Cystic Fibrosis (CF)

Disease-modifying therapies target the cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation directly and represent a major breakthrough in the treatment of cystic fibrosis (CF). These novel drugs improve cellular trafficking of the CFTR protein and/or potentiate mutated CFTR channels, facilitating chloride transport across cell membranes. The therapies listed below should be used with caution when administered concomitantly with moderate or strong inhibitors of CYP3A. 

Kalydeco (Ivacaftor)

Kalydeco^®, a CFTR potentiator, is a unique oral medication. Rather than treat symptoms, it targets a specific genetic defect associated with CF. Kalydeco, the first therapy of its kind, is designed to increase the flow of ions by opening defective CFTR channels.¹ The US Food and Drug Administration (FDA) initially approved Kalydeco in 2012, and revisions to its indications, use, and dosage were made in 2020. Currently, Kalydeco is approved for the treatment of CF in patients 4 months of age or older who have at least one mutation that is responsive to ivacaftor. Close to 100 mutations respond to ivacaftor therapy, which are listed in section 12 of the FDA package insert. If a patient’s genotype is unknown, it is recommended that the mutation be identified before treatment with Kalydeco is initiated.² 

Kalydeco is available as 150-mg tablets or as unit dose packets containing 25, 50, or 75 mg of oral granules.² 

Table 1. Dosage and Administration of Kalydeco (Ivacaftor) by Patient Population² 

Patient Population	Dosage and Administration
≥6 y	One 150-mg tablet orally every 12 hours with fat-containing food
4 to <6 mo, weight ≥5 kg	One 25-mg packet with 5 mL of soft food or liquid every 12 hours with fat-containing food
6 mo to <6 y, weight 5 to <7 kg	One 25-mg packet with 5 mL of soft food or liquid every 12 hours with fat-containing food
6 mo to <6 y, weight 7 to <14 kg	One 50-mg packet with 5 mL of soft food or liquid every 12 hours with fat-containing food
6 mo to <6 y, weight ≥14 kg	One 75-mg packet with 5 mL of soft food or liquid every 12 hours with fat-containing food

The dose should be reduced in patients who are at least 6 months old and have moderate or severe hepatic impairment.² 

The most common adverse reactions are headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, and dizziness. The transaminase levels should be assessed before Kalydeco is started; they should be reassessed every 3 months for the first year, then once yearly. Kalydeco should be stopped if the transaminase levels are increased to more than 5 times the upper limit of normal (ULN).²

Orkambi (Lumacaftor/Ivacaftor) 

Orkambi^® is a combination of ivacaftor (a CFTR potentiator) and lumacaftor, a CFTR corrector. Lumacaftor improves the conformational stability of CFTR channels with the specific F508del mutation, thereby increasing processing and trafficking of the mature protein to the cell surface. Once incorporated, ivacaftor potentiates the CFTR protein, facilitating chloride transport across cell membranes.³  

Orkambi is indicated for the treatment of CF in patients aged 2 years and older who are homozygous for the F508del mutation. If a patient’s genotype is unknown, it is recommended that the mutation be identified before treatment with Orkambi is initiated. Orkambi is available as tablets or unit dose packets. The tablets contain 100 mg of lumacaftor and 125 mg of ivacaftor, or 200 mg of lumacaftor and 125 mg of ivacaftor. Unit dose packets contain 100 mg of lumacaftor and 125 mg of ivacaftor, or 150 mg of lumacaftor and 188 mg of ivacaftor.³ 

Table 2. Dosage and Administration of Orkambi (Lumacaftor/Ivacaftor) by Patient Population³

Patient Population	Dosage and Administration
2-5 y, weight <14 kg	One 100/125-mg packet every 12 hours with fat-containing food
2-5 y, weight ≥14 kg	One 150/188-mg packet every 12 hours with fat-containing food.
6-11 y	Two 100/125-mg tablets every 12 hours with fat-containing food
≥12 y	Two 200/125-mg tablets every 12 hours with fat-containing food

Common side effects of Orkambi include dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, abnormal respiration, increased blood creatine phosphokinase, rash, flatulence, rhinorrhea, and influenza. The transaminase levels should be assessed before Orkambi is started; they should be reassessed every 3 months for the first year, then yearly. Interruption of therapy should be considered if the transaminase levels are elevated to more than 5 times the ULN, or if the level of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is increased to more than 3 times the ULN and the level of bilirubin is increased to more than 2 times the ULN.³ 

Symdeco (Tezacaftor/Ivacaftor)  

Symdeko^® is a combination of ivacaftor and tezacaftor that gained FDA approval in 2018. Tezacaftor, like lumacaftor, increases trafficking of the CFTR protein to the cellular surface. An additional benefit is its effectiveness across 27 CFTR gene mutations (including F508del). Symdeko is indicated for the treatment of CF in patients 12 years of age or older who are homozygous for the F508del mutation or who have at least one mutation that is responsive to tezacaftor/ivacaftor. A list of mutations that respond to this treatment can be found in section 12 of the FDA package insert. If a patient’s genotype is unknown, it is recommended that the mutation be identified before treatment with Symdeco is initiated. Symdeko is co-packaged as a fixed-dose combination tablet (tezacaftor 100 mg/ivacaftor 150 mg) and a 150-mg tablet of ivacaftor. The fixed-dose combination tablet is taken in the morning, and the ivacaftor tablet is taken in the evening approximately 12 hours later. Both tablets should be taken with fat-containing food. Common side effects include headache, nausea, sinus congestion, and dizziness. Symdekoand Orkambi carry identical warnings regarding rising transaminase and/or bilirubin levels (see above).⁴ 

Trikafta (Elexacaftor/Tezacaftor/Ivacaftor) 

Trikafta^® is a combination of tezacaftor, ivacaftor, and elexacaftor. Elexacaftor, like tezacaftor, binds to various sites on the CFTR protein, facilitating the transport of mutant forms (including those with the F508del mutation) to the cell membrane. Triple therapy with these drugs increases the quantity and function of the CFTR protein. Trikafta is indicated for use in patients with CF who are 6 years of age or older and have at least one F508del mutation in the CFTR gene or at least one mutation in the CFTR gene that is responsive to Trikafta according to in vitro data. More than 150 mutations of the CFTR gene are responsive to Trikafta, which are found in section 12 of the FDA package insert. If a patient’s genotype is unknown, it is recommended that the mutation be identified before treatment with Trikafta is initiated. Trikafta is available as a fixed-dose combination tablet containing 50 mg of elexacaftor, 25 mg of tezacaftor, and 37.5 mg of ivacaftor, which is co-packaged with a 75-mg tablet of ivacaftor, or as a fixed-dose combination tablet containing 100 mg of elexacaftor, 50 mg of tezacaftor, and 75 mg of ivacaftor, which is co-packaged with a 150-mg tablet of ivacaftor.⁵ 

Table 3. Dosage and Administration of Trikafta (Elexacaftor/Tezacaftor/Ivacaftor) by Patient Population.⁵ 

Patient Population	Dosage and Administration*
6 to <12 y, weight <30 kg	Two 50/25/37.5-mg tablets in the morning, followed by one 75-mg ivacaftor tablet 12 hours later
6 to <12 y, weight >30 kg	Two 100/50/75-mg tablets in the morning, followed by one 150-mg ivacaftor tablet 12 hours later
>12 y	Two 100/50/75-mg tablets in the morning, followed by one 150-mg ivacaftor tablet 12 hours later

*All doses should be taken with fat-containing food.

Common side effects include headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, increased ALT, nasal congestion, increased blood creatine phosphokinase, increased AST, rhinorrhea, rhinitis, influenza, sinusitis, and hyperbilirubinemia.

Trikafta, Symdeco, and Orkambi carry identical warnings regarding rising transaminase and/or bilirubin levels (see Orkambi above).⁵ 

References

1. Condren ME, Bradshaw MD. Ivacaftor: a novel gene-based therapeutic approach for cystic fibrosis. J Pediatr Pharmacol Ther. 2013;18(1):8-13. doi:10.5863/1551-6776-18.1.8

2. KALYDECO® (ivacaftor). Prescribing Information. Vertex Pharmaceuticals. Revised December 2020. Accessed January 20, 2022.

3. ORKAMBI® (lumacaftor/ivacaftor). Prescribing Information. Vertex Pharmaceuticals. Revised August 2018. Accessed January 20, 2022.

4. SYMDEKO™ (tezacaftor/ivacaftor) tablets. Prescribing information. Vertex Pharmaceuticals. Revised February 2018. Accessed January 20, 2022. 

5. TRIKAFTA® (elexacaftor, tezacaftor, and ivacaftor tablets; ivacaftor tablets). Prescribing Information. Vertex Pharmaceutials. Revised June 2021.

Reviewed by Hasan Avcu, MD, on 1/22/2022.

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Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.