Generic Ibrutinib Tablet Given Tentative FDA Approval in CLL/SLL, WM

The generic tablet is tentatively approved for CLL and SLL with 17p deletion and Waldenström macroglobulinemia.

The FDA has granted tentative approval to Zydus Lifesciences Limited’s abbreviated new drug application (ANDA) seeking the approval of the company’s generic ibrutinib tablet for use in some approved indications.¹

The tablet’s indications include chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) with 17p deletion and Waldenström macroglobulinemia.² The tentative approval will allow tablets of 140 mg, 280 mg, 420 mg, and 560 mg to be used to treat these patient populations. The generic tablet’s approval is tentative at this time due to market exclusivity limitations pertaining to Pharmacyclics’ ibrutinib (Imbruvica) tablets.¹

Ibrutinib’s Efficacy Data in CLL and SLL With 17p Deletion

Ibrutinib was approved for use in patients with CLL and SLL in 1 uncontrolled and 5 randomized, controlled trials, including the RESTONATE trial (NCT01578707).³ RESONATE’s investigators randomized patients to treatment with ibrutinib or ofatumumab (Kesimpta), including 127 patients (32%) with 17p deletion in CLL or SLL, with a median age of 67 years (range, 30-84).

The overall response rate (ORR) for ibrutinib in this patient population was 47.6%, compared with 4.7% in the ofatumumab population. After an overall follow-up of 63 months, median investigator-assessed progression-free survival (PFS) was 40.6 months (95% CI, 25.4-44.6) and 6.2 months (95% CI, 4.6-8.1) in the ibrutinib and ofatumumab arms, respectively. At that time, ORR was 88.9% and 18.8%, respectively.

Ibrutinib’s Efficacy Data in Waldenström Macroglobulinemia

The efficacy of ibrutinib was established for approval in the open-label, multicenter, single-arm Study 1118 (NCT01614821) and in the randomized, double-blind, placebo-controlled, phase 3 INNOVATE (NCT02165397) trial.

Patients enrolled in Study 1118 saw a 61.9% response rate (95% CI, 48.8%-73.9%; N = 63), with 50.8% achieving partial response and 11.1% achieving very good partial response. The median duration of response (DOR) was not evaluable. At an overall follow-up of 61 months, the response rate was 77%.

Patients enrolled in INNOVATE were randomly assigned to treatment with either ibrutinib or placebo, in combination with rituximab (Rituxan). Treatment with ibrutinib lessened the risk of progression or death by 75%, with a median PFS for those in the ibrutinib arm that was not evaluable (95% CI, 57.7%-NE), compared with 20.3 months (95% CI, 13.0-27.6) in the placebo arm (HR, 0.25; 95% CI, 0.15-0.42; P < .0001). The median DOR was not evaluable for either arm of this trial.

Safety Signals for Ibrutinib

The most common adverse events (AEs) associated with ibrutinib for patients with B-cell malignancies, occurring in at least 30% of patients as noted in ibrutinib’s label, are thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea.

Additionally, the label contains warnings for hemorrhage; infections; cardiotoxicities including cardiac arrhythmias, cardiac failure, and sudden death; cytopenias; second primary malignancies; hepatotoxicity including drug-induced liver injury; tumor lysis syndrome; and embryo-fetal toxicity.

Administration Types

Currently, ibrutinib is approved in 70-mg and 140-mg capsules; 140-mg, 280-mg, and 420-mg tablets; and a 70 mg/mL oral suspension. For patients with CLL, SLL, and Waldenström’s macroglobulinemia, ibrutinib should be taken orally once daily.

For patients with CLL, SLL, or Waldenström macroglobulinemia, a patient’s first instance of grade 2 cardiac failure should call for a reduction from the starting dose of 420 mg to 280 mg. At the second instance of grade 2 cardiac failure, the dose should be further reduced to 140 mg, and at the third instance, ibrutinib should be discontinued.

If a patient has grade 3 cardiac arrhythmia, the dose should first be reduced to 280 mg, followed by discontinuation if a second instance occurs. Likewise, any instance of grade 3/4 cardiac failure or grade 4 cardiac arrhythmias should call for discontinuation of ibrutinib.

References

1. ANDA 214296 Tentative Approval. FDA. Letter of tentative approval. July 22, 2025. Accessed July 25, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/214296Orig1s000TAltr.pdf
2. Zydus receives tentative approval from USFDA for Ibrutinib tablets 140 mg, 280 mg, and 420 mg. News release. Zydus Lifesciences Limited. July 24, 2025. Accessed July 25, 2025. https://zyduslife.com/investor/admin/uploads/21/83/Zydus-receives-tentative-approval-from-USFDA-for-Ibrutinib-tablets-140-mg--280-mg--and-420-mg.pdf
3. Ibrutinib. Prescribing information. Pharmacyclics LLC. Updated December 20, 2024. Accessed July 25, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/205552s043,210563s019,217003s004lbl.pdf