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  • CLASSES

    Aminosalicyclic Acid and Related Intestinal Antiinflammatory Agents

    DEA CLASS

    Rx

    DESCRIPTION

    5-Amino derivative of salicylic acid
    Used as an anti-inflammatory agent for ulcerative colitis, ulcerative proctitis (suppository only), and Crohn's disease
    Clinical response due to local effect

    COMMON BRAND NAMES

    Apriso, Asacol HD, Canasa, Delzicol, Lialda, Pentasa, Rowasa, sfRowasa

    HOW SUPPLIED

    Apriso/Pentasa Oral Cap ER: 0.375g, 250mg, 500mg
    Asacol HD/Lialda/Mesalamine Oral Tab DR: 1.2g, 800mg
    Canasa Rectal Supp: 1000mg
    Delzicol Oral Cap DR Pellets: 400mg
    Mesalamine/Rowasa/sfRowasa Rectal Enema: 4g, 60mL

    DOSAGE & INDICATIONS

    For the treatment of active ulcerative proctitis.
    Rectal dosage (suppositories)
    Adults

    500 mg PR twice daily retained in the rectum for 1 to 3 hours or more if possible; use for 3 to 6 weeks or until remission is achieved. May increase to 500 mg PR 3 times daily if inadequate response at 2 weeks. Alternatively, 1000 mg PR (using the 1 g suppository dosage form) once daily at bedtime may be used.

    For the treatment of ulcerative colitis or Crohn's disease†.
    For induction of remission of mild to moderate active ulcerative colitis or Crohn's disease†.
    Rectal dosage (suppositories)
    Adults

    500 mg PR twice daily retained in the rectum for 1 to 3 hours or more if possible; use for 3 to 6 weeks or until remission is achieved. May increase to 500 mg PR 3 times daily if inadequate response at 2 weeks. Alternatively, 1000 mg PR (using the 1 g suppository dosage form) once daily at bedtime may be used.

    Rectal dosage (enema)
    Adults

    4 g as an enema PR retained for approximately 8 hours if possible each night; use for 3 to 6 weeks or until remission is achieved.

    Oral dosage (delayed-release tablets; i.e., Asacol HD)
    Adults

    1600 mg PO 3 times daily for 6 weeks; total daily dose is 4.8 g.

    Oral dosage (delayed-release tablets; i.e., Asacol)
    Adults

    800 mg PO 3 times daily for 6 weeks; total daily dose is 2.4 g. Asacol tablets and Asacol HD tablets are not bioequivalent; do not use interchangeably.

    Children and Adolescents 5 years and older weighing 54 to 90 kg

    27 to 44 mg/kg/day PO given in 2 divided doses (Max: 2.4 g/day). Continue therapy for 6 weeks; duration beyond 6 weeks has not been studied. In a 6-week clinical study of pediatric patients with mildly to moderately active ulcerative colitis (n = 82, age 5 to 17 years), higher doses of mesalamine (up to 4.8 g/day PO) were not more effective than lower doses. Asacol tablets and Asacol HD tablets are not bioequivalent; do not use interchangeably.

    Children and Adolescents 5 years and older weighing 33 to 53 kg

    37 to 61 mg/kg/day PO given in 2 divided doses (Max: 2 g/day). Continue therapy for 6 weeks; duration beyond 6 weeks has not been studied. In a 6-week clinical study of pediatric patients with mildly to moderately active ulcerative colitis (n = 82, age 5 to 17 years), higher doses of mesalamine (up to 4.8 g/day PO) were not more effective than lower doses. Asacol tablets and Asacol HD tablets are not bioequivalent; do not use interchangeably.

    Children 5 years and older weighing 17 to 32 kg

    36 to 71 mg/kg/day PO given in 2 divided doses (Max: 1.2 g/day). Continue therapy for 6 weeks; duration beyond 6 weeks has not been studied. In a 6-week clinical study of pediatric patients with mildly to moderately active ulcerative colitis (n = 82, age 5 to 17 years), higher doses of mesalamine (up to 4.8 g/day PO) were not more effective than lower doses. Asacol tablets and Asacol HD tablets are not bioequivalent; do not use interchangeably.

    Oral dosage (delayed-release tablets; i.e., Lialda)
    Adults

    2.4 g PO once daily or 4.8 g PO once daily with a meal. Treatment duration in controlled trials was up to 8 weeks.

    Oral dosage (controlled-release capsules: i.e., Pentasa)
    Adults

    1 g PO 4 times daily. Treatment duration in controlled trials was up to 8 weeks.

    Oral dosage (delayed-release capsules: i.e., Delzicol)
    Adults

    800 mg PO 3 times daily for 6 weeks; total daily dose is 2.4 g. Delzicol capsules and Asacol HD tablets are not bioequivalent; do not use interchangeably.

    Children and Adolescents 5 years and older weighing 54 to 90 kg

    1200 mg PO twice daily (i.e., 27 to 44 mg/kg/day PO given in 2 divided doses; Max: 2.4 g/day). Continue therapy for 6 weeks; duration beyond 6 weeks has not been studied. In a 6 week clinical study of pediatric patients with mildly to moderately active ulcerative colitis (n = 82, age 5 to 17 years), higher doses of mesalamine (up to 4.8 g/day PO) were not more effective than lower doses. Delzicol capsules and Asacol HD tablets are not bioequivalent; do not use interchangeably.

    Children and Adolescents 5 years and older weighing 33 to 53 kg

    1200 mg PO in the morning and 800 mg PO in the afternoon (i.e., 37 to 61 mg/kg/day PO given in 2 divided doses; Max: 2 g/day). Continue therapy for 6 weeks; duration beyond 6 weeks has not been studied. In a 6 week clinical study of pediatric patients with mildly to moderately active ulcerative colitis (n = 82, age 5 to 17 years), higher doses of mesalamine (up to 4.8 g/day PO) were not more effective than lower doses. Delzicol capsules and Asacol HD tablets are not bioequivalent; do not use interchangeably.

    Children 5 years and older weighing 17 to 32 kg

    800 mg PO in the morning and 400 mg PO in the afternoon (i.e., 36 to 71 mg/kg/day PO given in 2 divided doses; Max: 1.2 g/day). Continue therapy for 6 weeks; duration beyond 6 weeks has not been studied. In a 6 week clinical study of pediatric patients with mildly to moderately active ulcerative colitis (n = 82, age 5 to 17 years), higher doses of mesalamine (up to 4.8 g/day PO) were not more effective than lower doses. Delzicol capsules and Asacol HD tablets are not bioequivalent; do not use interchangeably.

    For maintenance of remission of ulcerative colitis.
    Oral dosage (extended-release capsules; i.e., Apriso)
    Adults

    1500 mg PO once daily in the morning. The duration of therapy has been as long as 6 months during clinical studies.

    Oral dosage (delayed-release tablets; i.e., Lialda)
    Adults

    2.4 g PO once daily with a meal.

    Oral dosage (delayed-release capsules; i.e., Delzicol)
    Adults

    1600 mg per day administered PO in 2 to 4 divided doses. Delzicol capsules and Asacol HD tablets are not bioequivalent; do not use interchangeably.

    Oral dosage (delayed-release tablets; i.e., Asacol)
    Adults

    1.6 g/day PO given in 2 to 4 divided doses. Asacol tablets and Asacol HD tablets are not bioequivalent; do not use interchangeably.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    4 g/day PR for rectal enema; 1.5 g/day PR for rectal suppositories. For oral products: 1.5 g/day PO for extended-release capsules (i.e., Apriso); 2.4 g/day PO for delayed-release tablets or capsules (i.e, Asacol, Delzicol); 4 g/day PO for controlled-release capsules (i.e., Pentasa); 4.8 g/day PO for delayed-release tablets (i.e., Asacol HD, Lialda).

    Geriatric

    4 g/day PR for rectal enema; 1.5 g/day PR for rectal suppositories. For oral products: 1.5 g/day PO for extended-release capsules (i.e., Apriso); 2.4 g/day PO for delayed-release tablets or capsules (i.e, Asacol, Delzicol); 4 g/day PO for controlled-release capsules (i.e., Pentasa); 4.8 g/day PO for delayed-release tablets (i.e., Asacol HD, Lialda).

    Adolescents

    Safety and efficacy established for Asacol and Delzicol brands only. Maximum dosage determined by weight:
    54—90 kg: 44 mg/kg/day PO (Max: 2.4 g/day)
    33—53 kg: 61 mg/kg/day PO (Max: 2 g/day)
    17—32 kg: 71 mg/kg/day PO (Max: 1.2 g/day)

    Children

    5—12 years: Safety and efficacy established for Asacol and Delzicol brands only. Maximum dosage determined by weight:
        54—90 kg: 44 mg/kg/day PO (Max: 2.4 g/day)
        33—53 kg: 61 mg/kg/day PO (Max: 2 g/day)
        17—32 kg: 71 mg/kg/day PO (Max: 1.2 g/day)
    < 5 years: Safety and efficacy established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available.

    Renal Impairment

    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.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Delayed release tablets (Lialda): Recommended to be administered with food. Swallow the tablet whole; do not cut, break, or chew.
    Delayed release tablets (Asacol, Asacol HD): May be administered with or without food. Swallow the tablet whole; do not cut, break, or chew.
    Extended release capsules (Apriso): Administer in the morning with or without food. Swallow the capsule whole; do not chew or crush the capsule or its contents.
    Delayed release capsules (Delzicol): May be administered without regard to food. Swallow the capsule whole; do not open, cut, break, or chew.
    Controlled-release capsules (Pentasa): 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.

    Rectal Administration

    Rectal products are for rectal use only.
     
    Rectal suspension
    Administer at bedtime. Shake well prior to administering.
    Instruct patient on proper administration of rectal suspension.
    Encourage patient to retain suspension for at least 8 hours.
     
    Rectal suppository:
    NOTE: 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.
    Instruct patient on proper use of suppository and to avoid excessive handling of the suppository.
    Do not cut or break the suppository.
    Moisten the suppository with water prior to insertion. If 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.
    Suppository should be retained in rectum for at least 1 to 3 hour to ensure maximum benefit.

    STORAGE

    Apriso:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Asacol:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Asacol HD:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Canasa:
    - Avoid direct heat and sunlight
    - Avoid excessive humidity
    - May be refrigerated
    - Store below 77 degrees F
    Delzicol:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Lialda:
    - Store between 59 to 77 degrees F, limited excursions permitted up to 86 degrees F
    Pentasa:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Rowasa:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    sfRowasa:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in a cool, well ventilated, dry place

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Use of mesalamine may lead to spuriously elevated test results 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). An alternative, selective assay for normetanephrine should be considered.

    5-aminosalicylates hypersensitivity, salicylate hypersensitivity

    All dosage forms of mesalamine, 5-ASA are 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. Mesalamine suppositories are also 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, 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.

    Renal disease, renal failure, renal impairment

    Mesalamine, 5-ASA should be used with caution in patients with renal disease because mesalamine-induced nephrotoxicity, including nephropathy and interstitial nephritis, can occur. Patients with preexisting renal disease, increased BUN or serum creatinine, or proteinuria should be carefully monitored during therapy with mesalamine and particularly closely during the initial phase of treatment. The risk for renal complications can be increased in patients receiving concomitant NSAIDs or other agents containing mesalamine such as olsalazine or sulfasalazine. Mesalamine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with renal impairment or renal failure. It is recommended that all patients have an evaluation of renal function prior to initiation of mesalamine and periodically while on therapy.

    Hepatitis, myocarditis, pericarditis, pneumonitis

    Caution should be taken when prescribing mesalamine-containing products to patients with conditions predisposing to the development of myocarditis or pericarditis. Hypersensitivity reactions presenting as internal organ involvement, including nephritis, hepatitis, pneumonitis, hematologic abnormalities, myocarditis and pericarditis, have been reported with mesalamine-containing products, including sulfasalazine. Discontinue mesalamine in patients presenting with symptoms of internal organ involvement in which an alternate etiology can not be determined. Cases of pericarditis have also been reported as manifestations of inflammatory bowel disease. In cases reported with mesalamine, 5-ASA rectal suspension enema (Rowasa), there have been positive rechallanges. Symptoms of pericarditis such as chest pain or dyspnea in patients treated with mesalamine, 5-ASA rectal suspension enema (Rowasa) should be investigated with this information in mind. Discontinuation of mesalamine may be warranted in some cases.

    Geriatric

    Clinical studies of mesalamine, 5-ASA did not include sufficient numbers of geriatric subjects to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger adults. Reports from uncontrolled clinical studies and post-marketing reporting systems suggest a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia, pancytopenia) in elderly subjects receiving mesalamine. Caution should be taken to closely monitor blood cell counts during drug therapy. Because elderly patients are more likely to have decreased renal function, care should be taken when prescribing mesalamine.

    Pregnancy

    Mesalamine is known to cross the placental barrier. However, only small amounts of mesalamine are systemically circulating in the body after cecum and colon drug absorption, 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, or both. Animal studies have revealed no evidence of harm to the fetus associated with mesalamine use. However, dibutyl phthalate (DBP), an inactive ingredient found in the enteric coating of Asacol and Asacol HD brand tablets, has been associated with external and skeletal malformations as well as other adverse effects on the male reproductive system in animal studies. These adverse effects were observed in male rat offspring that were exposed in utero to maternal DBP doses greater than 190 times the human dose based on body surface area. The reproductive anomalies were consistent with a disruption of androgenic-dependent development; female offspring were not affected. According to the manufacturer, Asacol and Asacol HD should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. In spite of these findings, several published reports describe the successful use of mesalamine products during pregnancy. In 2004, a report described the outcomes of 100 pregnancies where 5-ASA agents, including mesalamine, were used at some time during pregnancy in the treatment of various inflammatory bowel diseases; the authors of this study concluded that there was no evidence that the 5-ASA agents, used either alone or in combination, were associated with poor pregnancy outcomes. Therefore, 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.

    Breast-feeding

    According to the manufacturer, caution should be exercised when mesalamine is administered to a nursing woman. Low concentrations of mesalamine (up to 0.11 mg/L) and higher concentrations of its N-acetyl metabolite (5 to 18.1 mg/L) have been detected in human breast milk. Based on these drug concentrations, the estimated daily infant exposure ranges are 0 to 0.017 mg/kg/day and 0.75 to 2.72 mg/kg/day, respectively. Previous recommendations from the American Academy of Pediatrics classified 5-ASA, the primary active ingredient produced by balsalazide metabolism, as a drug that should be given to nursing mothers with caution; infant diarrhea has been reported with maternal use of mesalamine during breast-feeding. However, many experts consider mesalamine safe for use during breast-feeding. Carefully monitor the nursing infant of a mother receiving mesalamine therapy for alterations in bowel function, such as persistent changes in stool frequency. In addition, dibutyl phthalate (DBP), an inactive ingredient found in the enteric coating of Asacol and Asacol HD brand mesalamine tablets may pose a risk to nursing babies. This ingredient and its primary metabolite, mono-butyl phthalate (MBP), are excreted into human milk. Animal studies conducted in pregnant rats revealed that high doses of maternal DBP (more than 190 times the human dose based on body surface area) caused fetal reproductive system aberrations/malformations in male offspring. The clinical significance of this finding has not been established. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    GI obstruction, pyloric stenosis

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

    Sulfite hypersensitivity

    The Rowasa brand of mesalamine, 5-ASA rectal suspension may cause an allergic-type reaction in patients with sulfite hypersensitivity because the rectal suspension contains potassium bisulfite. Sensitivity to 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.

    Hepatic disease

    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.

    Children, infants, neonates

    Safety and effectiveness of mesalamine delayed-release tablets (Asacol) and capsules (Delzicol) have not been established in neonates, infants, and children less than 5 years of age. Safety and effectiveness of other mesalamine oral and rectal dosage forms have not been established in pediatric patients of any age. Although efficacy of mesalamine rectal suppositories have not been established in pediatric patients, a 6-week study involving 49 patients (age 5 to 17 years) found adverse reactions in this population to be similar to those observed in adults.

    Phenylketonuria

    The Apriso brand of extended-release capsules contain aspartame and may be inappropriate for patients with phenylketonuria.

    ADVERSE REACTIONS

    Severe

    pancreatitis / Delayed / 0-1.0
    GI bleeding / Delayed / 2.0
    cholecystitis / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    erythema nodosum / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    diabetes insipidus / Delayed / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    pericarditis / Delayed / Incidence not known
    increased intracranial pressure / Early / Incidence not known
    myocarditis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    myelitis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    Guillain-Barre syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known

    Moderate

    colitis / Delayed / 3.0-12.0
    constipation / Delayed / 1.0-11.0
    chest pain (unspecified) / Early / 0-3.0
    proctitis / Delayed / 0.6-1.8
    anemia / Delayed / 0-1.0
    hypotension / Rapid / 0-1.0
    palpitations / Early / 0-1.0
    sinus tachycardia / Rapid / 0-1.0
    hypertension / Early / 0-1.0
    cholangitis / Delayed / 0-0.1
    hemorrhoids / Delayed / 2.0
    migraine / Early / 2.0
    peripheral vasodilation / Rapid / 2.0
    depression / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    melena / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    thrombocytosis / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    psoriasis / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    infertility / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known

    Mild

    headache / Early / 5.0-53.0
    eructation / Early / 16.0-26.0
    abdominal pain / Early / 2.0-21.0
    dizziness / Early / 2.0-15.0
    pharyngitis / Delayed / 0-15.0
    fatigue / Early / 1.0-10.0
    sinusitis / Delayed / 0-7.0
    flatulence / Early / 4.0-6.1
    nausea / Early / 0-6.0
    rash (unspecified) / Early / 5.0-6.0
    vomiting / Early / 5.0-5.0
    diarrhea / Early / 1.7-5.0
    cough / Delayed / 0-5.0
    dyspepsia / Early / 4.0-4.0
    acne vulgaris / Delayed / 0-3.0
    pruritus / Rapid / 0-3.0
    diaphoresis / Early / 0-3.0
    urticaria / Rapid / 0-3.0
    myalgia / Early / 0-3.0
    malaise / Early / 0-3.0
    syncope / Early / 0-1.0
    alopecia / Delayed / 0-1.0
    infection / Delayed / 0-1.0
    tenesmus / Delayed / 2.0
    paresthesias / Delayed / 2.0
    fever / Early / 5.0
    rhinitis / Early / 5.0
    influenza / Delayed / 4.0
    back pain / Delayed / 5.0
    arthralgia / Delayed / 5.0
    insomnia / Early / Incidence not known
    tremor / Early / Incidence not known
    drowsiness / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    leukocytosis / Delayed / Incidence not known
    oligospermia / Delayed / Incidence not known
    weakness / Early / Incidence not known

    DRUG INTERACTIONS

    Aluminum Hydroxide: (Major) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release product with an enteric coating that dissolves at a pH of at least 6. Theoretically, the delayed-release tablets, Lialda, may interact with drugs that raise the gastric pH. The delayed-release tablets have a gastroresistant film that covers the mesalamine tablet core; the film covering delays the initial release of the 5-ASA until the tablet is exposed to a pH of at least 7.
    Aluminum Hydroxide; Magnesium Carbonate: (Major) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release product with an enteric coating that dissolves at a pH of at least 6. Theoretically, the delayed-release tablets, Lialda, may interact with drugs that raise the gastric pH. The delayed-release tablets have a gastroresistant film that covers the mesalamine tablet core; the film covering delays the initial release of the 5-ASA until the tablet is exposed to a pH of at least 7.
    Aluminum Hydroxide; Magnesium Hydroxide: (Major) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release product with an enteric coating that dissolves at a pH of at least 6. Theoretically, the delayed-release tablets, Lialda, may interact with drugs that raise the gastric pH. The delayed-release tablets have a gastroresistant film that covers the mesalamine tablet core; the film covering delays the initial release of the 5-ASA until the tablet is exposed to a pH of at least 7.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release product with an enteric coating that dissolves at a pH of at least 6. Theoretically, the delayed-release tablets, Lialda, may interact with drugs that raise the gastric pH. The delayed-release tablets have a gastroresistant film that covers the mesalamine tablet core; the film covering delays the initial release of the 5-ASA until the tablet is exposed to a pH of at least 7.
    Aluminum Hydroxide; Magnesium Trisilicate: (Major) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release product with an enteric coating that dissolves at a pH of at least 6. Theoretically, the delayed-release tablets, Lialda, may interact with drugs that raise the gastric pH. The delayed-release tablets have a gastroresistant film that covers the mesalamine tablet core; the film covering delays the initial release of the 5-ASA until the tablet is exposed to a pH of at least 7.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like proton pump inhibitors.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like proton pump inhibitors.
    Antacids: (Major) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release product with an enteric coating that dissolves at a pH of at least 6. Theoretically, the delayed-release tablets, Lialda, may interact with drugs that raise the gastric pH. The delayed-release tablets have a gastroresistant film that covers the mesalamine tablet core; the film covering delays the initial release of the 5-ASA until the tablet is exposed to a pH of at least 7.
    Aspirin, ASA; Omeprazole: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like proton pump inhibitors.
    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.
    Calcium Carbonate: (Major) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release product with an enteric coating that dissolves at a pH of at least 6. Theoretically, the delayed-release tablets, Lialda, may interact with drugs that raise the gastric pH. The delayed-release tablets have a gastroresistant film that covers the mesalamine tablet core; the film covering delays the initial release of the 5-ASA until the tablet is exposed to a pH of at least 7.
    Calcium Carbonate; Magnesium Hydroxide: (Major) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release product with an enteric coating that dissolves at a pH of at least 6. Theoretically, the delayed-release tablets, Lialda, may interact with drugs that raise the gastric pH. The delayed-release tablets have a gastroresistant film that covers the mesalamine tablet core; the film covering delays the initial release of the 5-ASA until the tablet is exposed to a pH of at least 7.
    Calcium Carbonate; Risedronate: (Major) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release product with an enteric coating that dissolves at a pH of at least 6. Theoretically, the delayed-release tablets, Lialda, may interact with drugs that raise the gastric pH. The delayed-release tablets have a gastroresistant film that covers the mesalamine tablet core; the film covering delays the initial release of the 5-ASA until the tablet is exposed to a pH of at least 7.
    Calcium; Vitamin D: (Major) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release product with an enteric coating that dissolves at a pH of at least 6. Theoretically, the delayed-release tablets, Lialda, may interact with drugs that raise the gastric pH. The delayed-release tablets have a gastroresistant film that covers the mesalamine tablet core; the film covering delays the initial release of the 5-ASA until the tablet is exposed to a pH of at least 7.
    Celecoxib: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.
    Cimetidine: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like H2-blockers.
    Dexlansoprazole: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like proton pump inhibitors.
    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.
    Digoxin: (Moderate) The prodrug of mesalamine, sulfasalazine, has been shown to decrease the oral absorption of digoxin by 20%. It is unknown whether mesalamine causes a similar interaction.
    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.
    Esomeprazole: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like proton pump inhibitors.
    Esomeprazole; Naproxen: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like proton pump inhibitors. (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.
    Etodolac: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.
    Famotidine: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like H2-blockers.
    Famotidine; Ibuprofen: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like H2-blockers. (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.
    H2-blockers: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like H2-blockers.
    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; 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: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like proton pump inhibitors.
    Lansoprazole; Naproxen: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like proton pump inhibitors. (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.
    Magnesium Hydroxide: (Major) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release product with an enteric coating that dissolves at a pH of at least 6. Theoretically, the delayed-release tablets, Lialda, may interact with drugs that raise the gastric pH. The delayed-release tablets have a gastroresistant film that covers the mesalamine tablet core; the film covering delays the initial release of the 5-ASA until the tablet is exposed to a pH of at least 7.
    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) 5-aminosalicylates (e.g., balsalazide, olsalazine, mesalamine, or sulfasalazine) may inhibit the thiopurine methyltransferase (TPMT) enzyme, leading to increased sensitivity to the myelosuppressive effects of mercaptopurine and rapid development of bone marrow suppression following initiation of treatment. These agents should be administered with caution to patients receiving concurrent mercaptopurine, 6-MP therapy.
    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; Pseudoephedrine: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.
    Naproxen; Sumatriptan: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.
    Nizatidine: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like H2-blockers.
    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: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like proton pump inhibitors.
    Omeprazole; Sodium Bicarbonate: (Major) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release product with an enteric coating that dissolves at a pH of at least 6. Theoretically, the delayed-release tablets, Lialda, may interact with drugs that raise the gastric pH. The delayed-release tablets have a gastroresistant film that covers the mesalamine tablet core; the film covering delays the initial release of the 5-ASA until the tablet is exposed to a pH of at least 7. (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like proton pump inhibitors.
    Oxaprozin: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.
    Pantoprazole: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like proton pump inhibitors.
    Piroxicam: (Minor) The concurrent use of mesalamine with known nephrotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity.
    Proton pump inhibitors: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like proton pump inhibitors.
    Rabeprazole: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like proton pump inhibitors.
    Ranitidine: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like H2-blockers.
    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: (Major) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release product with an enteric coating that dissolves at a pH of at least 6. Theoretically, the delayed-release tablets, Lialda, may interact with drugs that raise the gastric pH. The delayed-release tablets have a gastroresistant film that covers the mesalamine tablet core; the film covering delays the initial release of the 5-ASA until the tablet is exposed to a pH of at least 7.
    Sulindac: (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) There is in vitro evidence that 5-aminosalicylate derivatives (e.g., balsalazide, olsalazine, mesalazine, or sulphasalazine) inhibit thiopurine methyltransferase (TPMT), the enzyme that metabolizes thioguanine. 5-Aminosalicylates should be administered with caution to patients receiving concurrent thioguanine therapy. Increased thioguanine concentrations can lead to an increased risk for severe thioguanine-induced myelosuppression. Monitor patients for signs and symptoms of hematologic toxicity and monitor liver function, another indicator of thioguanine toxiciy. In cases of bone marrow suppression, a dose reduction of thioguanine may be necessary.
    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.
    Warfarin: (Moderate) Mesalamine may decrease the anticoagulant effects of warfarin. A 51 year-old woman on chronic warfarin 5 mg/day with stable INR values between 2 and 3 was started on mesalamine 800 mg 3 times daily for cecal ulcer. Four weeks after mesalamine was initiated she was admitted to the hospital with DVT; her INR was 0.9 and plasma warfarin concentrations were undetectable. Six days later her INR peaked at 1.7. Mesalamine was discontinued and the following day her INR was 1.8 and, after 2 days, increased to 2.1. No other causes for the event were noted. The possibility of mesalamine inhibiting warfarin anticoagulation has not been studied.

    PREGNANCY AND LACTATION

    Pregnancy

    Mesalamine is known to cross the placental barrier. However, only small amounts of mesalamine are systemically circulating in the body after cecum and colon drug absorption, 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, or both. Animal studies have revealed no evidence of harm to the fetus associated with mesalamine use. However, dibutyl phthalate (DBP), an inactive ingredient found in the enteric coating of Asacol and Asacol HD brand tablets, has been associated with external and skeletal malformations as well as other adverse effects on the male reproductive system in animal studies. These adverse effects were observed in male rat offspring that were exposed in utero to maternal DBP doses greater than 190 times the human dose based on body surface area. The reproductive anomalies were consistent with a disruption of androgenic-dependent development; female offspring were not affected. According to the manufacturer, Asacol and Asacol HD should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. In spite of these findings, several published reports describe the successful use of mesalamine products during pregnancy. In 2004, a report described the outcomes of 100 pregnancies where 5-ASA agents, including mesalamine, were used at some time during pregnancy in the treatment of various inflammatory bowel diseases; the authors of this study concluded that there was no evidence that the 5-ASA agents, used either alone or in combination, were associated with poor pregnancy outcomes. Therefore, 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.

    According to the manufacturer, caution should be exercised when mesalamine is administered to a nursing woman. Low concentrations of mesalamine (up to 0.11 mg/L) and higher concentrations of its N-acetyl metabolite (5 to 18.1 mg/L) have been detected in human breast milk. Based on these drug concentrations, the estimated daily infant exposure ranges are 0 to 0.017 mg/kg/day and 0.75 to 2.72 mg/kg/day, respectively. Previous recommendations from the American Academy of Pediatrics classified 5-ASA, the primary active ingredient produced by balsalazide metabolism, as a drug that should be given to nursing mothers with caution; infant diarrhea has been reported with maternal use of mesalamine during breast-feeding. However, many experts consider mesalamine safe for use during breast-feeding. Carefully monitor the nursing infant of a mother receiving mesalamine therapy for alterations in bowel function, such as persistent changes in stool frequency. In addition, dibutyl phthalate (DBP), an inactive ingredient found in the enteric coating of Asacol and Asacol HD brand mesalamine tablets may pose a risk to nursing babies. This ingredient and its primary metabolite, mono-butyl phthalate (MBP), are excreted into human milk. Animal studies conducted in pregnant rats revealed that high doses of maternal DBP (more than 190 times the human dose based on body surface area) caused fetal reproductive system aberrations/malformations in male offspring. The clinical significance of this finding has not been established. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: 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 NF?B, a nuclear transcription factor that regulates the transcription of many genes for pro-inflammatory proteins.

    PHARMACOKINETICS

    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.

    Oral Route

    Uncoated 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—30% of a dose is absorbed, with peak plasma concentrations achieved in 3—12 hours. Administering mesalamine delayed-release tablets with a high fat meal results in delayed absorption and increased systemic exposure.
     
    Delayed-release tablets (Asacol and Asacol HD): Two Asacol 400 mg tablets are not bioequivalent to 1 Asacol HD 800 mg tablet. 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
    After rectal administration, 5-ASA absorption is poor. Product retention time plays an important role in absorption after rectal administration; mesalamine rectal suspension is usually retained for 3.5—12 hours and the suppositories for 1—3 hours. Absorption, as measured by urine recovery, is 10%—30% and about 20% after rectal suspension and rectal suppository administration, respectively. After administration of rectal suspension, peak plasma concentrations are seen at 10—12 hours post dosing.