Zydelig: Uses, Dosage & Side Effects
A selective PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia (CLL) and relapsed follicular lymphoma (FL) in adults
Zydelig (idelalisib) is a targeted anticancer medication that belongs to the class of phosphatidylinositol 3-kinase (PI3K) inhibitors. It works by selectively blocking the PI3K delta isoform, an enzyme that is overactivated in many B-cell malignancies. Zydelig is approved for the treatment of chronic lymphocytic leukemia (CLL) in combination with rituximab, and as monotherapy for relapsed follicular lymphoma (FL) in adults. It is taken orally as a film-coated tablet and requires a prescription. Regular blood monitoring is essential during treatment due to the risk of serious side effects including infections, liver toxicity, and colitis.
Quick Facts: Zydelig
Key Takeaways
- Zydelig (idelalisib) is a selective PI3K delta inhibitor that targets an overactivated enzyme in cancerous B lymphocytes, reducing cancer cell proliferation and survival in CLL and follicular lymphoma.
- For CLL, Zydelig is used in combination with rituximab in patients with high-risk features (such as 17p deletion or TP53 mutation) or whose disease has relapsed after at least one prior treatment.
- Prophylactic anti-infective treatment against Pneumocystis jirovecii pneumonia is mandatory throughout the entire course of Zydelig therapy, as serious and fatal infections have been reported.
- Regular blood tests every two weeks for the first six months are required to monitor liver function, as Zydelig can cause severe hepatotoxicity with elevated liver enzymes.
- Zydelig is a potent CYP3A4 inhibitor and interacts with many common medications; hormonal contraceptives may be less effective, requiring use of barrier contraception methods instead.
What Is Zydelig and What Is It Used For?
Zydelig contains the active substance idelalisib, a first-in-class selective inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ). PI3Kδ is a lipid kinase enzyme that plays a central role in the signaling pathways governing the proliferation, survival, migration, and homing of B lymphocytes. In many B-cell malignancies, this enzyme is constitutively overactivated, driving the uncontrolled growth and prolonged survival of malignant cells. By selectively blocking PI3Kδ, idelalisib disrupts these critical signaling cascades, leading to apoptosis (programmed cell death) of cancerous B cells and reducing the number of malignant lymphocytes circulating in the blood and accumulating in lymph nodes.
The PI3K pathway is one of the most frequently dysregulated pathways in human cancer. There are four class I PI3K isoforms (alpha, beta, gamma, and delta), each with distinct tissue distribution and functions. PI3Kδ expression is predominantly restricted to cells of the hematopoietic system, particularly B lymphocytes, making it an attractive therapeutic target for B-cell malignancies. By selectively targeting PI3Kδ rather than the other isoforms, idelalisib aims to minimize off-target effects while maximizing efficacy against B-cell cancers. Preclinical studies demonstrated that idelalisib induces apoptosis in cell lines derived from malignant B cells and also inhibits several important signaling pathways downstream of the B-cell receptor (BCR), as well as CXCR4 and CXCR5 chemokine receptor signaling, which are involved in lymphocyte trafficking and tissue retention.
Zydelig is approved by the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), and regulatory authorities in multiple other countries for the following indications:
Chronic Lymphocytic Leukemia (CLL)
Chronic lymphocytic leukemia is a type of cancer affecting a specific population of white blood cells known as B lymphocytes. In CLL, the malignant B lymphocytes multiply excessively and accumulate in the blood, bone marrow, lymph nodes, and spleen. The disease typically progresses slowly but can cause significant morbidity through bone marrow failure, immunodeficiency, and organ dysfunction. CLL is the most common type of leukemia in adults in Western countries, with a median age at diagnosis of approximately 70 years.
Zydelig is used in combination with the anti-CD20 monoclonal antibody rituximab for the treatment of adult patients with CLL who have certain high-risk disease features, such as 17p deletion or TP53 mutation, which are associated with poor response to conventional chemoimmunotherapy. It is also indicated for patients whose CLL has relapsed after (or not responded to) at least one prior line of treatment. The pivotal Study 312-0116 demonstrated that the combination of idelalisib plus rituximab significantly improved progression-free survival compared with placebo plus rituximab in patients with relapsed CLL, leading to regulatory approval.
Follicular Lymphoma (FL)
Follicular lymphoma is a type of non-Hodgkin lymphoma arising from B lymphocytes within the lymph nodes. It is generally an indolent (slow-growing) lymphoma, but it can transform into a more aggressive form over time. In follicular lymphoma, malignant B lymphocytes proliferate excessively and accumulate primarily in lymph nodes, causing lymph node enlargement (lymphadenopathy) and potentially affecting other organs. While FL often responds well to initial treatment, many patients experience multiple relapses requiring successive lines of therapy.
Zydelig is used as monotherapy for the treatment of adult patients with follicular lymphoma that is refractory to (has not responded to) two prior lines of cancer treatment. This approval was based on a single-arm study demonstrating durable responses in heavily pre-treated patients with limited remaining treatment options. In these difficult-to-treat cases, idelalisib offers a targeted oral therapy option that can achieve meaningful tumor shrinkage.
Unlike many cancer treatments that require intravenous infusion in a hospital, Zydelig is taken as an oral tablet at home. This targeted approach specifically inhibits an enzyme that is predominantly expressed in blood cells, aiming to disrupt cancer cell survival while preserving normal cell function. However, PI3Kδ also plays roles in immune regulation, which explains some of the immune-related side effects observed during treatment.
What Should You Know Before Taking Zydelig?
Contraindications
There are specific situations in which Zydelig must not be used. Understanding these absolute contraindications is critical before beginning treatment:
- Hypersensitivity: Do not take Zydelig if you are allergic to idelalisib or any of the other ingredients, including microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, magnesium stearate, or the film-coating components (including sunset yellow FCF/para-orange E110).
If you know you are allergic to sunset yellow (E110), inform your doctor before starting Zydelig, as the 100 mg tablet film coating contains this colorant which may cause allergic reactions in susceptible individuals.
Warnings and Precautions
Serious and fatal infections, including Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV) reactivation, have occurred in patients receiving Zydelig. You must take prophylactic medication against PJP throughout the entire duration of treatment. Your doctor will monitor you for signs of infection. Tell your doctor immediately if you develop fever, cough, or breathing difficulties while taking Zydelig.
Before and during treatment with Zydelig, inform your doctor about any of the following concerns:
- Liver problems: Zydelig can cause severe hepatotoxicity (liver damage). Your doctor will perform liver function tests (measuring liver enzymes in your blood) every two weeks for the first six months of treatment and at least monthly thereafter. If your liver enzymes become significantly elevated, your doctor may pause treatment, reduce the dose, or discontinue Zydelig permanently.
- Infections: Tell your doctor if you have any active infection or fever before starting treatment. Serious infections including bacterial, viral, and fungal infections have been reported. You must take additional medications prescribed by your doctor to prevent PJP while on Zydelig. Your doctor will also monitor you for signs of CMV reactivation.
- Severe diarrhea and colitis: Zydelig can cause severe diarrhea and inflammation of the large intestine (colitis). Tell your doctor immediately at the first sign of diarrhea. In some cases, treatment may need to be paused or discontinued. Do not try to self-manage persistent diarrhea without medical advice.
- Lung inflammation (pneumonitis): Tell your doctor immediately if you develop new or worsening cough, shortness of breath, or breathing difficulties. Cases of pneumonitis (non-infectious lung inflammation) have been reported with Zydelig treatment.
- Severe skin reactions: Serious skin reactions with blistering, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), as well as drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with idelalisib. Stop taking Zydelig and seek medical attention immediately if you develop reddish target-like spots or circular patches on the trunk, blistering of the skin or mucous membranes of the mouth, throat, nose, genitals, or eyes, or widespread skin rash with fever and enlarged lymph nodes.
- Blood count changes: Laboratory tests may show an increase in white blood cells (lymphocytes) in your blood during the first weeks of treatment. This is an expected pharmacological effect called lymphocytosis and does not usually mean your cancer is getting worse. It occurs because idelalisib disrupts the signals that keep malignant lymphocytes in the lymph nodes and bone marrow, causing them to be released into the bloodstream. This typically resolves within a few months. Your doctor will monitor your blood counts and in rare cases may prescribe additional medication.
Tell your doctor immediately if you or anyone around you notices memory loss, difficulty thinking, trouble walking, or vision loss. These may be symptoms of a very rare but serious brain infection called progressive multifocal leukoencephalopathy (PML) that can be fatal. Although extremely rare, PML has been reported in patients receiving Zydelig.
Pregnancy and Breastfeeding
Zydelig should not be used during pregnancy. There is no safety information available regarding the use of idelalisib in pregnant women, and the potential risks to the developing fetus are unknown. If you are a woman of childbearing potential, you must use a highly effective method of contraception to prevent pregnancy while being treated with Zydelig and for at least 1 month after the last dose.
It is important to note that Zydelig may reduce the effectiveness of hormonal contraceptives, including oral contraceptive pills and hormonal implants. This is because idelalisib is a potent inhibitor of the CYP3A4 enzyme, which can alter the metabolism of hormonal contraceptives. Therefore, you must use a barrier method of contraception such as a condom or intrauterine device (IUD) while taking Zydelig and for 1 month after the last dose.
You should not breastfeed while taking Zydelig. It is not known whether idelalisib or its metabolites pass into breast milk. If you are currently breastfeeding, discuss with your doctor before starting treatment.
Tell your doctor immediately if you become pregnant while taking Zydelig.
Driving and Operating Machinery
Zydelig is unlikely to affect your ability to drive or operate machinery. However, if you experience side effects that could impair your alertness or concentration, exercise caution until these symptoms resolve.
Important Information About Ingredients
Zydelig 100 mg tablets contain sunset yellow FCF (E110), which may cause allergic reactions in some people. Tell your doctor if you have a known allergy to this colorant. The tablets also contain less than 1 mmol (23 mg) of sodium per tablet, meaning they are essentially sodium-free.
How Does Zydelig Interact with Other Drugs?
Zydelig has extensive and clinically significant drug interactions because idelalisib is both a substrate and a potent inhibitor of the CYP3A4 enzyme system. CYP3A4 is the most important drug-metabolizing enzyme in the human body, responsible for the metabolism of approximately 50% of all drugs. When Zydelig inhibits CYP3A4, it slows the breakdown of many other medications, causing their blood levels to rise – sometimes to dangerous concentrations. Conversely, drugs that strongly induce CYP3A4 can accelerate the breakdown of idelalisib, potentially reducing its anticancer effectiveness. For these reasons, it is absolutely essential to inform your doctor about every medication, supplement, and herbal product you are taking.
Zydelig should not be used together with any other medication unless your doctor has confirmed it is safe to do so. The following tables summarize the most important drug interactions.
Major Interactions
| Interacting Drug | Effect | Clinical Significance |
|---|---|---|
| Midazolam, triazolam (oral benzodiazepines) | Greatly increased sedative effect; idelalisib increased midazolam exposure approximately 5-fold | Avoid combination; risk of excessive and prolonged sedation |
| Amiodarone, disopyramide, quinidine, lidocaine, bepridil (antiarrhythmics) | Increased blood levels of antiarrhythmic drugs | Risk of serious cardiac arrhythmias; avoid or use with extreme caution under close monitoring |
| Ergotamine, dihydroergotamine (ergot alkaloids) | Increased ergot levels | Risk of ergotism (vasospasm); combination contraindicated |
| Cisapride, pimozide | Increased blood levels leading to QT prolongation | Risk of life-threatening arrhythmias; combination contraindicated |
| Rifampicin (CYP3A4 inducer) | Significantly reduced idelalisib exposure (by approximately 75%) | Avoid combination; may render Zydelig ineffective |
| St. John’s Wort (Hypericum perforatum) | Reduced idelalisib blood levels via CYP3A4 induction | Do not use together; may reduce anticancer efficacy |
| Ciclosporin, sirolimus, tacrolimus (immunosuppressants) | Increased immunosuppressant levels; risk of toxicity | Monitor drug levels closely; dose adjustments likely required |
| Hormonal contraceptives (oral pills, implants) | Altered hormonal metabolism; reduced contraceptive efficacy | Use barrier contraception (condom, IUD) instead |
Other Significant Interactions
| Interacting Drug | Effect | Clinical Significance |
|---|---|---|
| Alfuzosin (alpha-blocker for prostate) | Increased alfuzosin levels | Risk of severe hypotension; avoid combination |
| Amlodipine, nifedipine, felodipine, diltiazem, nicardipine (calcium channel blockers) | Increased calcium channel blocker levels | Risk of hypotension and edema; dose reduction and monitoring needed |
| Atorvastatin, lovastatin, simvastatin (statins) | Increased statin levels | Risk of rhabdomyolysis (severe muscle breakdown); avoid or reduce statin dose |
| Budesonide, fluticasone (inhaled/nasal corticosteroids) | Increased systemic corticosteroid exposure | Risk of Cushing syndrome and adrenal suppression; consider alternatives |
| Sildenafil, tadalafil (PDE5 inhibitors) | Increased PDE5 inhibitor levels | Risk of severe hypotension; dose reduction required |
| Dasatinib, nilotinib, paclitaxel, vinblastine, vincristine (anticancer drugs) | Increased anticancer drug levels | Risk of increased toxicity; discuss with oncologist |
| Quetiapine (antipsychotic) | Increased quetiapine levels | Risk of excessive sedation and toxicity; dose adjustment needed |
| Carbamazepine, phenytoin (antiepileptics / CYP3A4 inducers) | Reduced idelalisib exposure | May decrease Zydelig efficacy; use alternative antiepileptics if possible |
| Dabigatran, warfarin (anticoagulants) | Altered anticoagulant levels | Increased bleeding risk; close monitoring of coagulation parameters required |
| Fentanyl, methadone, buprenorphine (opioids) | Increased opioid levels | Risk of respiratory depression; careful dose titration needed |
When Zydelig is prescribed in combination with rituximab for CLL treatment, it is important to also read the prescribing information for rituximab, as each medication carries its own set of interactions and precautions. Ask your doctor if you have any questions about your medications.
What Is the Correct Dosage of Zydelig?
Always take Zydelig exactly as your doctor has prescribed. Do not change the dose or stop taking the medication without consulting your doctor first. Zydelig is taken continuously until your doctor determines that treatment should be stopped, either due to disease progression or unacceptable side effects.
Adults
Standard Dosing
Indication: CLL (with rituximab) and Follicular Lymphoma (monotherapy)
Dose: 150 mg orally twice daily (every 12 hours)
Administration: Swallow the tablet whole with water. Can be taken with or without food.
Duration: Continue until disease progression or unacceptable toxicity
Reduced Dose (for Side Effect Management)
Dose: 100 mg orally twice daily
When used: Your doctor may reduce the dose if you experience certain side effects such as elevated liver enzymes, diarrhea, or other toxicities. In some cases, treatment may need to be temporarily paused before resuming at the lower dose.
Children and Adolescents
Zydelig should not be given to children or adolescents under 18 years of age. The safety and efficacy of idelalisib have not been studied in this age group, and it is not authorized for pediatric use.
Elderly Patients
No specific dose adjustment is required for elderly patients based on age alone. However, since CLL predominantly affects older adults and this population may have more comorbidities and be taking multiple medications, careful monitoring for drug interactions and side effects is particularly important. Elderly patients may also be more susceptible to infections and other treatment-related complications.
Missed Dose
If you forget to take a dose of Zydelig, the action you should take depends on how much time has passed since the scheduled dose:
- Less than 6 hours since the missed dose: Take the missed dose immediately. Then take the next dose at the regular scheduled time.
- More than 6 hours since the missed dose: Skip the missed dose and wait to take the next dose at your regular scheduled time. Do not take a double dose to make up for a missed one.
Overdose
If you accidentally take more than the recommended dose of Zydelig, you may be at greater risk of side effects. Contact your doctor or nearest emergency department immediately for advice. Bring the medication container and this information leaflet with you so that you can easily explain what you have taken. There is no specific antidote for idelalisib overdose; treatment would be supportive and based on symptoms.
Do not stop taking Zydelig unless your doctor tells you to. Stopping treatment prematurely may allow the cancer to progress. If you have any concerns about your treatment or its side effects, discuss them with your oncologist or hematologist before making any changes.
What Are the Side Effects of Zydelig?
Like all medicines, Zydelig can cause side effects, although not everyone experiences them. Some side effects can be serious and may require immediate medical attention. Your doctor will monitor you closely with regular blood tests and clinical assessments throughout treatment.
If you experience any of the following: reddish target-like spots or small circular areas of changed skin color, often with blisters in the center; peeling skin; sores in the mouth, throat, nose, genitals, or eyes (signs of Stevens-Johnson syndrome or toxic epidermal necrolysis); or widespread skin rash with high body temperature and enlarged lymph nodes (signs of DRESS syndrome).
Very Common
May affect more than 1 in 10 people
- Diarrhea / inflammation of the large intestine (colitis)
- Skin rash
- Changes in white blood cell counts (neutropenia, lymphocytosis)
- Infections (bacterial, viral, or fungal)
- Fever (pyrexia)
- Elevated liver enzymes (ALT, AST) in blood tests
- Elevated blood fat levels (triglycerides)
Common
May affect up to 1 in 10 people
- Inflammation of the lungs (pneumonitis)
- Liver damage (hepatotoxicity)
Rare
May affect up to 1 in 1,000 people
- Stevens-Johnson syndrome (SJS) – severe skin reaction with blistering and peeling
- Toxic epidermal necrolysis (TEN) – life-threatening skin reaction
Not Known
Frequency cannot be estimated from available data
- DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) – widespread rash, high fever, and enlarged lymph nodes
- Progressive multifocal leukoencephalopathy (PML) – rare brain infection
Understanding Lymphocytosis During Treatment
During the first weeks of Zydelig treatment, laboratory tests may show an increase in the number of white blood cells (lymphocytes) in your blood. This is a recognized pharmacological effect of PI3Kδ inhibition, not an indication that your cancer is worsening. Idelalisib disrupts the chemokine receptor signaling (CXCR4 and CXCR5) that normally retains malignant lymphocytes within lymph nodes and bone marrow. As a result, these cells are released into the peripheral blood, causing a transient rise in lymphocyte counts. This lymphocytosis typically peaks within the first few weeks and resolves over several months of continued treatment as the malignant cells undergo apoptosis. Your doctor will monitor your blood counts regularly, and in rare cases, additional treatment may be prescribed.
Reporting Side Effects
If you experience any side effects, including those not listed here, tell your doctor or nurse. You can also report suspected side effects to your national pharmacovigilance authority (such as the EMA in Europe, the FDA MedWatch program in the United States, or the MHRA Yellow Card Scheme in the United Kingdom) to help monitor the ongoing benefit-risk profile of Zydelig.
How Should You Store Zydelig?
Keep Zydelig out of the sight and reach of children at all times. Do not use the medicine after the expiry date stated on the bottle and outer carton after “EXP.” The expiry date refers to the last day of the stated month.
No special storage conditions are required for Zydelig. Store the tablets in the original container to protect them from moisture and keep the bottle tightly closed. There is no need for refrigeration.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist about how to dispose of medicines that are no longer needed. These measures help to protect the environment and reduce the risk of accidental exposure.
What Does Zydelig Contain?
Active Substance
The active substance is idelalisib. Each film-coated tablet contains 100 mg of idelalisib. Idelalisib is also available as 150 mg film-coated tablets (the recommended starting dose).
Inactive Ingredients (Excipients)
Tablet core:
- Microcrystalline cellulose
- Hydroxypropyl cellulose (E463)
- Croscarmellose sodium
- Sodium starch glycolate
- Magnesium stearate
Film coating:
- Poly(vinyl alcohol) (E1203)
- Macrogol (E1521)
- Titanium dioxide (E171)
- Talc (E553B)
- Sunset yellow FCF / para-orange (E110) – may cause allergic reactions in susceptible individuals
Appearance
Zydelig 100 mg film-coated tablets are orange, oval-shaped tablets imprinted with “GSI” on one side and “100” on the other side. They are supplied in a plastic bottle containing 60 film-coated tablets within an outer carton.
Sodium Content
This medicine contains less than 1 mmol (23 mg) of sodium per tablet, meaning it is essentially sodium-free. This is relevant for patients on a sodium-restricted diet.
Marketing Authorization Holder and Manufacturer
Zydelig is marketed by Gilead Sciences Ireland UC, Carrigtohill, County Cork, Ireland. The manufacturer is Gilead Sciences Ireland UC at the IDA Business & Technology Park, Carrigtohill, County Cork, Ireland.
Frequently Asked Questions About Zydelig
Zydelig (idelalisib) is used to treat two types of blood cancer in adults. For chronic lymphocytic leukemia (CLL), it is used in combination with rituximab in patients with certain high-risk features or whose cancer has relapsed after at least one prior treatment. For follicular lymphoma (FL), it is used as a single agent in patients whose cancer has not responded to two prior lines of treatment.
Zydelig works by selectively blocking an enzyme called PI3K delta (phosphatidylinositol 3-kinase delta) that is overactivated in cancerous B lymphocytes. This enzyme plays a crucial role in the growth, survival, and tissue homing of malignant B cells. By inhibiting PI3K delta, idelalisib triggers cancer cell death (apoptosis) and reduces the number of malignant cells.
Regular blood tests are essential during Zydelig treatment. Liver function tests (checking liver enzyme levels) should be performed every 2 weeks for the first 6 months and then at least monthly thereafter. Complete blood counts should also be monitored regularly. Additionally, patients must take prophylactic medication to prevent Pneumocystis jirovecii pneumonia throughout treatment. Your doctor will also monitor you for signs of infection, diarrhea/colitis, pneumonitis, and skin reactions at each visit.
An increase in white blood cells (lymphocytes) in the blood is a normal, expected effect of Zydelig treatment during the first few weeks. This does not mean your cancer is worsening. Idelalisib disrupts the chemical signals that keep malignant lymphocytes trapped in the lymph nodes and bone marrow, causing them to be released into the bloodstream. This lymphocytosis typically resolves within a few months as the released cancer cells undergo programmed cell death. Your doctor will monitor your blood counts and can explain what your results mean.
Zydelig interacts with many common medications because it potently inhibits the CYP3A4 enzyme that metabolizes approximately half of all drugs. This means it can significantly increase the blood levels of many other medications, potentially causing serious side effects. Particularly important interactions include certain heart medications, sedatives, painkillers, cholesterol-lowering drugs, immunosuppressants, and hormonal contraceptives. Always tell your doctor about every medication, supplement, and herbal product you are taking before starting Zydelig.
No, Zydelig should not be used during pregnancy. There are no safety data available for pregnant women. Women of childbearing potential must use effective barrier contraception (such as condoms or an intrauterine device) during treatment and for at least 1 month after the last dose. Importantly, hormonal contraceptives (pills and implants) may not work properly when taken with Zydelig because it inhibits CYP3A4, which can alter hormone metabolism. Breastfeeding should also be avoided during treatment.
References
- European Medicines Agency (EMA). Zydelig – Summary of Product Characteristics. Last updated 2024. Available at: EMA – Zydelig EPAR.
- U.S. Food and Drug Administration (FDA). Zydelig (idelalisib) Prescribing Information. Gilead Sciences, Inc. Revised 2024.
- Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007. doi:10.1056/NEJMoa1315226.
- Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-1018. doi:10.1056/NEJMoa1314583.
- Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines. Ann Oncol. 2021;32(1):23-33.
- National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 2.2025.
- World Health Organization (WHO). WHO Model List of Essential Medicines – 23rd List. Geneva: WHO; 2023.
- British National Formulary (BNF). Idelalisib. National Institute for Health and Care Excellence (NICE). Accessed January 2026.
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