Giazo

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Giazo

Classes

Aminosalicyclic Acid and Related Intestinal Antiinflammatory Agents

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 forfuture 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.

Adverse Reactions
Severe

GI bleeding / Delayed / 1.0-2.0
hepatic necrosis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
bronchospasm / Rapid / Incidence not known
pancreatitis / Delayed / Incidence not known
pleural effusion / Delayed / Incidence not known
myocarditis / Delayed / Incidence not known
vasculitis / Delayed / Incidence not known
eosinophilic pneumonia / Delayed / Incidence not known
pericarditis / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
interstitial nephritis / Delayed / Incidence not known
nephrotic syndrome / Delayed / Incidence not known
nephrotoxicity / Delayed / Incidence not known
diabetes insipidus / Delayed / Incidence not known
acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known

Moderate

constipation / Delayed / 1.0-2.0
elevated hepatic enzymes / Delayed / 0-1.0
jaundice / Delayed / 0-1.0
cholestasis / Delayed / 0-1.0
hematuria / Delayed / 0-1.0
proteinuria / Delayed / 0-1.0
hepatitis / Delayed / Incidence not known
eosinophilia / Delayed / Incidence not known
nephrolithiasis / Delayed / Incidence not known

Mild

headache / Early / 8.0-8.0
abdominal pain / Early / 6.0-6.0
diarrhea / Early / 5.0-5.0
nausea / Early / 5.0-5.0
arthralgia / Delayed / 4.0-4.0
vomiting / Early / 4.0-4.0
infection / Delayed / 0-4.0
musculoskeletal pain / Early / 2.4-2.4
pharyngitis / Delayed / 1.0-2.0
sinusitis / Delayed / 1.0-2.0
dyspepsia / Early / 1.0-2.0
anorexia / Delayed / 1.0-2.0
insomnia / Early / 1.0-2.0
back pain / Delayed / 1.0-2.0
xerostomia / Early / 1.0-2.0
cough / Delayed / 1.0-2.0
rhinitis / Early / 1.0-2.0
fever / Early / 1.0-2.0
flatulence / Early / 1.0-2.0
myalgia / Early / 1.0-2.0
fatigue / Early / 1.0-2.0
dizziness / Early / 1.0-2.0
increased urinary frequency / Early / 0-1.0
rash / Early / Incidence not known
pruritus / Rapid / Incidence not known
alopecia / Delayed / Incidence not known

Common Brand Names

Colazal

Dea Class

Rx

Description

Oral diazo-bonded 5-aminosalicylate (5-ASA) prodrug; releases mesalamine (5-ASA) in colon
Capsules (e.g., Colazal) used in adult and pediatric patients 5 years and older for mild to moderately active ulcerative colitis (UC)
Improved tolerability vs. olsalazine

Dosage And Indications
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.

Dosing Considerations
Hepatic Impairment

No dosage adjustments are recommended for patients with hepatic impairment ; however, monitor these patients during treatment.

Renal Impairment

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.

Drug Interactions

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.

How Supplied

Balsalazide/Balsalazide Disodium/Colazal Oral Cap: 750mg

Maximum Dosage
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.

Mechanism Of Action

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.

Pharmacokinetics

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.

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.

Pregnancy And Lactation
Pregnancy

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.[27628] [45899] [64164] 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.[33082] [45899] [64164] 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).[33082] Guidelines state that medical therapy for IBD does not decrease fertility.[64164]

Experts and guidelines consider balsalazide compatible for use during breast-feeding.[64164] 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.[33082] 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.[45899] [64164] 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.[45899] [59766] [59767] [64164]