MESALAMINE (Generic for ASACOL HD)

Mesalamine is a 5-aminosalicylate (5-ASA). Mesalamine is used, either orally or rectally, as an anti-inflammatory agent in treating ulcerative colitis (UC). The clinical response to 5-ASA is believed to be due to a local effect. The guidelines support the use of high to standard-dose oral 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. Fewer patients on the high-to-standard doses of 5-ASA experienced relapse of their quiescent disease compared with those on lower doses (RR of relapse, 0.79; 95% CI, 0.64 to 0.97). Those with moderate symptoms of UC 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. Escalation to high-dose (i.e., more than 3 grams/day) oral with rectal 5-ASA in patients with suboptimal response to standard-dose therapy may also be beneficial. 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 corticosteroid enemas or foams. Oral mesalamine has not been consistently been demonstrated to be effective compared with placebo for induction of remission and achieving mucosal healing in patients with active Crohn's disease (CD) and should not be used to treat patients with active CD. Mesalamine is ineffective for fistulizing CD. The drug is is a safe but minimally effective medication to prevent postoperative CD recurrence; 5-ASA is of limited beneit in preventing postoperative CD but is an option (vs. no treatment) for patients with an isolated ileal resection and no risk factors for CD recurrence, or if immunosuppressive therapy (e.g., thiopurine treatment) is not warranted or is contraindicated.

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
Delayed-release tablets (Lialda):
-Recommended to be administered with food.
-Have the patient swallow the tablet whole; do not cut, break, or chew.
-Patients should drink an adequate amount of fluids each day during treatment.

Delayed-release tablets (Asacol HD):
-Take on an empty stomach, at least 1 hour before and 2 hours after a meal.
-Have the patient swallow the tablet whole; do not cut, break, or chew.
-Intact, partially intact, and tablet shells have been reported in the stool. Instruct patients to contact their physician if this occurs repeatedly.
-Patients should drink an adequate amount of fluids each day during treatment.

Extended-release capsules (Apriso):
-Administer in the morning with or without food.
-Have the patient swallow the capsule whole; do not chew or crush the capsule or its contents.
-Patients should drink an adequate amount of fluids each day during treatment.

Delayed-release capsules (Delzicol):
-May be administered without regard to food.
-Have the patient swallow the capsule whole; do not open, cut, break, or chew.
-For patients who are unable to swallow the capsules whole, carefully open the capsule (s) and swallow the contents (four 100 mg tablets). Open the number of capsules required to make up a complete dose. There are 4 tablets per capsule. Ensure all tablets per capsule are swallowed, and no tablets are retained in the mouth.
-Intact, partially intact, and tablet shells have been reported in the stool. Instruct patients to contact their physician if this occurs repeatedly.
-Patients should drink an adequate amount of fluids each day during treatment.

Controlled-release capsules (Pentasa):
-Have the patient swallow the capsule whole; do not cut, break, or chew.
-Alternatively, the capsule may be opened, and the contents may be sprinkled onto applesauce or yogurt. Consume contents immediately. The capsule contents should not be crushed or chewed.
-Patients should drink an adequate amount of fluids each day during treatment.



Rectal Administration
-Rectal products are for rectal use only.

Rectal suspension
-Administer at bedtime. Shake well before administering.
-Instruct patient on proper administration of rectal suspension.
-Encourage patient to retain suspension for at least 8 hours.

Rectal suppository
-Instruct patient on the proper use of suppository and to avoid excessive handling of the suppository.
-Do not cut or break the suppository.
-Moisten the suppository with water before insertion. If the suppository is too soft because of storage in a warm place, chill in the refrigerator for 30 minutes or run cold water over it before removing the wrapper.
-The suppository should be retained in the rectum for at least 1 to 3 hour to ensure maximum benefit.
-Mesalamine suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Wash hands after use.

Rectal irritation or proctitis, including burning, pain, and soreness, has occurred with rectal suppositories and suspension in 1.8% (Canasa) and 0.61% (Rowasa) of patients, respectively. Discontinuation of mesalamine may be required; however, most side effects are mild and transient. Rectal disorder, rectal hemorrhage, stool abnormalities, and tenesmus have been reported in 2% or more of adult patients receiving oral mesalamine in clinical trials. Hemorrhoids have also been reported with postmarketing use of oral mesalamine. Fecal incontinence, rectal bleeding, stool discoloration, and stool abnormalities (texture change) were reported infrequently (i.e., less than 1%) during ulcerative colitis and Crohn's disease trials.

Headache was the most common adverse effect seen with the oral tablets (35%) and was also reported with oral capsule use (11%), rectal suppository use (14.4%), and with rectal suspension use (53%). Dizziness has been reported from both oral (9%) and rectal (3% to 15%) administration of mesalamine. Dizziness (2% to 7%), headache (5% to 10%), and fatigue (2% to 10%) were reported in a clinical trial of pediatric patients (n = 82, age 5 to 17 years) receiving delayed-release mesalamine tablets; syncope was reported as a serious adverse reaction in 1 patient. Headache was reported in at least 5% of pediatric patients treated with mesalamine delayed-release tablets. Other central nervous system (CNS) adverse reactions reported in 2% or more of adult patients receiving oral mesalamine include migraine, nervousness, and paresthesias. CNS adverse reactions reported in 1% or less of adult patients receiving oral or rectal mesalamine include fatigue, depression, insomnia, tremor, and drowsiness. Somnolence was reported infrequently (i.e., less than 1%) during ulcerative colitis and Crohn's disease trials.

Mild alopecia has been described as 'more hair in the comb' by patients (incidence less than 1%); discontinuation of the medication due to this side effect is rare. Retreatment with mesalamine is not always associated with repeated hair loss.

Abdominal pain, nausea, and vomiting frequently are reported with oral administration of mesalamine. In clinical evaluation with oral delayed-release tablets, abdominal pain (18% to 21%), vomiting (5%), and dyspepsia (4%) occurred in adult patients at incidences higher than with placebo. Ulcerative colitis (5% to 12%), abdominal pain (2% to 10%), and diarrhea (5%) were reported in a clinical trial of 82 pediatric patients receiving delayed-release mesalamine tablets. Serious gastrointestinal adverse reactions reported in pediatric patients include ulcerative colitis (2 subjects), abdominal pain (1), decreased body mass index (1), bloody diarrhea (1), and sclerosing cholangitis (1). Abdominal pain and vomiting were reported in at least 5% of pediatric patients treated with another mesalamine delayed-release tablet form. Nausea has been reported by less than 1% to 6% of subjects in clinical trials of various dosage forms. Flatulence is commonly seen with rectal use, occurring in 6.1% of patients using rectal suspension and 5.2% of using rectal suppositories vs. approximately 4% with oral dosage forms. Additional gastrointestinal adverse reactions reported in adult patients receiving oral and rectal mesalamine include eructation (16% to 26%), constipation (1% to 11%), GI bleeding (greater than 2%), diarrhea (1.7%), abdominal distension (1.3%), anorexia (1%), and gastroenteritis (2% or more). Perforated peptic ulcer, cholecystitis, and gastritis have been reported with postmarketing use of mesalamine. Fever was also reported in 5% or more of patients receiving delayed-release mesalamine in uncontrolled studies. In rare cases, mesalamine 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 mesalamine 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 mesalamine-treated group compared to the placebo-treated group. Duodenal ulcer, dysphagia, esophageal ulceration, oral ulceration, oral moniliasis, and thirst were reported infrequently (i.e., less than 1%) during ulcerative colitis and Crohn's disease trials.

During mesalamine therapy asymptomatic, mildly elevated hepatic enzymes have been seen, with resolution to baseline levels after continued use or discontinuation of the drug. Increased GGTP, alkaline phosphatase, LDH, SGOT, SGPT, and hyperamylasemia were reported infrequently (i.e., less than 1%) during ulcerative colitis and Crohn's disease trials. Products that are metabolized to (or contain) mesalamine have been reported during postmarket use to cause rare cases of hepatitis, hyperbilirubinemia, jaundice, cholestasis with jaundice, cirrhosis, hepatotoxicity, 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-syndrome, which included hepatic changes, was also reported. Increased lipase occurred in 5% of pediatric patients who received high-dose therapy (2 to 4.8 grams/day) in a clinical trial of delayed-release mesalamine tablets; none of the patients in the low dose group (1.2 to 2.4 grams/day) experienced this increase. Pancreatitis (1%) was reported as a serious adverse reaction. Pancreatitis has also been reported in adults during postmarketing use.

Published case reports and/or spontaneous postmarketing surveillance have described rare instances of aplastic anemia, agranulocytosis (severe neutropenia), granulocytopenia, neutropenia, leukopenia, pancytopenia, thrombocytopenia, eosinophilia, or lymphadenopathy in patients receiving mesalamine therapy. Anemia was reported as a serious adverse reaction in 1 patient during a pediatric trial (n = 82) of delayed-release mesalamine tablets. Anemia was reported in at least 5% of pediatric patients treated with mesalamine delayed-release tablets. Thrombocythemia was reported infrequently (i.e., less than 1%) during ulcerative colitis and Crohn's disease trials. If the patient develops unexplained bleeding, bruising, purpura, anemia, fever or sore throat, hematological investigations should be performed. Reports from uncontrolled clinical studies and postmarketing reporting systems suggest a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia, pancytopenia) in geriatric subjects (65 years and older) receiving mesalamine vs. younger adult patients, which may also be associated with ulcerative colitis, use of interacting drugs, or reduced renal function.

Rash has been reported in 5% and 6% of pediatric and adult patients, respectively, treated with oral delayed-release mesalamine tablets; such a reaction may occur during therapy with other mesalamine formulations. Further workup may be needed in patients who develop a rash as this may be indicative of colitis exacerbation or hypersensitivity. Other dermatologic adverse reactions reported in 3% of adult patients or less receiving mesalamine include diaphoresis, pruritus, urticaria, and acne vulgaris. Psoriasis, pyoderma gangrenosum, xerosis, and erythema nodosum were reported during postmarketing surveillance. Patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions. Nail disorder, conjunctivitis, ecchymosis, and lichen planus were reported infrequently (i.e., less than 1%) during ulcerative colitis and Crohn's disease trials.

Mesalamine is known to be substantially excreted by the kidney. Albuminuria (proteinuria), increased urinary frequency, and hematuria were reported infrequently (i.e., less than 1%) during ulcerative colitis and Crohn's disease trials with 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.

Allergic or anaphylactoid reactions may occur in patients with drug or preservative sensitivities; anaphylactoid reactions have been reported with postmarketing use of mesalamine, 5-ASA. Angioedema has been identified during postmarketing use of products that contain (or are metabolized to) mesalamine, 5-ASA in clinical practice. Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with postmarketing use of mesalamine, 5-ASA. At the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity, discontinue mesalamine, 5-ASA and consider further evaluation. Mesalamine, 5-ASA is contraindicated in patients having severe salicylate hypersensitivity. Patients sensitive to sulfasalazine, balsalazide, or olsalazine also may demonstrate cross-sensitivity. Historically, some mesalamine rectal suspensions were associated with an allergic-type reaction in patients with sulfite hypersensitivity due to potassium bisulfite in the products; exposure to sulfites has caused anaphylaxis including life-threatening or less severe asthmatic episodes.

Cardiovascular and vascular adverse reactions occurring in adult patients receiving mesalamine, 5-ASA treatment include peripheral vasodilation (2% or more), chest pain (unspecified) (3%), palpitations (less than 1%), sinus tachycardia (less than 1%), hypertension (1% or less), and hypotension (less than 1%). In addition, mesalamine-induced cardiac hypersensitivity, including myocarditis and pericarditis (with chest pain (unspecified) and/or dyspnea), increased intracranial pressure (intracranial hypertension), T-wave abnormalities, and pericardial effusion have been reported during postmarketing surveillance. Edema and pulmonary infiltrates were reported infrequently (i.e., less than 1%) during ulcerative colitis and Crohn's disease trials.

The following pulmonary adverse reactions have been identified during postmarketing use of products that contain (or are metabolized to) mesalamine, 5-ASA in clinical practice: interstitial lung disease, pleurisy/pleuritis, and hypersensitivity pneumonitis (including allergic alveolitis, eosinophilic pneumonitis, and interstitial pneumonitis). Cases of fibrosing alveolitis (pulmonary fibrosis) have been reported as well, but may be manifestations of inflammatory bowel disease. Guillain-Barre syndrome, peripheral neuropathy, transverse myelitis have been reported as neurological adverse events to mesalamine, 5-ASA; weakness, numbness, and tingling may be reported. Cases of lupus-like symptoms have also been reported. Any of these complications, if drug-induced, usually require discontinuation of the drug.

Naso-pharyngitis (12% to 15%), sinusitis (0% to 7%), and cough (0% to 5%) were reported in a clinical trial of pediatric patients (n = 82, age 5 to 17 years) who received delayed-release mesalamine tablets. Adenovirus infection (1 patient) and sinusitis (1 patient) were reported as serious adverse reactions. Influenza or influenza-like syndrome and rhinitis were reported in 4% or more of adult patients receiving mesalamine. Upper respiratory tract infection and viral infection were reported in at least 5% of pediatric patients treated with another mesalamine delayed-release tablet form.

Musculoskeletal adverse reactions reported in 5% or more of adult patients receiving mesalamine, 5-ASA include pain, back pain, asthenia, and arthralgia. Myalgia, malaise, and arthritis were reported in 3% or less of adult patients. Leg cramps were reported infrequently (i.e., less than 1%) during ulcerative colitis and Crohn's disease trials.

Menorrhagia was reported infrequently (i.e., less than 1%) during ulcerative colitis and Crohn's disease trials with mesalamine, 5-ASA. An adverse effect of mesalamine on fertility has not been noted.

Reversible oligospermia in men has been identified during postmarketing use of products that contain (or are metabolized to) mesalamine, 5-ASA in clinical practice. Guidelines have not noted an adverse effect of mesalamine on fertility.

Cases of nephrolithiasis have been reported with the use of mesalamine, 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 mesalamine.

Mesalamine, 5-ASA is contraindicated in patients with salicylate hypersensitivity. Patients sensitive to sulfasalazine, balsalazide, or olsalazine also may demonstrate cross-sensitivity; therefore, do not use in patients with a history of 5-aminosalicylates hypersensitivity. As with sulfasalazine, mesalamine-induced hypersensitivity reactions may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis, and hematologic abnormalities. Serious rash including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue mesalamine if an alternative etiology for the signs or symptoms cannot be established. Mesalamine suppositories are contraindicated in patients who have demonstrated hypersensitivity to the suppository vehicle (saturated vegetable fatty acid esters; Hard Fat, NF). Mesalamine has 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 rare cases, pancolitis has occurred. In cases of acute exacerbation of disease, prompt withdrawal of mesalamine therapy is required; symptoms typically resolve after discontinuation. The patient's history of sulfasalazine intolerance, if any, should be re-evaluated.

Hepatic failure has been reported in patients with pre-existing hepatic disease who received mesalamine. Caution is advised if mesalamine is administered to a patient with hepatic disease; consider the risks and benefits of mesalamine treatment.

Evaluate renal function prior to prescribing mesalamine, 5-ASA, and periodically during treatment. Mesalamine is 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 mesalamine-related adverse reactions. Mesalamine-induced nephrotoxicity, including nephropathy and interstitial nephritis, can occur.

Patients with pyloric stenosis or any other functional or organic upper GI obstruction can have prolonged gastric retention of mesalamine, 5-ASA delayed-release tablets or capsules, which could delay release in the colon. Avoid in patients at risk of upper GI tract obstruction.

Reported clinical experience has not identified differences in efficacy responses between older and younger adults receiving mesalamine. Reports from uncontrolled clinical studies and postmarketing reporting systems suggest a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia, pancytopenia) in geriatric subjects (65 years and older) receiving mesalamine vs. younger adult patients, which may also be associated with ulcerative colitis, use of interacting drugs, or reduced renal function. Caution should be taken to closely monitor complete blood cell (CBC) and platelet counts during drug therapy, especially if the patient is also taking anticoagulants. Because older adult patients are more likely to have decreased renal function, care should be taken when prescribing mesalamine.

There is no evidence that mesalamine is associated with poor pregnancy outcomes; experts recommend that patients maintained on mesalamine pre-pregnancy continue their treatment regimens. The use of mesalamine during pregnancy appears to pose no significant harm to the developing fetus, and the maternal benefits of therapy may outweigh any potential for risk to the fetus. Mesalamine is known to cross the placental barrier. However, only small amounts of mesalamine are systemically circulating in the body, and most of any systemically available drug is rapidly excreted in the urine. Published human data (including case series, prospective controlled studies, and population-based cohorts) suggest no increase risk of congenital malformations with mesalamine use. Data from some studies have shown an increased rate of preterm birth, stillbirth, and low birth weight; however, it is not certain whether these adverse outcomes are attributable to mesalamine therapy, underlying inflammatory bowel disease (IBD), or both. Animal studies have revealed no evidence of harm to the fetus from mesalamine. Dibutyl phthalate (DBP), which was an ingredient in some products historically, has been associated with external and skeletal malformations as well as other adverse effects on the male reproductive system in animal studies; the reproductive anomalies were consistent with a disruption of androgenic-dependent development by the phthalates; female offspring were not affected. All mesalamine preparations are now phthalate-free. Guidelines state that medical therapy for IBD, including mesalamine, does not decrease fertility.

Experts and guidelines consider mesalamine compatible and safe for use during breast-feeding. In published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to 3 grams daily. The concentration of mesalamine in milk ranged from non-detectable to 0.11 mg/L. The concentration of the N-acetyl-5-aminosalicylic acid metabolite ranged from 5 to 18.1 mg/L. Based on these concentrations, estimated infant daily doses for an exclusively breastfed infant are 0 to 0.017 mg/kg/day of mesalamine and 0.75 to 2.72 mg/kg/day of N-acetyl-5-aminosalicylic acid. Carefully monitor the nursing infant for alterations in bowel function, such as persistent changes in stool frequency. Infant diarrhea has been infrequently reported with maternal use of mesalamine during breast-feeding. Among the 5-ASA agents, the drugs mesalamine, balsalazide, and olsalazine are preferred to sulfasalazine due to the unknown side effects of sulfasalzine's sulfapyridine metabolite, which is excreted into milk at higher concentrations than the parent drug and has hemolytic and antimicrobial properties.

Photosensitivity has been reported in patients receiving systemic dosage forms of mesalamine. 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.

Mesalamine has been used in children 4 years and older with inflammatory bowel disease (ulcerative colitis); selection of a dosage form that is age-appropriate is required for treatment. Mesalamine delayed-release capsule (Delzicol) and mesalamine delayed-release tablet (Lialda) use in pediatric patients is supported by well-controlled trials in patients aged 5 to 17 years of age. Other mesalamine oral and rectal dosage forms have not been formally approved for use in pediatric patients, infants, or neonates. As with adults, there is little evidence of efficacy for the use of mesalamine in inducing or maintaining remission in pediatric patients with Crohn's disease.

The use of mesalamine 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.

The Apriso brand of mesalamine extended-release capsules and some of the equivalent generics to this product contain aspartame, which is a source of phenylalanine. These specific products should be used with caution in patients with phenylketonuria.

Some mesalamine oral products contain iron oxide (ferric oxide) as a colorant. Before prescribing these mesalamine delayed-release dosage forms to patients receiving iron supplementation or those at risk of developing iron overload (e.g., hemochromatosis, chronic transfusional iron overload), consider the combined daily amount of iron from all sources, including the mesalamine product.

Some mesalamine, 5-ASA rectal suspensions may cause an allergic-type reaction in patients with sulfite hypersensitivity. Some of the rectal suspensions contain potassium metabisulfite. Sensitivity to such sulfites appears to be increased in asthmatic compared with non-asthmatic patients. Exposure to sulfites has caused anaphylaxis including life-threatening or less severe asthmatic episodes. Sulfite-free formulas are also available for product selection.

Cases of nephrolithiasis have been reported with the use of mesalamine, 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 mesalamine.

For the treatment of mildly to moderately active ulcerative colitis:
Oral dosage (delayed-release capsules; Delzicol and generic equivalents):
Adults: 800 mg PO 3 times daily for 6 weeks, then 800 mg PO twice daily or 400 mg PO 4 times daily.
Children and Adolescents 5 to 17 years weighing 54 to 90 kg: 1,200 mg PO twice daily (Dose range: 27 to 44 mg/kg/day) for 6 weeks. Safety and effectiveness beyond 6 weeks have not been established.
Children and Adolescents 5 to 17 years weighing 33 to 53 kg: 1,200 mg PO once daily in the morning and 800 mg PO once daily in the afternoon (Dose range: 37 to 61 mg/kg/day) for 6 weeks. Safety and effectiveness beyond 6 weeks have not been established.
Children and Adolescents 5 to 17 years weighing 17 to 32 kg: 800 mg PO once daily in the morning and 400 mg PO once daily in the afternoon (Dose range: 36 to 71 mg/kg/day) for 6 weeks. Safety and effectiveness beyond 6 weeks have not been established.
Oral dosage (delayed-release tablets; Asacol HD and generic equivalents):
Adults: 1.6 g PO 3 times daily for 6 weeks. Safety and effectiveness beyond 6 weeks have not been established.
Oral dosage (delayed-release tablets; Lialda and generic equivalents):
Adults: 2.4 to 4.8 g PO once daily, initially, then 2.4 g PO once daily.
Children and Adolescents 5 to 17 years weighing more than 50 kg: 4.8 g PO once daily for 8 weeks, then 2.4 g PO once daily.
Children and Adolescents 5 to 17 years weighing 36 to 50 kg: 3.6 g PO once daily for 8 weeks, then 2.4 g PO once daily.
Children and Adolescents 5 to 17 years weighing 24 to 35 kg: 2.4 g PO once daily for 8 weeks, then 1.2 g PO once daily.
Oral dosage (extended-release capsules; Apriso and generic equivalents):
Note: Mesalamine extended-release capsules are indicated for the maintenance of remission of ulcerative colitis.
Adults: 1.5 g PO once daily in the morning.
Oral dosage (extended-release capsules; Pentasa and generic equivalents):
Adults: 1 g PO 4 times daily. Treatment duration in controlled trials was up to 8 weeks.
Rectal dosage (enema):
NOTE: Mesalamine enema is indicated for mildly to moderately active distal ulcerative colitis.
Adults: 1 to 4 g rectally once daily at bedtime for 3 to 6 weeks. Safety and effectiveness beyond 6 weeks have not been established.

For the treatment of active ulcerative proctitis:
Rectal dosage (enema):
Adults: 1 to 4 g rectally once daily at bedtime for 3 to 6 weeks. Safety and effectiveness beyond 6 weeks have not been established. Guidelines suggest enemas rather than oral mesalamine in persons with left-sided mild to moderate ulcerative proctosigmoiditis or proctitis.
Rectal dosage (suppository):
Adults: 1 g rectally once daily at bedtime for 3 to 6 weeks. Safety and effectiveness beyond 6 weeks have not been established. Guidelines suggest suppositories rather than oral mesalamine in persons with left-sided mild to moderate ulcerative proctosigmoiditis or proctitis.

Maximum Dosage Limits:
-Adults
4 grams/day PR for rectal enema; 1 gram/day PR for rectal suppositories. For oral products: 1.5 grams/day PO for extended-release capsules (i.e., Apriso); 2.4 grams/day PO for delayed-release tablets or capsules (i.e, Delzicol); 4 grams/day PO for controlled-release capsules (i.e., Pentasa); 4.8 grams/day PO for delayed-release tablets (i.e., Asacol HD, Lialda).
-Geriatric
4 grams/day PR for rectal enema; 1 gram/day PR for rectal suppositories. For oral products: 1.5 grams/day PO for extended-release capsules (i.e., Apriso); 2.4 grams/day PO for delayed-release tablets or capsules (i.e, Delzicol); 4 grams/day PO for controlled-release capsules (i.e., Pentasa); 4.8 grams/day PO for delayed-release tablets (i.e., Asacol HD, Lialda).
-Adolescents
Delzicol - Maximum dosage determined by weight:
54 to 90 kg: 44 mg/kg/day PO (Max: 2.4 grams/day)
33 to 53 kg: 61 mg/kg/day PO (Max: 2 grams/day)
17 to 32 kg: 71 mg/kg/day PO (Max: 1.2 grams/day)

Lialda - Maximum dosage determined by weight:
More than 50 kg: 4.8 grams/day PO
More than 35 kg to 50 kg: 3.6 grams/day PO
24 kg to 35 kg: 2.4 grams/day PO
-Children
5 to 12 years: Maximum dosage determined by weight and product chosen:
Delzicol
54 to 90 kg: 44 mg/kg/day PO (Max: 2.4 grams/day)
33 to 53 kg: 61 mg/kg/day PO (Max: 2 grams/day)
17 to 32 kg: 71 mg/kg/day PO (Max: 1.2 grams/day)

Lialda
More than 50 kg: 4.8 grams/day PO
More than 35 kg to 50 kg: 3.6 grams/day PO
24 kg to 35 kg: 2.4 grams/day PO


1 to 4 years: Safety and efficacy have not been established; off-label use reported for some formulations in children as young as 4 years of age.
-Infants
Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available.

Patients with Renal Impairment Dosing
Mesalamine 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 dosage adjustments in renal impairment are not available.

*non-FDA-approved indication

Aluminum Hydroxide: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Amlodipine; Celecoxib: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Antacids: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Ardeparin: (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.

Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

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.

Bupivacaine; Meloxicam: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Calcium Carbonate: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Calcium Carbonate; Magnesium Hydroxide: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Calcium Carbonate; Risedronate: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Calcium Carbonate; Simethicone: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Calcium; Vitamin D: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Celecoxib: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Celecoxib; Tramadol: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Clindamycin: (Moderate) Concomitant use of mesalamine and clindamycin may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.

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.

Diclofenac: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Diclofenac; Misoprostol: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Diflunisal: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Diphenhydramine; Ibuprofen: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Diphenhydramine; Naproxen: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

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.

Etodolac: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Fenoprofen: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Flurbiprofen: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

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.

Hydrocodone; Ibuprofen: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Ibuprofen: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Ibuprofen; Famotidine: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Ibuprofen; Oxycodone: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Ibuprofen; Pseudoephedrine: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Indomethacin: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Ketoprofen: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Ketorolac: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Lansoprazole; Naproxen: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

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.

Magnesium Hydroxide: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Meclofenamate Sodium: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Mefenamic Acid: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Meloxicam: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Mercaptopurine, 6-MP: (Moderate) Increased bone marrow suppression may occur if mercaptopurine is coadministered with mesalamine. If concomitant use is necessary, use the lowest possible doses of each drug and closely monitor the patient for myelosuppression. 5-Aminosalicylates, such as mesalamine, have been shown to inhibit the thiopurine methyltransferase (TPMT) enzyme in vitro. Mercaptopurine is inactivated via the TPMT enzyme.

Nabumetone: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Naproxen: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Naproxen; Esomeprazole: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Naproxen; Pseudoephedrine: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Nonsteroidal antiinflammatory drugs: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Omeprazole; Sodium Bicarbonate: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Oxaprozin: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Piroxicam: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Porfimer: (Major) Avoid coadministration of porfimer with mesalamine due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like mesalamine may increase the risk of a photosensitivity reaction.

Rofecoxib: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Sodium Bicarbonate: (Moderate) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release capsule product with an enteric coating that dissolves at a pH of at least 6. Other mesalamine products do not have an interaction with antacids.

Sulindac: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Sumatriptan; Naproxen: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

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.

Tinzaparin: (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.

Tolmetin: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Valdecoxib: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.

Verteporfin: (Moderate) Use caution if coadministration of verteporfin with mesalamine is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like mesalamine may increase the risk of a photosensitivity reaction.

Voclosporin: (Moderate) Concomitant use of voclosporin and mesalamine may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.

Warfarin: (Moderate) Mesalamine may alter the anticoagulant effects of warfarin. Closely monitor a patient's PT and INR during and following concomitant mesalamine therapy; dosage adjustments of anticoagulants may be necessary. In elderly patients taking mesalamine with anticoagulants, consider regularly monitoring complete blood cell counts and platelet counts, as an increased risk for blood dyscrasia has been reported in geriatric adults. In a published case study, a decreased effect of warfarin was reported when mesalamine was prescribed. Iincreased prothrombin time (PT) in patients taking concomitant warfarin has been reported during mesalamine treatment.

The antiinflammatory actions of mesalamine are believed to be secondary to, at least in part, the inhibition of arachidonic acid in the bowel mucosa by the enzyme cyclooxygenase. Inhibition of cyclooxygenase effectively diminishes the production prostaglandins, thereby reducing colonic inflammation. Production of these arachidonic metabolites appears to be increased in patients with inflammatory bowel disease. Mesalamine also interferes with leukotriene synthesis, possibly by inhibiting the lipoxygenase enzyme. In support of prostaglandins as a mediator for inflammatory bowel disease are reports of disease exacerbation after oral administration of misoprostol. However, specific inhibitors of prostaglandin and leukotriene synthesis, respectively, are less effective than mesalamine and related compounds. Thus, the exact mechanism of action of mesalamine is as yet uncertain.

Inhibition of colonic mucosal sulfidopeptide leukotriene synthesis and chemotactic stimuli for polymorphonuclear leukocytes also may occur. Mesalamine inhibits accumulation of thromboxane A and superoxide formation in the rectal mucosa, which may contribute to its antiinflammatory action. Other possible mechanisms include alterations in colonic fluid balance, immunosuppression, and alteration of the GI bacterial flora. Recent data also support the mechanism that mesalamine may inhibit the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), a nuclear protein complex that controls transcription of DNA, cytokine and other pro-inflammatory protein production, and cell survival.

Mesalamine (5-ASA) is administered by rectal suspension or suppository, or by oral delayed-release tablets or capsules. The clinical response of 5-ASA is believed to be due to a local effect. Therefore, mesalamine preparations are designed to deliver drug to the large bowel where its therapeutic action is driven by intestinal lumen absorption. Following administration, 5-ASA absorption is variable and highly dependent on disease activity and colonic pH. Altered mucosal uptake of 5-ASA can occur during periods of active disease when local inflammation causes histological changes to the mucosa as well as epithelial damage and increased blood flow. In addition, as luminal pH drops across the gastric mucosa so does 5-ASA absorption. Mesalamine may be distributed to the kidneys, but the overall distribution is uncertain. Mesalamine is acted upon by N-acetyltransferse in the liver and intestinal mucosa to produce N-acetylsalicylic acid (N-acetyl-5-ASA). The activity of N-acetyl-5-ASA, the major metabolite, is unknown. Any systemically absorbed mesalamine is eliminated from plasma mainly by urinary excretion, predominantly as N-acetyl-5-ASA; less than 8% of the absorbed dose is excreted unchanged in the urine. The mean elimination half-life at steady-state for both mesalamine and N-acetyl-5-ASA is 7-12 hours. Absorbed 5-ASA does not accumulate in plasma with repeated daily dosing.

Affected cytochrome P450 isoenzymes and drug transporters: thiopurine methyltransferase (TPMT)
Aminosalicylates, such as mesalamine, have been shown to inhibit the TPMT enzyme in vitro. The inhibition of TPMT activity could result in a higher risk of bone marrow suppression or other dose-related side effects of drugs that are metabolized by this enzyme.


-Route-Specific Pharmacokinetics
Oral Route
Uncoated mesalamine tablets are absorbed extensively in the proximal portion of the GI tract; therefore, delayed-release tablets are used to achieve a local effect in the colon. After oral administration, 20% to 30% of a dose is absorbed, with peak plasma concentrations achieved in 3 to 12 hours. Administering mesalamine delayed-release tablets with a high-fat meal results in delayed absorption and increased systemic exposure. In a single-dose pharmacokinetic study in healthy volunteers, the mean mesalamine Cmax and AUC were 36% and 25% lower, respectively, after administration of 1 Asacol HD 800 mg tablet compared to 2 Asacol 400 mg tablets. Due to the topical mechanism of mesalamine, the clinical effects of this difference in systemic exposure is not known.

Other Route(s)
Rectal Route
-Mesalamine rectal suspension: The extent of absorption is dependent upon the retention time of the drug product, and there is considerable individual variation. At steady-state, approximately 10% to 30% of the daily 4-gram dose can be recovered in cumulative 24-hour urine collections.
-Mesalamine rectal suppository: Mesalamine rectal suppository is variably absorbed. In patients with ulcerative colitis treated with mesalamine 500 mg rectal suppositories given once every 8 hours for 6 days, the mean mesalamine peak plasma concentration (Cmax) was 353 ng/mL (CV=55%) following the initial dose and 361 ng/mL (CV = 67%) at steady state. The mean minimum steady-state plasma concentration (Cmin) was 89 ng/mL (CV = 89%). Any absorbed mesalamine does not accumulate in the plasma.


-Special Populations
Pediatrics
In pediatric patients 5 years to 17 years of age diagnosed with ulcerative colitis, systemic exposure of mesalamine, as measured by mean steady-state AUC and Cmax, increased in a dose-proportional manner between 30 and 60 mg/kg/day PO of mesalamine delayed-release tablets and increased in a less than proportional manner between 60 and 100 mg/kg/day doses. Pharmacokinetic parameters had moderate to high inter-subject variability with CV% ranging from 36% to 52% in pediatric patients. The overall systemic exposure of mesalamine following oral administration of 4.8 grams once daily for 7 days in a limited number of pediatric patients 5 years to 17 years of age (AUC range of 30,556 to 50,388 ng x hour/mL, n = 3) was a similar range to that was observed in the healthy adults (AUC of 41,434 +/- 26,640 ng x hour/mL, n = 48) after single-dose administration. The mean renal clearance (CLR) of mesalamine in pediatric patients (range approximately 5 to 6.5 L/hour) seems to be similar to that observed with healthy adult subjects after multiple-dose administration.