Lumacaftor/Ivacaftor

Mechanism :

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.

Indication :

Treatment of cystic fibrosis (CF) in patients age 2 years and older who are homozygous for the F508del mutation in the CFTR gene.

Contraindications :

Hypersensitivity to lumacaftor, ivacaftor or any component of the formulation.

Dosing :

Oral Children 2 to 5 years:

<14 kg:

Lumacaftor 100 mg/ivacaftor 125 mg every 12 hours.

≥14 kg:

Lumacaftor 150 mg/ivacaftor 188 mg every 12 hours.

Oral Children 6 to 11 years:

Lumacaftor 200 mg/ivacaftor 250 mg every 12 hours.

Oral Children ≥12 years and Adolescents:

Lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.

Adverse Effect :

Chest discomfort, headache, nausea, abdominal pain, diarrhea, increased AST & ALT, dyspnea, changes in respiration, nasal congestion, increased systolic blood pressure, fatigue, skin rash, menstrual disease, increased creatine phosphokinase.

Interaction :

CYP3A4 Inducers: May decrease the serum concentration of Ivacaftor.
CYP3A4 Inhibitors: May increase the serum concentration of Ivacaftor.
CYP3A4 Substrates: CYP3A4 Inducers (Strong) may increase the metabolism of CYP3A4 Substrates.
CYP2C19 Substrates: Lumacaftor may decrease the serum concentration of CYP2C19 Substrates.
CYP2C8 Substrates: Lumacaftor may increase the serum concentration of CYP2C8 Substrates.

Hepatic Dose :

Hepatic impairment prior to initiation:
Children =2 years to 5 years: Oral:
Weighing <14 kg: Lumacaftor 100 mg/ivacaftor 125 mg granule packet
Mild impairment (Child-Pugh Class A): No dosage adjustment necessary.
Moderate impairment (Child-Pugh Class B): Reduce the dose to lumacaftor 100 mg/ivacaftor 125 mg every morning and every alternate evening.
Severe impairment (Child-Pugh Class C): Use with caution, weighing the risks and benefits of treatment. If therapy is appropriate, reduce the dose to lumacaftor 100 mg/ivacaftor 125 mg every morning.
Weighing =14 kg: Lumacaftor 150 mg/ivacaftor 188 mg granule packet
Mild impairment (Child-Pugh Class A): No dosage adjustment necessary.
Moderate impairment (Child-Pugh Class B): Reduce the dose to lumacaftor 150 mg/ivacaftor 188 mg every morning and lumacaftor 150 mg/ivacaftor 188 mg every alternate evening.
Severe impairment (Child-Pugh Class C): Use with caution, weighing the risks and benefits of treatment. If therapy is appropriate, reduce the dose to lumacaftor 150 mg/ivacaftor 188 mg every morning.
Children =6 to 11 years:
Mild impairment (Child-Pugh Class A): No dosage adjustment necessary.
Moderate impairment (Child-Pugh Class B): Reduce the dose to lumacaftor 200 mg/ivacaftor 250 mg in the morning and lumacaftor 100 mg/ivacaftor 125 mg in the evening.
Severe impairment (Child-Pugh Class C): Use with caution, weighing the risks and benefits of treatment. If therapy is appropriate, reduce the dose to lumacaftor 100 mg/ivacaftor 125 mg every 12 hours.
Children =12 years and Adolescents:
Mild impairment (Child-Pugh Class A): No dosage adjustment necessary.
Moderate impairment (Child-Pugh Class B): Reduce the dose to lumacaftor 200 mg/ivacaftor 250 mg in the morning and lumacaftor 100 mg/ivacaftor 125 mg in the evening.
Severe impairment (Child-Pugh Class C): Use with caution, weighing the risks and benefits of treatment. If therapy is appropriate, reduce the dose to lumacaftor 100 mg/ivacaftor 125 mg every 12 hours.

Hepatotoxicity during treatment: Children =2 years and Adolescents:
ALT or AST >5 times ULN without concomitant elevated bilirubin: Temporarily discontinue lumacaftor/ivacaftor; may resume if elevated transaminases resolved and after assessing benefits vs risks of continued treatment/
ALT or AST >3 times ULN with concomitant bilirubin >2 times ULN: Temporarily discontinue lumacaftor/ivacaftor; may resume if elevated transaminases resolved and after assessing benefits vs risks of continued treatment.