Included as part of the "PRECAUTIONS" Section
Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and renal failure, has been reported in patients given products such as CANASA that contain mesalamine or are converted to mesalamine [see ADVERSE REACTIONS].
Evaluate renal function prior to initiation of CANASA therapy and periodically while on therapy.
Evaluate the risks and benefits of using CANASA in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs. In animal studies, the kidney was the principal organ for toxicity [see DRUG INTERACTIONS, Use In Specific Populations and Nonclinical Toxicology].
Mesalamine-Induced Acute Intolerance Syndrome
Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, and sometimes fever, headache, and rash. Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with CANASA.
Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to CANASA or to other compounds that contain or are converted to mesalamine.
As with sulfasalazine, mesalamine-induced hypersensitivity reactions may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis and hematologic abnormalities. Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue CANASA if an alternative etiology for the signs and symptoms cannot be established.
There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered other products containing mesalamine. Evaluate the risks and benefits of using CANASA in patients with known liver impairment.
Interaction With Laboratory Test For Urinary Normetanephrine
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, N-acetylaminosalicylic acid. Consider an alternative, selective assay for normetanephrine.
Patient Counseling Information
Advise patients to read the FDA-approved patient labeling (PATIENT INFORMATION)
- Do not cut or break the suppository.
- Retain the suppository for one to three hours or longer, if possible.
- If a dose of CANASA is missed, administer as soon as possible, unless it is almost time for next dose. Do not use two CANASA suppositories at the same time to make up for a missed dose.
- CANASA suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep CANASA away from these surfaces to prevent staining.
Inform patients that CANASA may decrease their renal function, especially if they have known renal impairment or are taking nephrotoxic drugs, including NSAIDs, and periodic monitoring of renal function will be performed while they are on therapy. Advise patients to complete all blood tests ordered by their healthcare provider [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
Mesalamine-Induced Acute Intolerance Syndrome And Other Hypersensitivity Reactions
Inform patients of the signs and symptoms of hypersensitivity reactions. Instruct patients to stop taking CANASA and report to their healthcare provider if they experience new or worsening symptoms Acute Intolerance Syndrome (cramping, abdominal pain, bloody diarrhea, fever, headache, and rash) or other symptoms suggestive of mesalamine-induced hypersensitivity [see WARNINGS AND PRECAUTIONS].
Inform patients with known liver disease of the signs and symptoms of worsening liver function and advise them to report to their healthcare provider if they experience such signs or symptoms [see WARNINGS AND PRECAUTIONS].
Blood Disorders Inform elderly patients and those taking azathioprine or 6-mercaptopurine of the risk for blood disorders and the need for periodic monitoring of complete blood cell counts and platelet counts while on therapy. Advise patients to complete all blood tests ordered by their healthcare provider [see DRUG INTERACTIONS, Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Mesalamine caused no increase in the incidence of neoplastic lesions over controls in a two-year study of Wistar rats fed up to 320 mg/kg/day of mesalamine admixed with diet (about 1.7 times the recommended human intra-rectal dose of CANASA, based on body surface area).
Mesalamine was not mutagenic in the Ames test, the mouse lymphoma cell (TK+/-) forward mutation test, or the mouse micronucleus test.
No effects on fertility or reproductive performance of the male and female rats were observed at oral mesalamine doses up to 320 mg/kg/day (about 1.7 times the recommended human intra-rectal dose of CANASA, based on body surface area).
Use In Specific Populations
Limited published data on mesalamine use in pregnant women are insufficient to inform a drug-associated risk. No evidence of teratogenicity was observed in rats or rabbits when treated during gestation with orally administered mesalamine at doses greater than the recommended human intra-rectal dose [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Reproduction studies have been performed in rats at oral doses up to 320 mg/kg/day (about 1.7 times the recommended human intra-rectal dose of CANASA, based on body surface area) and in rabbits at oral doses up to 495 mg/kg/day (about 5.4 times the recommended human intra-rectal dose of CANASA, based on body surface area) following administration during the period of organogenesis, and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine.
Mesalamine and its N-acetyl metabolite are present in human milk in undetectable to small amounts [see Data]. There are limited reports of diarrhea in breastfed infants. There is no information on the effects of the drug on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of CANASA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CANASA and any potential adverse effects on the breastfed child from CANASA or from the underlying maternal conditions.
Monitor breastfed infants for diarrhea.
In published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to 3 g daily. The concentration of mesalamine in milk ranged from non-detectable to 0.11 mg/L. The concentration of the N-acetyl-5aminosalicylic acid metabolite ranged from 5 to 18.1 mg/L. Based on these concentrations, estimated infant daily dosages 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.
The safety and effectiveness of CANASA in pediatric patients for the treatment of mildly to moderately active ulcerative proctitis have not been established. CANASA was evaluated for the treatment of ulcerative proctitis in a 6-week, open-label, single-arm study in 49 patients 5 to 17 years of age, which only included 14 patients with histologically-confirmed cases of ulcerative proctitis. However, efficacy was not demonstrated. Adverse reactions seen in pediatric patients in this trial (abdominal pain, headache, pyrexia, pharyngolaryngeal pain, diarrhea and vomiting) were similar to those seen in adult patients.
Clinical trials of CANASA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Systemic exposures are increased in elderly subjects [See CLINICAL PHARMACOLOGY]. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia and pancytopenia) in patients receiving mesalamine-containing products such as CANASA who were 65 years or older compared to younger patients. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with CANASA. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients should be considered when prescribing CANASA [see Renal Impairment].
Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Evaluate renal function in all patients prior to initiation and periodically while on CANASA 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 [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS and ADVERSE REACTIONS].