Canasa

8.1        Pregnancy

Risk Summary

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.

Data

Animal Data

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.

8.2        Lactation

Risk Summary

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.  

Clinical Considerations

Monitor breastfed infants for diarrhea.

Data

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-5-aminosalicylic 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.

8.4        Pediatric Use

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.

8.5        Geriatric Use

Clinical trials of CANASA did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. 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, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients when prescribing CANASA [see Use in Specific Populations ( 8.6)].

8.6        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. Discontinue CANASA if renal function deteriorates while on therapy [see Warnings and Precautions ( 5.1), Adverse Reactions ( 6.2), Drug Interactions ( 7.1)].

5.1        Renal Impairment

Renal impairment, including minimal change disease, 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. In animal studies, the kidney was the principal organ of mesalamine toxicity [see Adverse Reactions ( 6.2), Nonclinical Toxicology ( 13.2)]. 

Evaluate renal function prior to initiation of CANASA 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. Discontinue CANASA if renal function deteriorates while on therapy [see Drug Interactions ( 7.1), Use in Specific Populations ( 8.6)].

5.2        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, malaise, pruritus, conjunctivitis, and rash. Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with CANASA.

5.3        Hypersensitivity Reactions

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. 

5.4        Hepatic Failure

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. 

5.5         Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of mesalamine [see Adverse Reactions ( 6.2)]. Discontinue CANASA at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6        Photosensitivity

In patients treated with mesalamine or sulfasalazine who have pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors.

5.7        Nephrolithiasis

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 hydration during treatment with CANASA.

5.8        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.