Ivacaftor-induced cataract (cystic fibrosis)

Key Points at a Glance

Key Points of This Disease

• CFTR modulators containing ivacaftor, used to treat cystic fibrosis (CF), can cause non-congenital cataracts in children.
• Cortical and subcapsular cataracts have been reported, but none are considered to affect visual function.
• The incidence is higher in younger children: 4.17% at ages 2–6, 1.72% at ages 6–11, and 0.57% at ages 12 and older.
• The exact mechanism of cataract development is currently unknown.
• Baseline eye examination and regular follow-up are recommended when starting CFTR modulator therapy.

1. What is ivacaftor-induced cataract?

Cystic fibrosis (CF) is an autosomal recessive disorder caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It is characterized by recurrent lung infections and pancreatic insufficiency, with over 200 known pathogenic mutations in the CFTR protein.

Ivacaftor is one of the first marketed drugs that directly targets CFTR function. It was originally developed to treat CF caused by gating mutations (mutations affecting channel opening and closing) such as G551D [3]. Subsequently, Trikafta (tezacaftor/ivacaftor/elexacaftor) emerged and has been shown to restore CFTR function in patients with at least one F508del mutation, which is present in 90% of CF patients [4].

One notable side effect of ivacaftor is the potential to cause noncongenital cataracts in children [1,2]. With the widespread use of Trikafta, the number of CF patients taking ivacaftor-containing medications is expected to increase significantly, making this a condition that ophthalmologists should be aware of [6].

Q Are all patients with cystic fibrosis at risk for cataracts?

A

The risk of cataracts has been reported in patients taking CFTR modulators that include ivacaftor. In CF patients not taking CFTR modulators, this risk of drug-induced cataracts does not apply.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Ivacaftor-related cataracts were not considered visually significant in clinical trials. Therefore, it is thought that patients rarely report subjective symptoms.

Clinical Findings

The types of cataracts reported are as follows.

• Cortical cataracts: Reported in patients aged 2 to 6 years after ivacaftor monotherapy [1].
• Subcapsular cataracts: Reported in patients aged 12 years and older after combination therapy with lumacaftor and ivacaftor [2].
• Unclassified cataracts: Cataracts were confirmed in patients aged 6 to 11 years after combination therapy with lumacaftor and ivacaftor, but the exact type was not identified [2].

Ivacaftor-related cataracts have also been reported in preclinical studies using rats [1,5].

3. Causes and Risk Factors

Ivacaftor-related cataracts have been reported with both ivacaftor monotherapy and combination therapy with other CFTR modulators such as lumacaftor.

The incidence by age group in studies conducted by Vertex Pharmaceuticals is shown below.

Age group	Incidence	Time from treatment initiation
2–6 years	4.17% (1/24 cases)	Within 84 weeks
6–11 years	1.72% (1/58 cases)	Within 24 weeks
12 years and older	0.57% (1/176 cases)	Within 96 weeks

The incidence tends to be higher in younger children [1,2]. However, the difference in risk levels between younger and older patients has not been fully defined. The possibility of additional comorbidities and their impact on the development of ivacaftor-related cataracts cannot be completely excluded. A pharmacovigilance analysis of pediatric cataracts using the FDA Adverse Event Reporting System (FAERS) also showed high disproportionality signals for ivacaftor (reporting odds ratio: 30.75) and elexacaftor/tezacaftor/ivacaftor combination (ROR: 15.58), supporting the warning for CFTR modulators as a class [7].

Q Does the risk of cataracts differ by age?

A

Reported incidence rates are 4.17% in ages 2–6, 1.72% in ages 6–11, and 0.57% in ages 12 and older, showing a higher tendency in younger children. However, the number of cases in each study is limited, and the risk difference by age group has not been fully elucidated.

Prevention and Daily Care

When starting a CFTR modulator (ivacaftor-containing preparation), be sure to undergo a baseline eye examination before starting treatment. Thereafter, continue regular ophthalmologic follow-up as directed by your primary care physician.

4. Diagnosis and Examination Methods

Vertex Pharmaceuticals recommends the following eye examinations for CF patients starting ivacaftor treatment:

• Baseline examination: An eye examination performed before starting treatment with an ivacaftor-containing preparation. Records the condition of the lens.
• Follow-up examination: Regular eye examinations after starting treatment. Aimed at early detection of cataracts.

For children under 12 years of age in particular, regular ophthalmologic screening is recommended [1,2]. A recent review suggests that for children initiating CFTR modulator therapy, baseline evaluation with slit-lamp examination before treatment and ophthalmologic follow-up during the first year of treatment are desirable [6].

Q How often should eye examinations be performed?

A

Specific examination intervals have not been established, but baseline examination before starting treatment and regular follow-up thereafter are recommended. Closer monitoring is especially desirable for children under 12 years of age.

5. Standard Treatment

No established specific treatment for ivacaftor-related cataracts has been reported to date. The cataracts reported in clinical trials have not been considered to affect visual function, and the mainstay of treatment is as follows.

• Regular ophthalmologic screening: To detect progression of cataracts early.
• Observation: Regularly evaluate changes in lens opacification.

Precautions in Treatment

If ivacaftor-related cataract is detected, discontinuation of CFTR modulators should be thoroughly discussed with a pulmonologist. Since CFTR modulators significantly impact respiratory function and life prognosis in CF patients, discontinuation should not be decided lightly based solely on ophthalmological findings.

6. Pathophysiology and Detailed Mechanism of Onset

Molecular Mechanism of CFTR and Ivacaftor

The CFTR protein is a chloride channel in exocrine glands that plays a crucial role in airway mucociliary clearance and pancreatic enzyme secretion. Over 200 pathogenic mutations in CFTR are known, ranging from complete loss of protein to formation of unstable channels [3]. CFTR is expressed in multiple tissues including the eye from the embryonic stage, and has been reported to be involved in fluid and ion transport in lens and ocular surface epithelial cells [6].

Ivacaftor increases chloride transport through CFTR by enhancing the opening probability of the CFTR channel [3]. In vitro studies using bronchial epithelial cells from CF patients have shown that ivacaftor improves ion transport through abnormal CFTR, leading to the following effects.

• Increased airway surface liquid volume
• Increased ciliary beat frequency

Mechanism of Cataract Development

The exact pathophysiology of ivacaftor-associated cataracts remains unknown [1,6]. Preclinical studies in juvenile rats aged 7–35 days reported cataract development even at doses as low as 0.1 times the maximum recommended human dose [2]. However, there are known differences in eye development between rats and humans, limiting the direct extrapolation of animal study results to humans [5,6]. Cases of congenital cataracts have been reported in infants exposed to elexacaftor/tezacaftor/ivacaftor during pregnancy or breastfeeding, highlighting the potential effects on the lens during intrauterine and perinatal exposure [5,6].

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7. Latest Research and Future Prospects (Research Stage Reports)

For Patients: Please Read Carefully

The following content is currently at the research stage or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Additional studies are currently underway to evaluate the risk of cataract formation in pediatric patients taking ivacaftor [5,6].

With the widespread prescription of tezacaftor/ivacaftor for patients with the F508del mutation (present in 90% of CF patients), the number of patients taking ivacaftor-containing formulations is expected to increase significantly in the future [4]. Consequently, accumulating data on the incidence and long-term effects of ivacaftor-associated cataracts has become an important issue, and signal detection using real-world pharmacovigilance data such as FAERS is ongoing [7].

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8. References

1. McColley SA. A safety evaluation of ivacaftor for the treatment of cystic fibrosis. Expert Opin Drug Saf. 2016;15(5):709-715. doi:10.1517/14740338.2016.1165666. PMID: 26968005
2. Talamo Guevara M, McColley SA. The safety of lumacaftor and ivacaftor for the treatment of cystic fibrosis. Expert Opin Drug Saf. 2017;16(11):1305-1311. doi:10.1080/14740338.2017.1372419. PMID: 28846049
3. Kramer EL, Clancy JP. CFTR Modulator Therapies in Pediatric Cystic Fibrosis: Focus on Ivacaftor. Expert Opin Orphan Drugs. 2016;4(10):1033-1042. doi:10.1080/21678707.2016.1226800. PMID: 28042521; PMCID: PMC5193376
4. Ridley K, Condren M. Elexacaftor-Tezacaftor-Ivacaftor: The First Triple-Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulating Therapy. J Pediatr Pharmacol Ther. 2020;25(3):192-197. doi:10.5863/1551-6776-25.3.192. PMID: 32265602
5. Zhu Y, Li D, Reyes-Ortega F, Chinnery HR, Schneider-Futschik EK. Ocular development after highly effective modulator treatment early in life. Front Pharmacol. 2023;14:1265138. doi:10.3389/fphar.2023.1265138. PMID: 37795027; PMCID: PMC10547496
6. Schneider-Futschik EK, Zhu Y, Li D, et al. The role of CFTR in the eye, and the effect of early highly effective modulator treatment for cystic fibrosis on eye health. Prog Retin Eye Res. 2024;103:101299. doi:10.1016/j.preteyeres.2024.101299. PMID: 39245300
7. Ali A, Dockery PW, Downes DG, VanderVeen DK, Elhusseiny AM. Primary suspect drugs of cataracts in pediatric patients: FDA adverse events reporting database analysis. J Cataract Refract Surg. 2025;51(12):1044-1050. doi:10.1097/j.jcrs.0000000000001738. PMID: 40643173