Balsalazide

Summary

Abstract

The aminosalicylate balsalazide is a prodrug which is metabolised by bacterial azo reductases in the colon to release its therapeutically active moiety mesalazine [mesalamine (US) or 5-aminosalicylic acid] and an inert carrier molecule. The systemic absorption of balsalazide and its metabolites is not required for the therapeutic efficacy of the drug, and has been demonstrated to be limited.

Data from well designed trials with a duration of 8 to 12 weeks show that oral balsalazide 6.75 g/day is as effective as (two trials) or more effective than (one trial) oral delayed-release (pH-dependent) mesalazine 2.4 g/day and appears to be as effective as oral sulfasalazine 3 g/day in the treatment of active mild-to-moderate ulcerative colitis. In addition, balsalazide appears to have a faster onset of action than mesalazine.

Furthermore, balsalazide was as effective as delayed-release mesalazine (dosages used were 1.2 and 1.5 g/day, where 1.6 g/day is recommended) and oral sulfasalazine 2 g/day (recommended dosage) in the prevention of relapse in ulcerative colitis in remission after 6 to 12 months of treatment; the balsalazide dosage was 3 g/day versus mesalazine and 2 g/day versus sulfasalazine. Although not well established, additional benefits may be achieved with balsalazide dosages up to 6 g/day.

Data from well designed, 2- to 12-month trials show that balsalazide is well tolerated by patients with ulcerative colitis in both acute and maintenance indications, and is better tolerated than standard formulations of sulfasalazine at therapeutically relevant dosages.

Conclusion: Balsalazide is a well tolerated and effective first-line therapeutic option for patients with ulcerative colitis, both for the treatment of active mild-to-moderate disease and as maintenance therapy to prevent disease relapse.

Pharmacodynamic Profile

Metabolism of the aminosalicylate balsalazide by bacterial azo-reductases in the colon yields the active moiety mesalazine [mesalamine (US) or 5-aminosalicylic acid] and the inert carrier molecule 4-aminobenzoyl-β-alanine (4-ABA).

The mechanism by which mesalazine (and thus balsalazide) exerts its therapeutic effects in ulcerative colitis is unclear. Potential anti-inflammatory effects of mesalazine include modification of the mucosal prostaglandin profile, mucosal electrolyte transport and possibly alteration of the microflora in the colon.

In addition, mesalazine has been reported to inhibit the release and synthesis of proinflammatory mediators in vitro (e.g. nitric oxide, leukotrienes, thromboxanes and platelet-activating factor). Furthermore, the compound inhibits the function of natural killer cells, mast cells, neutrophils, mucosal lymphocytes and macrophages, and is a scavenger/inhibitor of reactive oxygen species.

For patients with ulcerative colitis, mesalazine has been shown to inhibit the activation of nuclear factor κB, which is an important transcription factor involved in the regulation of the expression of a number of (proinflammatory) cytokines and which regulates the expression of cellular adhesion molecules involved in inflammatory-cell migration.

Pharmacokinetic Profile

Systemic absorption of balsalazide is not likely to be relevant to its therapeutic efficacy because its active moiety exerts its effects locally in the colon. Systemic absorption of balsalazide is low.

Median maximum plasma concentration (C_max) and area under the plasma concentration-time curve (0 to 12 hours) were 0.324 µmol/L and 1.34 µmol · h/L, respectively, for balsalazide after long-term administration of 3 to 6 g/day (data normalised to a statim dose of 3 g/day) to 54 adult patients with ulcerative colitis. In patients with ulcerative colitis receiving balsalazide 3 g/day for over 1 year, the systemic exposure to balsalazide was approximately 57 times greater than in healthy volunteers, but was still low.

The median time to Cmax of balsalazide is about 2 hours. In contrast, C_max values of mesalazine (2.62 µmol/L) and 4-ABA (<0.096 µmol/L) were achieved 9 and 10 hours after a single dose of balsalazide 2.25g. The systemic uptake of balsalazide and its metabolites appears to be slightly increased in fasting patients.

Balsalazide is mainly eliminated via the faeces. In total, up to 25% of its metabolites (mesalazine, N-acetyl-mesalazine, 4-ABA and N-acetyl-4-ABA) are systemically absorbed and appear in the urine after inactivation by colonic mucosa and the liver. The clearance of N-acetylated mesalazine and 4-ABA is high (12 to 18 L/h and 24 to 30 L/h). The clearance of balsalazide itself is about 4.5 L/h. The half-life of N-acetyl-mesalazine is about 6 to 9 hours and the half-life of mesalazine is about 1 hour.

Balsalazide drug interaction studies are not available. Administration of orally administered antibacterials, however, putatively interferes with the release of mesalazine in the colon although no data are available to confirm this potential interaction.

Therapeutic Use

Data from randomised, double-blind trials show that balsalazide is an effective treatment for active mild-to-moderate ulcerative colitis and for the prevention of relapse in ulcerative colitis in remission.

Active Ulcerative Colitis The efficacy of oral balsalazide in the treatment of active mild-to-moderate ulcerative colitis has been compared with that of oral delayed-release (pH-dependent) mesalazine and oral sulfasalazine during five randomised, double-blind, 8- to 12-week trials.

Balsalazide 6.75 g/day was as effective as (two trials) or more effective than (one trial) delayed-release mesalazine 2.4 g/day (recommended dosage) in the treatment of active disease as shown by data from well designed trials (percentage of patients achieving remission, primary outcomes). Importantly, the onset of action appeared to be faster for balsalazide 6.75 g/day than for mesalazine 2.4 g/day during some trials. During one trial, significantly more patients receiving balsalazide 6.75 g/day than those receiving delayed-release mesalazine 2.4 g/day were in complete remission at 4 and 8 weeks, and also at the end of this 12-week trial (primary outcome, p < 0.05). Furthermore, significant differences in secondary outcomes favouring balsalazide were recorded during this trial [these included sigmoidoscopic improvement, number of days without symptoms and use of relief medication, night-time rescue corticosteroid use, median time to complete relief and patient satisfaction (p < 0.05 for all items)].

Data from two small randomised, double-blind trials (8 and 12 weeks) primarily designed to assess tolerability suggest that balsalazide 6.75 g/day is as effective as sulfasalazine 3 g/day in the treatment of active ulcerative colitis (percentage of patients achieving remission).

Maintenance of Remission in Ulcerative Colitis Data from randomised, double-blind trials with a duration of 6 and 12 months show that balsalazide is an effective maintenance treatment for patients with ulcerative colitis in remission. Active comparators in these trials included oral delayed-release mesalazine and oral sulfasalazine. In addition, balsalazide dose-comparison trials have been performed.

The efficacy of oral balsalazide 3 g/day in the maintenance of remission in ulcerative colitis was similar to that of oral delayed-release mesalazine 1.2 g/day (the recommended oral delayed-release mesalazine dosage is 1.6 g/day) during a 12-month trial. Nonetheless, significant differences (secondary outcomes) in favour of balsalazide were recorded after 3 months of treatment [i.e. blood in stool, blood on toilet paper, mucus with stool, disturbed sleep, symptom interference with sleep, asymptomatic nights (p < 0.05 for all items)].

Oral balsalazide 6 g/day proved to be more effective than both oral delayed-release mesalazine 1.5 g/day and oral balsalazide 3 g/day during another trial in patients with ulcerative colitis in remission (percentage of patients still in remission after 6 months of treatment, primary outcome).

After 6 months, there was no significant difference in the percentage of patients with ulcerative colitis still in remission between oral balsalazide 2 g/day and oral sulfasalazine 2 g/day (primary outcome).

Although oral balsalazide 6 g/day was significantly more effective than oral balsalazide 3 g/day in maintaining remission after 6 months in one trial (p = 0.001), no significant differences in the efficacy of maintaining remission were recorded during a 12-month trial specifically designed to compare the efficacy of oral balsalazide 3 and 6 g/day. Balsalazide 4 g/day, however, was significantly more effective than balsalazide 2 g/day in maintaining remission during another dose-comparison trial (p < 0.01).

Tolerability

In general, oral balsalazide is well tolerated at therapeutically relevant dosages, both by patients with active disease and by patients with ulcerative colitis in remission. The tolerability of balsalazide is likely to be similar to that of mesalazine, and does not appear to be dose-related. The most frequently reported (≥3%) adverse events in patients with ulcerative colitis receiving balsalazide 6.75 g/day in placebo-controlled trials include headache (8%), abdominal pain (6%) diarrhoea (5%), nausea (5%), vomiting (4%), respiratory infection (4%) and arthralgia (4%).

During two clinical trials primarily designed to assess tolerability in patients with active disease, the number of withdrawals because of adverse events was significantly greater in the sulfasalazine (3 g/day) than in the balsalazide (6.75 g/day) groups (38 vs 4%, p = 0.004 and 31 vs 7% patients, p = 0.041). In addition, troublesome adverse events (not specified) occurred significantly more often in sulfasalazine 2 g/day than in balsalazide 2 g/day recipients (26 vs 5%, p = 0.017) during one, 6-month maintenance trial.

The tolerability of balsalazide 2.25 to 6.75 g/day was generally similar to or better than that of delayed-release mesalazine 1.2 to 2.4 g/day in patients with ulcerative colitis during well designed clinical trials (both indications). During one trial in patients with active disease, however, a significant difference favouring balsalazide 6.75 g/day over delayed-release mesalazine 2.4 g/day in the number of patients reporting adverse events was recorded (48 vs 71%, p = 0.024).

Dosage and Administration

Balsalazide is indicated for the treatment of adult patients with mild-to-moderate active ulcerative colitis in both the US and the UK. In addition, the drug is approved as maintenance therapy for ulcerative colitis in remission in the UK.

For the treatment of active ulcerative colitis, an oral dosage of 2.25g (three 750mg capsules) three times daily is recommended, until remission is achieved or for 8 (US) or 12 (UK) weeks maximum.

As approved in the UK, balsalazide may be given orally at a dosage of 1.5g twice daily as maintenance treatment for ulcerative colitis in remission. In this context, UK prescribing information mentions possible additional benefits with balsalazide dosages up to 6 g/day.

In both the US and the UK, balsalazide is contraindicated for patients with hypersensitivity to any balsalazide component or metabolites including mesalazine or patients with a history of hypersensitivity to salicylates. Balsalazide is not recommended for use in children, as the tolerability of the drug in these patients has not been established. In the UK, the administration of balsalazide to breastfeeding or pregnant women, patients with severe hepatic impairment and patients with moderate to severe renal impairment is contraindicated. US prescribing information recommends caution when administering balsalazide to these patients. No dosage adjustments are required when balsalazide is administered to elderly patients.