5-Aminosalicylic acid derivatives appear to diminish inflammation by inhibiting cyclo-oxygenase and lipoxygenase, hence decreasing the production of prostaglandins, leukotrienes and hydroxyeicosatetraenoic acids (HETEs). It also appears to act as a scavenger of oxygen-derived free radicals, produced in greater numbers in those with inflammatory bowel disease.

Pharmacologic Category

5-Aminosalicylic Acid Derivative

Dosing: Adult

Treatment of ulcerative colitis: Oral: Usual course of therapy is 3-8 weeks:

Capsule (Pentasa®): 1 g 4 times/day; Note: Apriso™ capsules are approved for maintenance of remission only.

Tablet: Initial:

Asacol®: 800 mg 3 times/day for 6 weeks

Asacol® HD: 1.6 g 3 times/day for 6 weeks

Lialda™, Mezavant®: 2.4-4.8 g once daily for up to 8 weeks

Maintenance of remission of ulcerative colitis: Oral:

Capsule:

Apriso™: 1.5 g once daily in the morning

Pentasa®: 1 g 4 times/day

Tablet (Asacol®): 1.6 g/day in divided doses; Note: Asacol® HD, Lialda™ and Mezavant® tablets are approved for treatment only.

Active mild-to-moderate distal ulcerative colitis, proctosigmoiditis, or proctitis: Retention enema: 60 mL (4 g) at bedtime, retained overnight, approximately 8 hours

Active ulcerative proctitis: Rectal suppository (Canasa®): Insert one 1000 mg suppository in rectum daily at bedtime; retained for at least 1-3 hours to achieve maximum benefit

Note: Duration of rectal therapy is 3-6 weeks; some patients may require rectal and oral therapy concurrently.

Dosing: Geriatric

Refer to adult dosing

Administration

Oral: Swallow capsules or tablets whole, do not break, chew, or crush.

Apriso™: Administer with or without food; do not administer with antacids

Asacol®: Do not break outer coating.

Asacol® HD: Do not break outer coating; administer with or without food.

Lialda™: Do not break outer coating; should be administered once daily with a meal

Mezavant®: Do not break outer coating; should be administered once daily with a meal

Rectal enema: Shake bottle well. Retain enemas for 8 hours or as long as practical.

Suppository: Remove foil wrapper; avoid excessive handling. Should be retained for at least 1-3 hours to achieve maximum benefit.

Use;

Oral:

Asacol®, Pentasa®: Treatment and maintenance of remission of mildly- to moderately-active ulcerative colitis

Apriso™: Maintenance of remission of ulcerative colitis

Asacol® HD: Treatment of moderately-active ulcerative colitis

Lialda™: Treatment of mildly- to moderately-active ulcerative colitis

Rectal: Treatment of active mild-to-moderate distal ulcerative colitis, proctosigmoiditis, or proctitis

Adverse Reactions Significant

Adverse effects vary depending upon dosage form. Incidence usually on lower end with enema and suppository dosage forms.

>10%:

Central nervous system: Headache (2% to 35%), pain (≤14%)

Gastrointestinal: Abdominal pain (1% to 18%), eructation (16%), nausea (3% to 13%)

Respiratory: Pharyngitis (11%)

1% to 10%:

Cardiovascular: Chest pain (3%), peripheral edema (3%), vasodilation (≥2%)

Central nervous system: Dizziness (2% to 8%), fever (1% to 6%), chills (3%), malaise (2% to 3%), fatigue (<3%), vertigo (<3%), anxiety (≥2%), migraine (≥2%), nervousness (≥2%), insomnia (2%),

Dermatologic: Rash (1% to 6%), pruritus (1% to 3%), alopecia (<3%), acne (1% to 2%)

Endocrine & metabolic: Triglyceride increased (<3%)

Gastrointestinal: Diarrhea (2% to 8%), dyspepsia (1% to 6%), flatulence (1% to 6%), constipation (5%), vomiting (1% to 5%), colitis exacerbation (1% to 3%), rectal bleeding (<3%), abdominal distention (≥2%), gastroenteritis (≥2%), gastrointestinal bleeding (≥2%), stool abnormalities (≥2%), tenesmus (≥2%), rectal pain (1% to 2%), hemorrhoids (1%)

Genitourinary: Polyuria (≥2%)

Hematologic: Hematocrit/hemoglobin decreased (<3%)

Hepatic: Cholestatic hepatitis (<3%), transaminases increased (<3%), ALT increased (1%)

Local: Pain on insertion of enema tip (1%)

Neuromuscular & skeletal: Back pain (1% to 7%), arthralgia (≤5%), hypertonia (5%), myalgia (3%), paresthesia (≥2%), weakness (≥2%), arthritis (2%), leg/joint pain (2%)

Ocular: Vision abnormalities (≥2%), conjunctivitis (2%)

Otic: Tinnitus (<3%), ear pain (≥2%)

Renal: Creatinine clearance decreased (<3%), hematuria (<3%)

Respiratory: Nasopharyngitis (1% to 4%), dyspnea (<3%), bronchitis (≥2%), sinusitis (≥2%), cough (≤2%)

Miscellaneous: Flu-like syndrome (1% to 5%), infection (≥2%), diaphoresis (3%), intolerance syndrome (3%)

<1% (Limited to important or life-threatening): Agranulocytosis, albuminuria, alkaline phosphatase increased, anxiety, anemia, angioedema, aplastic anemia, asthma exacerbation, bilirubin increased, bloody diarrhea, BUN increased, cholestatic jaundice, cholecystitis, drug fever, dysuria, edema, eosinophilia, eosinophilic pneumonia, erythema nodosum, facial edema, fibrosing alveolitis, gastrointestinal bleeding, GGT increased, granulocytopenia, Guillain-Barré syndrome, hepatic failure, hepatic necrosis, hepatitis, hepatocellular damage, hepatotoxicity, hypersensitivity pneumonitis, hyper-/hypotension, interstitial nephritis, interstitial pneumonia, jaundice, Kawasaki-like syndrome, LDH increased, leukopenia, lupus-like syndrome, lymphadenopathy, metrorrhagia, minimal change nephrotic syndrome, myocarditis, nephropathy, nephrotoxicity, neutropenia, oligospermia, palpitation, pancreatitis, pancytopenia, paresthesia, perforated peptic ulcer, pericardial effusion, pericarditis, peripheral neuropathy, pharyngolaryngeal pain, photosensitivity, pleuritis, pneumonitis, pyoderma gangrenosum, rectal polyp, renal failure, serum creatinine increased, systemic lupus erythematosus, tachycardia, tenesmus, thrombocythemia, thrombocytopenia, transverse myelitis, T-wave abnormalities, vasodilation

Contraindications

Hypersensitivity to mesalamine, aminosalicylates, salicylates, or any component of the formulation

Warnings/Precautions

Concerns related to adverse effects:

• Abdominal discomfort: Pancreatitis should be considered in patients with new abdominal discomfort.

• Cardiac effects: Pericarditis or myocarditis have been reported with use and should be considered in patients with chest pain. Use with caution in patients predisposed to these conditions.

• Colitis: Symptomatic worsening of colitis/IBD may occur following initiation of therapy.

• Intolerance syndrome: May cause an acute intolerance syndrome (cramping, acute abdominal pain, bloody diarrhea; sometimes fever, headache, rash); discontinue if this occurs.

• Oligospermia: In males, oligospermia (rare, reversible) has been reported.

• Sulfasalazine hypersensitivity: Patients with hypersensitivity to sulfasalazine may react to mesalamine; although usually well-tolerated in this population, use with caution.

Disease-related concerns:

• Hepatic impairment: Use caution in patients with hepatic dysfunction; hepatic failure has been reported.

• Peptic ulcer: Use with caution in patients with active peptic ulcers.

• Pyloric stenosis: Patients with pyloric stenosis may have prolonged gastric retention of tablets, delaying the release of mesalamine in the colon.

• Renal impairment: Use with caution in patients with renal impairment or a history of renal disease. Renal disease (including minimal change nephropathy, acute/chronic interstitial nephritis, nephrotic syndrome, and rarely renal failure) has been reported; use caution with other medications converted to mesalamine. An evaluation of renal function is recommended prior to initiation of mesalamine products and periodically during treatment.

Special populations:

• Elderly: Use with caution in the elderly; postmarketing reports suggest an increased incidence of blood dyscrasias in patients >65 years of age. In addition, elderly may have difficulty administering and retaining rectal suppositories or may have decreased renal function.

Dosage form specific issues:

• Apriso™: Contains phenylalanine.

• Asacol®: The Asacol® HD 800 mg tablet has not been shown to be bioequivalent to 2 Asacol® 400 mg tablets.

• Canasa® suppositories: Contain saturated vegetable fatty acid esters (contraindicated in patients with allergy to these components).

• Rowasa® enema: Contains potassium metabisulfite; may cause severe hypersensitivity reactions (ie, anaphylaxis) in patients with sulfite allergies.

Drug Interactions

(For additional information: Launch Lexi-Interact™ Drug Interactions Program )

Antacids: May diminish the therapeutic effect of Mesalamine. Antacid-mediated increases in gastrointestinal pH may cause the premature release of mesalamine from specific sustained-release mesalamine products. Management: Avoid concurrent administration of antacids with sustained-release mesalamine products. Separating antacid and mesalamine administration, and/or using lower antacid doses may be adequate means of avoiding this interaction. Risk D: Consider therapy modification

Cardiac Glycosides: 5-ASA Derivatives may decrease the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

H2-Antagonists: May diminish the therapeutic effect of Mesalamine. Histamine H2-Antagonist-mediated increases in gastrointestinal pH may cause the premature release of mesalamine from specific sustained-release mesalamine products. Management: Consider avoiding concurrent administration of high-dose histamine H2-receptor antagonists with sustained-release mesalamine products. Risk D: Consider therapy modification

Heparin: 5-ASA Derivatives may enhance the adverse/toxic effect of Heparin. Specifically, the risk for bleeding/bruising may be increased. Risk C: Monitor therapy

Heparin (Low Molecular Weight): 5-ASA Derivatives may enhance the adverse/toxic effect of Heparin (Low Molecular Weight). Specifically, the risk for bleeding/bruising may be increased. Risk C: Monitor therapy

Proton Pump Inhibitors: May diminish the therapeutic effect of Mesalamine. Proton pump inhibitor-mediated increases in gastrointestinal pH may cause the premature release of mesalamine from specific sustained-release mesalamine products. Management: Consider avoiding concurrent administration of high-dose proton pump inhibitors (PPIs) with sustained-release mesalamine products. Risk D: Consider therapy modification

Thiopurine Analogs: 5-ASA Derivatives may decrease the metabolism of Thiopurine Analogs. Risk C: Monitor therapy

Varicella Virus-Containing Vaccines: 5-ASA Derivatives may enhance the adverse/toxic effect of Varicella Virus-Containing Vaccines. The primary concern is the potential development of Reye's Syndrome, a condition that has been associated with the use of salicylates in children with varicella infections. Risk D: Consider therapy modification

Pregnancy Risk Factor

B/C (product specific) (show table)

Pregnancy Implications

Animal reproduction studies with mesalamine have not demonstrated teratogenicity or fertility impairment. Dibutyl phthalate (DBP) is an inactive ingredient in the enteric coating of Asacol® and Asacol® HD; adverse effects in male rats were noted at doses greater than the recommended human dose. Mesalamine is known to cross the placenta. An increased rate of congenital malformations has not been observed in human studies. Preterm birth, still birth and decreased birth weight have been observed; however, these events may also be due to maternal disease.

Lactation

Enters breast milk/use caution

Breast-Feeding Considerations

Adverse effects (diarrhea) in a nursing infant have been reported while the mother received rectal administration of mesalamine within 12 hours after the first dose. Low concentrations of the parent drug and higher concentrations of the N-acetyl metabolite of the parent drug have been detected in human breast milk.

Dietary Considerations

Some products may contain phenylalanine.

Apriso™: Take with or without food; do not administer with antacids.

Asacol® HD: Take with or without food.

Canasa® rectal suppository contains saturated vegetable fatty acid esters.