Balsalazide is a diazo-bonded 5-aminosalicylate and is a prodrug; the drug utilizes bacterial azoreduction to release the antiinflammatory agent 5-ASA (also known as mesalamine). Balsalazide capsules (e.g., Colazal) are indicated for the treatment of mildly to moderately active ulcerative colitis (UC) in adult and pediatric patients 5 years and older. The tablets (i.e., Giazo) were indicated only in adult male patients with UC but are no longer marketed. Although there is little evidence to suggest differences in efficacy between the diazo-bonded 5- ASA preparations, balsalazide is the often the preferred diazo-bonded 5-ASA over olsalazine due to its better tolerability. The guidelines support the use of standard-dose mesalamine (2 to 3 grams/day) or diazo-bonded 5-ASAs (balsalazide or olsalazine) for induction and maintenance of remission in patients with extensive mild to moderate UC. Those with moderate symptoms may benefit from early use of combination oral and rectal 5-ASA. Use of combined oral and rectal 5-ASA in patients with extensive disease may improve rates of induction of remission, as may escalation to high-dose (more than 3 grams/day) oral with rectal 5-ASA in patients with suboptimal response to standard-dose therapy. In patients with inadequate response to optimized 5-ASA, consider oral prednisone or budesonide MMX 9 mg/day to induce remission instead of changing to an alternate 5-ASA formulation. Systemic corticosteroids should not be used for maintenance of remission in patients with UC. In patients with mildly active ulcerative proctitis, rectal 5-ASA at a dose of 1 gram/day should be used to maintain remission rather than oral 5-ASA. Those patients with suboptimal response or intolerance to rectal mesalamine may opt to use rectal corticosteroids.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Balsalazide is administered orally. Clinical efficacy is primarily due to local effects on the colonic mucosa; efficacy does not appear altered by the presence of food.
Oral Solid Formulations
-Swallow capsules whole; do not cut, crush, or chew capsules.
-Take balsalazide with or without food.
-For patients who cannot swallow intact capsules, the capsule may be carefully opened and contents sprinkled on applesauce immediately before administration. If the capsules are opened for sprinkling, color variation of the powder inside the capsules ranges from orange to yellow and is expected due to color variation of the active ingredient.
--Place a small amount (approximately 10 mL) of applesauce into a clean container.
-Carefully open the capsules.
-Sprinkle the capsule contents on the applesauce.
-Mix the capsule contents with the applesauce. The contents may be chewed, if necessary.
-Consume the entire amount of applesauce mixture immediately. Do not store the applesauce mixture for
future use.
-Teeth and/or tongue staining may occur in some patients when administered sprinkled on applesauce.
-Patients should drink an adequate amount of fluids every day.
Four controlled clinical trials were used to assess adverse reactions to balsalazide. Greater than 1000 patients received balsalazide in these trials. The most frequently reported (3% or more) adverse reactions at the usual daily dose were headache (8%), abdominal pain (6%), diarrhea (5%), nausea (5%), vomiting (4%), respiratory infection (4%), and arthralgia (4%). Withdrawal from therapy due to adverse reactions was comparable with placebo. Adverse events also reported by at least 1% of patients but less than 3% include anorexia, back pain, constipation, cough, cramps, dizziness, dyspepsia, fatigue, fever, flatulence, flu-like symptoms, frequent stools, insomnia, musculoskeletal pain, myalgia, pain (unspecified), pharyngitis, rectal GI bleeding, rhinitis, sinusitis, urinary tract infection, and xerostomia. In rare cases, 5-ASA (mesalamine) products, such as balsalazide, can cause an acute intolerance syndrome, which may be difficult to distinguish from an ulcerative colitis exacerbation, with symptoms including abdominal pain or stomach cramps, melena, bloody diarrhea, fever, severe headache, malaise, or skin eruptions. Observe patients closely for worsening of these symptoms while on treatment. Acute intolerance syndrome occurs in approximately 3% of patients and is reversible upon discontinuation of the drug. Prompt withdrawal of balsalazide is recommended. Some patients have gone on to develop pancolitis. However, in clinical evaluations, the extension of upper disease boundary and flare-ups occurred less often in the 5-ASA-treated group vs. the placebo-treated group.
Balsalazide as well as other products metabolized to (or that contain) mesalamine have been reported in post-market use to cause rare cases of elevated hepatic enzymes, hepatitis, hyperbilirubinemia, jaundice, cholestasis with jaundice, cirrhosis, and possible hepatocellular damage including hepatic necrosis and hepatic failure. The incidence of hepatic adverse events is not known. In some cases, the reactions were fatal. One case of Kawasaki-like syndrome which included hepatic function changes was also reported, however, this adverse reaction was not reported in balsalazide clinical trials.
Hypersensitivity reactions to balsalazide may include but are not limited to the following: anaphylaxis, anaphylactoid reactions, acute bronchospasm, and skin reaction (rash). The following adverse reactions have been identified during the postmarketing use of balsalazide in clinical practice. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure; there have been reports of myocarditis, pericarditis, vasculitis, pruritus, pleural effusion, pneumonia (with or without eosinophilia or eosinophilic pneumonia), alveolitis, pancreatitis, and alopecia.
5-ASA (mesalamine) is known to be substantially excreted by the kidney, and the risk of adverse reactions to balsalazide, which is converted to mesalamine, may be greater in patients with impaired renal function. Albuminuria (proteinuria), increased urinary frequency, and hematuria were reported infrequently (i.e., less than 1%) during ulcerative colitis and Crohn's disease trials with 5-ASA (mesalamine) products. In clinical practice, reports of renal failure (unspecified), nephropathy such as minimal change syndrome and nephrotic syndrome, and acute or chronic interstitial nephritis have been associated with products that contain (or are metabolized to) mesalamine. In addition, cases of nephrogenic diabetes insipidus have been reported during postmarketing experience with mesalamine. There are no particular signals for nephropathy; evaluate renal function in all patients prior to initiation and periodically while on mesalamine therapy. Monitor patients with known renal impairment or history of renal disease or taking nephrotoxic drugs for decreased renal function and mesalamine-related adverse reactions. The risk of nephrotoxicity may be greater in patients with pre-existing renal impairment or other risk factors for decreased renal function. Patients should be made aware that urine may become discolored reddish-brown while taking 5-ASA (mesalamine) when it comes in contact with surfaces or water treated with hypochlorite-containing bleach. If urine discoloration is observed, advise patients to observe their urine flow and report to the healthcare provider only if urine is discolored on leaving the body, before contact with any surface or water (e.g., in the toilet).
Cases of nephrolithiasis have been reported with the use of mesalamine, the active moiety in balsalazide, including stones of 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment with balsalazide.
Postmarketing reports of severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), have been reported with the use of mesalamine, the active moiety in balsalazide. At the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity, discontinue balsalazide and consider further evaluation.
Balsalazide is contraindicated in patients with hypersensitivity to balsalazide or other salicylate hypersensitivity, including other 5-aminosalicylates hypersensitivity or sensitivity to balsalazide metabolites (e.g., 5-ASA or mesalamine). Patients with severe allergies or asthma should be monitored for signs of worsening symptoms. As with sulfasalazine, balsalazide-induced hypersensitivity reactions may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis, and hematologic abnormalities. Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue the drug if an alternative etiology for the signs or symptoms cannot be established. 5-ASA (mesalamine) products, such as balsalazide, have been implicated in the production of an acute intolerance syndrome characterized by worsening colitis and symptoms such as abdominal cramping, acute abdominal pain, bloody diarrhea (melena and hematochezia), fever, headache, malaise, pruritus, rash (unspecified), and conjunctivitis. In cases of acute exacerbation of disease, prompt withdrawal of balsalazide therapy is required; symptoms typically resolve after discontinuation. The patient's history of sulfasalazine intolerance, if any, should be re-evaluated.
Exacerbation of the symptoms of colitis has been noted during balsalazide therapy, which may not be distinguishable from the underlying disease. In adult clinical studies, 3 of 259 patients (i.e., roughly 1%) reported worsening of symptoms of ulcerative colitis. In pediatric studies, 4 of 68 patients (i.e., roughly 6%) reported excerebration of symptoms. Observe patients closely for worsening of these symptoms while on treatment.
Patients with pyloric stenosis or any other functional or organic upper GI obstruction can have prolonged gastric retention of balsalazide capsules, which could delay mesalamine release in the colon. Avoid in patients at risk of upper GI tract obstruction.
Evaluate renal function prior to prescribing balsalazide, and periodically during treatment. 5-ASA (mesalamine) products, such as balsalazide, are known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with renal impairment or renal failure. Monitor patients with a known history of renal disease or taking nephrotoxic drugs for decreased renal function and balsalazide-related adverse reactions. Discontinue balsalazide if renal function deteriorates while on therapy. AGA guidelines recommend the periodic monitoring of renal function in all patients.
Hepatic failure has been reported in patients with pre-existing hepatic disease who received 5-ASA (mesalamine) products, like balsalazide. Caution is advised if balsalazide is administered to a patient with hepatic disease; consider the risks and benefits of balsalazide treatment.
There is no evidence that balsalazide is associated with poor pregnancy outcomes; experts recommend that patients maintained on balsalazide pre-pregnancy continue their treatment regimens. The use of balsalazide during pregnancy appears to pose no significant harm to the developing fetus, and the maternal benefits of therapy appear to outweigh any potential for risk to the fetus. Mesalamine, the active metabolite of balsalazide, is known to cross the placental barrier. However, following administration of balsalazide, only a small portion of a dose is absorbed systemically and then is rapidly excreted in the urine. Published data from meta-analyses, cohort studies and case series on the use of mesalamine, the active metabolite of balsalazide, during pregnancy have not reliably informed an association with mesalamine and major birth defects, miscarriage, or adverse maternal or fetal outcomes. The human data include case series, controlled prospective trials, and population-based cohort studies. In animal reproduction studies, there were no adverse developmental effects observed after oral administration of balsalazide disodium in pregnant rats and rabbits during organogenesis at doses up to 2.4 and 4.7 times, respectively, the maximum recommended human dose (MRHD). Guidelines state that medical therapy for IBD does not decrease fertility.
Experts and guidelines consider balsalazide compatible for use during breast-feeding. Mesalamine, the active metabolite of balsalazide, is excreted in breast milk in small amounts. Following oral administration, only a small portion of a balsalazide dose is absorbed systemically and then is rapidly excreted in the urine. Infant diarrhea has been infrequently reported with maternal use of mesalamine during breast-feeding. Carefully monitor the nursing infant for alterations in bowel function, such as persistent changes in stool frequency. Among the 5-ASA agents, the drugs mesalamine, balsalazide, and olsalazine are preferred to sulfasalazine due to the unknown side effects of sulfasalazine's sulfapyridine metabolite, which is excreted into milk at higher concentrations than the parent drug and has hemolytic and antimicrobial properties.
Safe and effective use of balsalazide in neonates, infants and children less than 5 years of age has not been determined. Balsalazide has been shown to be safe and effective in adolescents and children 5 years and older for the treatment of ulcerative colitis.
Photosensitivity has been reported in patients receiving systemic dosage forms of 5-ASA (mesalamine), such as balsalazide. Patients should be advised to limit sunlight (UV) exposure. Patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions. Use with caution in patients with a previous history of a skin photosensitivity disorder. Instruct patients to avoid sunlight (UV) exposure and tanning booths, and to wear sunscreen (and if possible protective clothing) on exposed skin.
Cases of nephrolithiasis have been reported with the use of 5-ASA (mesalamine) products, such as balsalazide, including kidney stones of 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment with balsalazide.
Reported clinical experience has not identified differences in efficacy responses between geriatric and younger adults receiving balsalazide. Reports from uncontrolled clinical studies and postmarketing reporting systems suggest a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia, pancytopenia) in elderly subjects receiving 5-ASA (mesalamine) products such as balsalazide. Caution should be taken to closely monitor complete blood cell (CBC) and platelet counts during drug therapy. Because elderly patients are more likely to have decreased renal function, care should be taken when prescribing balsalazide.
The use of balsalazide may lead to laboratory test interference. Spuriously elevated test results may occur when measuring urinary normetanephrine by liquid chromatography with electrochemical detection, because of the similarity in the chromatograms of normetanephrine and mesalamine's main metabolite, Nacetylaminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine.
For the treatment of mildly to moderately active ulcerative colitis:
Oral dosage (capsules):
Adults: 2,250 mg (3 x 750 mg capsules) PO 3 times per day (total daily dose of 6.75 grams/day) for up to 8 weeks. Some patients in the adult clinical trials required treatment for up to 12 weeks; however, safety and effectiveness beyond 12 weeks has not been established.
Children and Adolescents 5 years and older: 2,250 mg (3 x 750 mg capsules) PO 3 times per day, for a total daily dose of 6.75 grams for 8 weeks. Alternatively, one 750 mg capsule PO 3 times per day, for a total daily dose of 2.25 grams for 8 weeks. Use in the pediatric population for more than 8 weeks has not been evaluated in clinical trials. Fifteen (45%) patients in the 6.75 grams/day group and 13 (37%) patients in the 2.25 grams/day group showed clinical improvement. Low versus higher dose balsalazide induced remission in 3/35 (9%) versus 4/33 (12%) of children, respectively. Mesalamine (5-ASA) or sulfasalazine products are preferred by guidelines given the strong evidence of efficacy of 5-ASA for both induction and maintenance of remission in mild-moderate UC, and the availability of sulfasalazine in oral dosage forms amenable for use in younger children.
Maximum Dosage Limits:
-Adults
6.75 grams/day PO.
-Geriatric
6.75 grams/day PO.
-Adolescents
6.75 grams/day PO.
-Children
5 to 12 years: 6.75 grams/day PO.
Less than 5 years: Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustments are recommended for patients with hepatic impairment ; however, monitor these patients during treatment.
Patients with Renal Impairment Dosing
Balsalazide is converted to mesalamine, which is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Dosage adjustments may be needed; however, specific guidelines for balsalazide dosage adjustments in renal impairment are not available. Discontinue balsalazide if renal function deteriorates while on therapy.
*non-FDA-approved indication
Amlodipine; Celecoxib: (Moderate) Monitor patients for signs of worsening renal function during coadministration of balsalazide and celecoxib. Coadministration may increase the risk for drug-induced nephrotoxicity. Balsalazide is converted to mesalamine in the gastrointestinal tract; nephrotoxicity has been observed during mesalamine treatment.
Azathioprine: (Moderate) 5-aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine) may interact with azathioprine and increase the risk of azathioprine-related toxicity. The inhibition of thiopurine methyltransferase activity, one of the enzymes responsible for azathioprine metabolism, by 5-aminosalicylates has been described via in vitro and in vivo study. Theoretically, this interaction could result in a higher risk of bone marrow suppression or other azathioprine dose-related side effects. If concurrent therapy cannot be avoided, closely monitor platelet and complete blood cell counts.
Celecoxib: (Moderate) Monitor patients for signs of worsening renal function during coadministration of balsalazide and celecoxib. Coadministration may increase the risk for drug-induced nephrotoxicity. Balsalazide is converted to mesalamine in the gastrointestinal tract; nephrotoxicity has been observed during mesalamine treatment.
Celecoxib; Tramadol: (Moderate) Monitor patients for signs of worsening renal function during coadministration of balsalazide and celecoxib. Coadministration may increase the risk for drug-induced nephrotoxicity. Balsalazide is converted to mesalamine in the gastrointestinal tract; nephrotoxicity has been observed during mesalamine treatment.
Dalteparin: (Moderate) Coadministration of 5-aminosalicylates and low molecular weight heparins may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of a low molecular weight heparins. If this is not possible, it is recommended to monitor patients closely for bleeding.
Enoxaparin: (Moderate) Coadministration of 5-aminosalicylates and low molecular weight heparins may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of a low molecular weight heparins. If this is not possible, it is recommended to monitor patients closely for bleeding.
Heparin: (Moderate) Coadministration of 5-aminosalicylates and heparin may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of heparin. If this is not possible, it is recommended to monitor patients closely for bleeding.
Low Molecular Weight Heparins: (Moderate) Coadministration of 5-aminosalicylates and low molecular weight heparins may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of a low molecular weight heparins. If this is not possible, it is recommended to monitor patients closely for bleeding.
Mercaptopurine, 6-MP: (Moderate) Increased myelosuppression may occur if mercaptopurine is coadministered with balsalazide. If concomitant use is necessary, use the lowest possible doses of each drug and closely monitor the patient for bone marrow suppression. 5-Aminosalicylates, such as balsalazide, have been shown to inhibit the thiopurine methyltransferase (TPMT) enzyme in vitro. Mercaptopurine is inactivated via the TPMT enzyme.
Thioguanine, 6-TG: (Moderate) Use these drugs together with caution; concomitant use may result in reduced metabolism of thioguanine via TPMT and an increased risk for thioguanine-induced toxicity. Monitor patients for signs and symptoms of hematologic and hepatic toxicity. There is in vitro evidence that 5-aminosalicylate derivatives inhibit thiopurine methyltransferase (TPMT), the enzyme that metabolizes thioguanine. Increased thioguanine concentrations can lead to an increased risk for severe thioguanine-induced myelosuppression. In cases of bone marrow suppression, a dose reduction of thioguanine may be necessary.
Warfarin: (Moderate) Increased prothrombin time in patients taking concomitant 5-aminosalicylates and warfarin has been reported. Closely monitor patients PT and INR during and following concomitant balsalazide therapy; dosage adjustments of anticoagulants may be necessary.
Balsalazide remains intact until it reaches the colon where bacterial action within the colon reduces balsalazide to the active component mesalamine (5-ASA). The exact mechanism of action of mesalamine is unknown. It is believed, however, that mesalamine blocks production of arachidonic acid metabolites in the colon. This action appears to be topical rather than systemic in nature.
Balsalazide is administered orally. Systemic absorption is very low and variable in healthy subjects. However, the primary action of the drug is local, not systemic. Once in the colon, bacterial azoreductases cleave the compound to release 5-aminosalicylic acid (5-ASA), the therapeutically active portion, and 4-aminobenzoyl-beta-alanine (4-ABA). The compounds 5-ASA and 4-ABA are further metabolized to N-acetylated metabolites (N-Ac-5-ASA and N-Ac-4-ABA). Balsalazide is 99% or more bound to human plasma proteins; 5-ASA and N-Ac-5-ASA are 43% and 78% bound, respectively. Balsalazide and its metabolites have been identified in plasma, urine, and feces. The major route of elimination is via the feces; approximately 65% of a single dose (2.25 grams/dose) has been recovered as metabolites in healthy subjects. Less than 1% of an oral dose has been recovered from the urine as parent compound. The elimination half-life cannot be determined because of large intersubject variability.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None
Balsalazide and its metabolites were not shown to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.
-Route-Specific Pharmacokinetics
Oral Route
Balsalazide capsules contain acid-insoluble balsalazide disodium granules. The effect of food on the absorption of balsalazide has been studied; data indicate that both Cmax and AUC are lower, while Tmax is markedly prolonged, when balsalazide is administered along side a high-fat meal as compared to fasting. No inference can be made as to how these systemic exposure differences predict the clinical efficacy of the drug since clinical efficacy is primarily determined by the local effects of 5-ASA on the colonic mucosa.
-Special Populations
Hepatic Impairment
Given the low systemic absorption, hepatic impairment is not expected to change the pharmacokinetic parameters of balsalazide to a clinically relevant extent. However, patients with impaired liver function should be monitored.
Renal Impairment
The mean urinary recovery of balsalazide, 5-ASA, and N-Ac-5-ASA was 0.20%, 0.22% and 10.2%, respectively; renal impairment is not expected to change the pharmacokinetic parameters to a clinically relevant extent. However, patients with impaired renal function should be monitored.
Pediatrics
In studies of pediatric patients with mild-to-moderate active ulcerative colitis receiving 6.75 grams/day, steady-state was reached within 2 weeks, similar to what is observed in adult patients. Likewise, the pharmacokinetics of balsalazide, 5-ASA, and N-Ac-5-ASA were characterized by very large interpatient variability, which is also similar to that seen in adult patients. The pro-drug moiety, balsalazide, appeared to exhibit dose-independent (i.e., dose-linear) kinetics in children, and the systemic exposure parameters (Cmax and AUC) increased in an almost dose-proportional fashion after the 6.75 grams/day versus the 2.25 grams/day doses. However, the absolute magnitude of these exposure parameters was greater relative to adults. The Cmax and AUC observed in pediatric patients were 26% and 102% greater than those observed in adult patients at the 6.75 grams/day dosage level. In contrast, the systemic exposure parameters for the active metabolites, 5-ASA and N-Ac-5-ASA, in pediatric patients increased in a less than dose-proportional manner after the 6.75 grams/day dose versus the 2.25 grams/day dose. Additionally, the magnitude of these exposure parameters was decreased for both metabolites relative to adults. For the metabolite of key safety concern from a systemic exposure perspective, 5-ASA, the Cmax and AUC observed in pediatric patients were 67% and 64% lower than those observed in adult patients at the 6.75 grams/day dosage level. Likewise, for N-Ac-5-ASA, the Cmax and AUC observed in pediatric patients were 68% and 55% lower than those observed in adult patients at the 6.75 grams/day dosage level.
Other
Systemic absorption of balsalazide can be significantly higher in ulcerative colitis patients.