Long-term safety and tolerability of twice-daily balsalazide disodium tablets in patients with ulcerative colitis

Purpose: Balsalazide disodium is an azo‐bonded 5‐aminosalicylic acid prodrug cleaved by colonic bacteria, providing direct drug delivery to the colon with efficacy in inducing and maintaining ulcerative colitis (UC) remission. This study evaluated long‐term safety and tolerability of a new formulation, balsalazide disodium tablets (BDT), which was developed to allow less frequent dosing and enhance compliance in the treatment of UC. Methods: In a phase 3, multicenter, open‐label extension study, adults in UC remission or with mildto‐ moderate active UC received 3.3 g of BDT (dosed as three 1.1 g tablets) twice daily for up to 1.4 years. Eligible patients had participated in previous double‐blind, phase 3 studies (a placebo‐controlled or actively controlled [mesalamine] trial) of BDT for active UC. Patients were assessed in the clinic at baseline, months 1 and 3, every 3 months through the end of treatment (EOT), and at 2 weeks after EOT, with a telephone interview at week 2. Safety assessments included monitoring of AEs and clinical laboratory and vital sign measurements. Results: Of the 443 patients enrolled, 253, 142, and 48 had been treated with BDT, mesalamine, or placebo, respectively, during the double‐blind studies. The safety population (n=440) was 50.9% male and 85.2% white, with a mean (SD) age of 43.1 (13.2) years. Median (range) duration of exposure was 277.5 days (1 to 495), with 317 (72.0%) and 84 (19.1%) patients receiving >6 and >12 months of treatment, respectively. The most common adverse events (AEs; in >5% of patients) were worsening UC (10.9%), diarrhea (6.1%), abdominal pain (5.9%), and headache (5.5%). The majority of patients (86.1%) reported AEs with mild or moderate severity. Gastrointestinal AEs were most commonly reported during the 0‐8 and >8‐26 week time periods; infection‐related AEs (eg, upper respiratory tract infection) were most common at >26‐52 weeks. Drug‐related AEs occurred in 8.9% of patients; most common were worsening UC (1.6%) and headache (1.1%). Twenty‐seven patients (6.1%) discontinued from the study due to an AE, including worsening UC in 18 patients (4.1%). Serious AEs occurred in 21 patients (4.8%), with one death that was not drug‐related; only one serious AE (worsening UC) was drug‐related. Pancreatic, renal, and hepatic AEs occurred in 13 patients (3.0%); all events were mild or moderate, and only one event (increased alanine aminotransferase levels) was drug‐related. There were no clinically meaningful mean changes from baseline in clinical laboratory parameters. Conclusion: Twice‐daily balsalazide disodium tablets were safe and well‐tolerated for the long‐term (up to 1.4 years) management of UC.