doses of ivacaftor (450 mg tablets every 12 hours for 4.5 days (9 doses)) compared with placebo. THERAPEUTIC DOSES: ADULT: IVACAFTOR: 150 mg orally every 12 hours. LUMACAFTOR/IVACAFTOR: Lumacaftor 400 mg/ivacaftor 250 mg (2 tablets) orally every 12 hours with fat-containing food. PEDIATRIC: IVACAFTOR: The safety and efficacy of ivacaftor in children less than 2 years of age have not been established. 6 YEARS AND OLDER: 150 mg orally every 12 hours. 2 TO LESS THAN 6 YEARS: LESS THAN 14 KG: 50 mg oral granules every 12 hours; MAX: 100 mg/day. 14 KG OR GREATER: 75 mg oral granules every 12 hours; MAX: 150 mg/day. LUMACAFTOR/IVACAFTOR: UNDER 12 YEARS: The safety and efficacy of ivacaftor/lumacaftor in children less than 12 years have not been established. 12 YEARS OF AGE AND OLDER: Lumacaftor 400 mg/ivacaftor 250 mg (2 tablets) orally every 12 hours with fat-containing food.
    B) 2 TO LESS THAN 6 YEARS
    1) LESS THAN 14 KG: 50 mg oral granules every 12 hours; MAX: 100 mg/day (Prod Info KALYDECO(R) oral tablets oral granules, 2015)
    2) 14 KG OR GREATER: 75 mg oral granules every 12 hours; MAX: 150 mg/day (Prod Info KALYDECO(R) oral tablets oral granules, 2015)
    C) 6 YEARS AND OLDER
    1) 150 mg orally every 12 hours (Prod Info KALYDECO(TM) oral tablets, 2012)

Therapeutic Dose

    7.2.1) ADULT
    A) IVACAFTOR
    1) One 150 mg tablet orally every 12 hours (Prod Info KALYDECO(R) oral tablets oral granules, 2015)
    B) IVACAFTOR/LUMACAFTOR
    1) Lumacaftor 400 mg/ivacaftor 250 mg (2 tablets) orally every 12 hours with fat-containing food (Prod Info ORKAMBI(TM) oral tablets, 2015)
    7.2.2) PEDIATRIC
    A) IVACAFTOR
    1) UNDER 2 YEARS
    a) The safety and efficacy of ivacaftor in children less than 2 years have not been established (Prod Info KALYDECO(R) oral tablets oral granules, 2015).
    2) 2 TO LESS THAN 6 YEARS
    a) LESS THAN 14 KG: 50 mg oral granules every 12 hours; MAX: 100 mg/day (Prod Info KALYDECO(R) oral tablets oral granules, 2015)
    b) 14 KG OR GREATER: 75 mg oral granules every 12 hours; MAX: 150 mg/day (Prod Info KALYDECO(R) oral tablets oral granules, 2015)
    3) 6 YEARS AND OLDER
    a) One 150 mg tablet orally every 12 hours (Prod Info KALYDECO(R) oral tablets oral granules, 2015)
    B) IVACAFTOR/LUMACAFTOR
    1) 12 YEARS OF AGE AND OLDER: Lumacaftor 400 mg/ivacaftor 250 mg (2 tablets) orally every 12 hours with fat-containing food (Prod Info ORKAMBI(TM) oral tablets, 2015)
    2) UNDER 12 YEARS: The safety and efficacy of ivacaftor/lumacaftor in children less than 12 years have not been established (Prod Info KALYDECO(R) oral tablets oral granules, 2015).

Maximum Tolerated Exposure

    A) In a clinical study, the highest single dose of ivacaftor 800 mg solution did not cause any adverse events (Prod Info KALYDECO(TM) oral tablets, 2012).
    B) In a study evaluating the effect of ivacaftor on ECGs of healthy subjects, more patients developed dizziness and diarrhea after receiving repeated doses of ivacaftor (450 mg tablets every 12 hours for 4.5 days (9 doses)) compared with placebo (Prod Info KALYDECO(TM) oral tablets, 2012).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) IVACAFTOR: Ivacaftor potentiates the cystic fibrosis transmembrane conductance protein (CFTR), specifically G551D-CFTR, resulting in increased chloride transport on the surface of epithelial cells in multiple organs (Prod Info KALYDECO(TM) oral tablets, 2012).
    B) LUMACAFTOR/IVACAFTOR: Lumacaftor/ivacaftor is a combination drug that improves the functionality and stability of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel proteins with F508del mutations. Lumacaftor acts by improving the conformation of the protein which allows increased processing and trafficking of mature proteins to the cell surface. Ivacaftor potentiates the opening of the protein channel, which improves chloride transport (Prod Info ORKAMBI(TM) oral tablets, 2015).

Physicochemical

Physical Characteristics

    A) IVACAFTOR is a white to off-white powder that is practically insoluble in water (less than 0.05 mcg/mL) (Prod Info ORKAMBI(TM) oral tablets, 2015; Prod Info KALYDECO(R) oral tablets, 2015).
    B) LUMACAFTOR is a white to off-white powder that is practically insoluble in water (0.02 mg/mL) (Prod Info ORKAMBI(TM) oral tablets, 2015).

Molecular Weight

    A) IVACAFTOR: 392.49 (Prod Info KALYDECO(R) oral tablets, 2015)
    B) LUMACAFTOR: 452.41 (Prod Info ORKAMBI(TM) oral tablets, 2015)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    3) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    4) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    5) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    6) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    7) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    8) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    9) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    10) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    11) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    12) Product Information: KALYDECO(R) oral tablets oral granules, ivacaftor oral tablets oral granules. Vertex Pharmaceuticals Incorporated (per manufacturer), Boston, MA, 2015.
    13) Product Information: KALYDECO(R) oral tablets, ivacaftor oral tablets. Vertex Pharmaceuticals Incorporated (per Manufacturer), Boston, MA, 2015.
    14) Product Information: KALYDECO(TM) oral tablets, ivacaftor oral tablets. Vertex Pharmaceuticals Incorporated (per FDA), Cambridge, MA, 2012.
    15) Product Information: ORKAMBI(R) oral tablets, lumacaftor ivacaftor oral tablets. Vertex Pharmaceuticals Incorporated (per Manufacturer), Boston, MA, 2016.
    16) Product Information: ORKAMBI(TM) oral tablets, lumacaftor, ivacaftor oral tablets. Vertex Pharmaceuticals Inc. (per manufacturer), Boston, MA, 2015.
    17) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    18) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    19) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.