Ivacaftor-induced cataracts (cystic fibrosis)

Key points about this condition

• CFTR modulators, including ivacaftor, a treatment for cystic fibrosis (CF), may cause non-congenital cataracts in children.
• Cortical cataracts and posterior subcapsular cataracts have been reported, but neither has been considered to affect visual function.
• The incidence tends to be higher in younger children: 4.17% at 2–6 years, 1.72% at 6–11 years, and 0.57% at 12 years and older.
• The exact mechanism by which cataracts develop is currently unknown.
• A baseline ophthalmic examination and regular follow-up thereafter are recommended when starting a CFTR modulator.

1. What are ivacaftor-induced cataracts?

Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It is characterized by recurrent lung infections and pancreatic insufficiency, and more than 200 disease-causing mutations in the CFTR protein are known.

Ivacaftor is one of the first commercially available treatments to directly target CFTR function. It was initially developed to treat CF caused by gating mutations, such as the G551D mutation, which affect the opening and closing of the channel[3]. Trikafta (tezacaftor/ivacaftor/elexacaftor) was subsequently introduced and has been shown to restore CFTR function in patients with at least one F508del mutation, which is found in 90% of patients with CF[4].

One notable adverse effect of ivacaftor is its reported potential to cause noncongenital cataracts in children[1,2]. As the use of Trikafta expands, the number of patients with CF taking ivacaftor-containing products is expected to increase substantially, making this a condition that ophthalmologists should recognize[6].

A similar risk has not been clearly demonstrated in adults.

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

A

The reported risk of cataracts is in patients taking CFTR modulators that contain ivacaftor. Patients with CF who are not taking a CFTR modulator do not have this risk of drug-induced cataracts.

2. Main symptoms and clinical findings

Symptoms

Ivacaftor-related cataracts were not considered visually significant in clinical trials. Therefore, patients are thought to rarely report symptoms themselves.

Clinical findings

The types of cataracts reported are as follows.

• Cortical cataracts: Reported after ivacaftor monotherapy in patients aged 2–6 years[1].
• Posterior subcapsular cataracts: Reported after combination therapy with lumacaftor and ivacaftor in patients aged 12 years and older[2].
• Unclassified cataracts: Cataracts were identified after combination treatment with lumacaftor and ivacaftor in patients aged 6–11 years, but the exact type was not specified[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 age-specific incidence reported in a study conducted by Vertex Pharmaceuticals is shown below.

Age group	Incidence	Time since 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

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

Known risk factors for drug-induced cataracts in general include long-term use of inhaled or oral steroids⁸⁾. It is necessary to distinguish the effects of the drug itself from those of the treated disease and comorbidities.

The mechanism of ivacaftor-induced cataracts is thought to differ from that of steroid-induced cataracts, but the details remain unclear.

Q Does the risk of cataracts vary with age?

A

The reported incidence was 4.17% at 2–6 years, 1.72% at 6–11 years, and 0.57% at 12 years and older, showing a tendency to be higher in younger children. However, the number of cases in each study was limited, and differences in risk between age groups have not been fully clarified.

Prevention and daily care

When starting a CFTR modulator (a product containing ivacaftor), be sure to undergo a baseline eye examination before beginning treatment. Continue regular ophthalmic follow-up thereafter as directed by your treating physician.

4. Diagnosis and examination methods

Vertex Pharmaceuticals recommends the following eye examinations when patients with CF begin ivacaftor treatment.

• Baseline examination: An eye examination performed before starting a product containing ivacaftor. The condition of the lens is documented.
• Follow-up examination: Regular eye examinations after treatment begins. The aim is to detect cataracts early.

Regular ophthalmic screening is particularly recommended for children younger than 12 years[1,2]. A recent review suggests that children starting CFTR modulators should have a baseline assessment with slit-lamp examination before treatment and ophthalmic follow-up during the first year of treatment[6].

Lens opacities are evaluated by slit-lamp biomicroscopy after pupil dilation. Nuclear opacities are examined using the slit method, while cortical and posterior subcapsular opacities can also be assessed using the retroillumination method.

Q How often should eye examinations be performed?

A

Although a specific examination interval has not been established, a baseline examination before treatment and regular follow-up afterward are recommended. More careful monitoring is considered desirable, especially for children younger than 12 years.

5. Standard treatment

No established specific treatment for ivacaftor-related cataracts has been reported to date. None of the cataracts reported in clinical trials were considered to affect visual function, so management centers on the following:

• Regular ophthalmic screening: To detect cataract progression early.
• Observation: To assess changes in lens opacity regularly.

If cataracts affecting visual function are found, phacoemulsification and aspiration (PEA) with intraocular lens implantation should be considered, as for other forms of cataract. In children, postoperative treatment such as spectacle or contact lens correction and occlusion therapy may be needed to prevent amblyopia. This does not mean that surgery was required for the minor opacities reported in clinical trials.

Points to consider in treatment

Even when ivacaftor-related cataracts are detected, discontinuation of the CFTR modulator should be discussed thoroughly with a pulmonologist. Because CFTR modulators have a major effect on respiratory function and life expectancy in people with CF, discontinuation should not be decided hastily based solely on ophthalmic findings.

6. Pathophysiology and detailed mechanisms of onset

Molecular mechanisms of CFTR and ivacaftor

The CFTR protein is a chloride channel in exocrine glands that plays an important role in airway mucociliary clearance and pancreatic enzyme secretion. More than 200 disease-causing CFTR variants are known, ranging from variants causing complete absence of the protein to those that form unstable channels[3]. CFTR is expressed in multiple tissues, including the eyes, from the fetal period, and has been reported to be involved in fluid and ion transport in epithelial cells of the lens and ocular surface[6].

Ivacaftor increases CFTR-mediated chloride transport by increasing the opening probability of the CFTR channel [3]. An in vitro study using bronchial epithelial cells from patients with CF showed that ivacaftor improved ion transport through abnormal CFTR, producing the following effects:

• Increased airway surface liquid volume
• Increased ciliary beat frequency

Mechanisms of cataract development

The exact pathophysiology of ivacaftor-associated cataracts remains unknown [1,6]. In a preclinical study in young rats aged 7–35 days after birth, cataracts were reported even at a low dose equivalent to 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 also been reported in infants exposed to elexacaftor/tezacaftor/ivacaftor during pregnancy or breastfeeding, raising concern about effects on the lens during in utero and perinatal exposure [5,6].

The following mechanisms have been proposed as hypotheses, but none has been proven.

• Changes in ion transport: CFTR may also be expressed in lens epithelial cells. Changes in chloride ion transport may affect the ionic environment within the lens.
• Interaction with eye development: The timeline of eye development differs between rats and humans. Changes in CFTR function during the development of an immature eye may affect lens formation.
• Direct effects on lens epithelial cells: Normal ion transport by epithelial cells is essential for maintaining lens transparency, and this function may be impaired.

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7. Latest research and future prospects (reports at the research stage)

For patients: Please read carefully

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

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

As Trikafta has become widely prescribed for patients with the F508del mutation (present in 90% of patients with CF), the number of patients taking ivacaftor-containing products is expected to increase substantially in the future [4]. Accordingly, 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 also continuing [7].

Rapamycin and statins are also being studied for complementary effects on cystic fibrosis-related symptoms, but their effects on ophthalmic complications are unknown.

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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
8. Miller KM, Oetting TA, Tweeten JP, Carter K, Lee BS, Lin S, et al. Cataract in the Adult Eye Preferred Practice Pattern. Ophthalmology. 2022;129(1):P1-P126. doi:10.1016/j.ophtha.2021.10.006. PMID:34780842.