Canasa (mesalamine)

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Mesalamine is administered orally as delayed-release tablets and as extended-release capsules. Mesalamine is administered rectally as a retention enema or suppositories.

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There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Aminosalicylate Derivatives/Azathioprine; Mercaptopurine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is not known. Aminosalicylic acid and its derivatives (balsalazide, mesalamine, olsalazine, sulfasalazine) may inhibit azathioprine or mercaptopurine inactivation via the thiopurine methyltransferase (TPMT) pathway. Aminosalicylates, azathioprine and mercaptopurine are all associated risk for neutropenia, thrombocytopenia, and anemia and so these risks could be additive.

CLINICAL EFFECTS: Concurrent use of azathioprine or mercaptopurine with aminosalicylates may increase the risk for anemia, neutropenia, or thrombocytopenia.

PREDISPOSING FACTORS: Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are at higher risk of accumulating thiopurine metabolites and severe myelosuppression. Approximately 0.3 % of patients of European, Latino, or African descent have mutations of the TPMT gene resulting in little to no TPMT activity (homozygous deficiency), and approximately 10 % have intermediate TPMT activity (heterozygous deficiency). NUDT15 deficiency is not seen in patients of African descent and is seen in less than 1 % of patients of European descent. Approximately 1 % of patients of East Asian descent, 0.5 % of patients of central/south Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15 deficiency. About 17 % of patients of East Asian descent, 13 % of patients of central/south Asian descent, and 8 % of patients of Latino descent have heterozygous NUDT15 deficiency. Added risk for myelosuppression would be expected in patients who also receive allopurinol or other agents which block xanthine oxidase (XO), the other major inactivation pathway for azathioprine and mercaptopurine.

PATIENT MANAGEMENT: Use the lowest possible dose of each drug and monitor closely for myelosuppression.

DISCUSSION: Manufacturer prescribing information states that concurrent use of aminosalicylates with azathioprine or mercaptopurine has been reported to cause bone marrow suppression. In a prospective study, 22 inflammatory bowel disease (IBD) patients on concurrent 5-aminosalicylate with (2 g daily and later increased to 4 g daily) with azathioprine had increased levels of 6-thioguanine (6-TGN) metabolites. One patient had signs of myelosuppression.(3) A prospective study in 183 IBD patients on concurrent 5-aminosalicylic acid and thiopurines found no significant interaction between thiopurines and 5-aminosalicylic acid.(4) A retrospective study in 199 IBD patients reported an increased rate of adverse events in the dual 5-aminosalicylates and azathioprine dual therapy group compared (48%) to the monotherapy azathioprine group (30%)(chi = 6.4, p = 0.05). Discontinuation of azathioprine because of adverse events was higher in the dual therapy group (52% vs. 24%).(5) In a prospective study, 16 Crohn's disease patients on a stable dose of azathioprine with sulfasalazine or mesalamine discontinued the aminosalicylate after 3 months, which resulted in an average decrease 0f 10% in 6-TGN levels. Myelosuppression may be related to increased levels of 6-TGN.(6) In a 8 week non-randomized parallel group drug interaction study, 34 patients with Crohn's disease receiving azathioprine or 6-mercaptopurine with mesalamine (4 g/day), or sulfasalazine (4 g/day), or balsalazide (6.75 g/day) had a high frequency of leukopenia (20-55%) and significant increases in whole blood 6-TGN levels.(7) A 16 year-old Crohn's disease patient on concurrent 6-mercaptopurine (75 mg) and olsalazine (1000 mg) developed leukopenia (WBC count 1.7 x 10*9/L, ANC 1.309 x 10*9/L, hemoglobulin 113 gm/L, platelet count 550 x 10*9/L) and required a dose reduction for 6-mercaptopurine. Another episode occurred later on after increasing her dose of olsalazine and 6-mercaptopurine which resulted in discontinuation of olsalazine.(8) An in vitro study showed that sulfasalazine and other aminosalicylate derivatives were able to inhibit recombinant human TPMT.(9) In a prospective study, 17 IBD patients on stable mercaptopurine and mesalamine therapy had a 23% reduction in 6-TGN levels after discontinuing mercaptopurine.(10)

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There are no contraindication contraindications for this drug.

• Increased risk of bleeding
• Interstitial nephritis
• Minimal change glomerulonephritis

• Atopic dermatitis
• Disease of liver
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Kidney disease with reduction in glomerular filtration rate (GFr)

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Rare or Very Rare

• Abnormal hepatic function tests
• Acute generalized exanthematous pustulosis
• Acute pancreatitis
• Agranulocytosis
• Alveolitis
• Aplastic anemia
• Bloody diarrhea
• Colitis
• DRESS syndrome
• Eosinophilia
• Erythema nodosum
• Gastrointestinal hemorrhage
• Guillain-barre syndrome
• Hepatic failure
• Hepatic necrosis
• Hepatitis
• Hypersensitivity drug reaction
• Hypersensitivity pneumonitis
• Interstitial nephritis
• Intracranial hypertension
• Jaundice
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Kidney stone
• Lupus-like syndrome
• Myelitis
• Myocarditis
• Nephrogenic diabetes insipidus
• Obstructive hyperbilirubinemia
• Pancytopenia
• Pericarditis
• Pleuritis
• Pyoderma gangrenosum
• Rectal irritation
• Skin photosensitivity
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Toxic epidermal necrolysis
• Vasculitis

More Frequent

• Abdominal pain with cramps
• Headache disorder

Less Frequent

• Abdominal distension
• Acne vulgaris
• Diarrhea
• Dizziness
• Fatigue
• Fever
• Flatulence
• Flu-like symptoms
• Gastritis
• Nausea
• Pruritus ani
• Rectal pain
• Skin rash

Rare or Very Rare

• Alopecia
• Back pain
• Constipation
• Discolored feces
• Erythema
• Female infertility
• Hemorrhoids
• Oligospermia
• Pain in extremities
• Periorbital edema
• Peripheral neuropathy
• Pruritus of skin
• Psoriasis
• Tenesmus
• Urine discoloration
• Urticaria

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Reproduction studies in rats and rabbits using oral mesalamine dosages of up to 1000 mg/kg daily and up to 800 mg/kg daily, respectively, have not revealed evidence of teratogenic effects or harm to the fetus. In addition, reproduction studies in rats and rabbits using oral mesalamine daily doses up to 5 and 8 times the maximum recommended human rectal dose, respectively, have not revealed evidence of fetal malformation. Sulfasalazine (a prodrug of mesalamine) has been used for the treatment of inflammatory bowel disease, including Crohn's disease and ulcerative colitis, during pregnancy. Although fetal abnormalities have been reported in infants born to women with inflammatory bowel disease who received sulfasalazine alone or combined with corticosteroids during pregnancy, most evidence indicates that sulfasalazine is not associated with a substantial risk of teratogenicity. The effect of sulfasalazine on subsequent growth, development, and functional maturation in children whose mothers received sulfasalazine during pregnancy has not been determined. Although the relevance to mesalamine of the experience with sulfasalazine in pregnant women currently is not known, placental transfer of mesalamine, but not sulfasalazine or sulfapyridine, has been reported to be negligible in pregnant women receiving oral sulfasalazine. Mesalamine crosses the placental barrier. Because there are no adequate and controlled studies to date using mesalamine or sulfasalazine in pregnant women, and animal studies are not always predictive of human response, the drugs should be used during pregnancy only when clearly needed.

Following oral administration, low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. Although the clinical importance of this effect is not known, mesalamine should be used with caution and only if the benefits outweigh the risks in nursing women. The manufacturer of mesalamine extended-release capsules states that hypersensitivity reactions (e.g., diarrhea) in the infant of a breast-feeding woman receiving mesalamine cannot be excluded. The manufacturer of mesalamine rectal suspension recommends that the drug not be used in nursing women.

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