Mesalamine Rectal Suspension: Package Insert / Prescribing Info

5.1 Hypersensitivity Reactions

Sulfite-Related Reactions

Mesalamine rectal suspension enema contains potassium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low. Sulfite sensitivity is seen more frequently in asthmatic or in atopic nonasthmatic persons.

Epinephrine is the preferred treatment for serious allergic or emergency situations even though epinephrine injection contains sodium or potassium metabisulfite with the above-mentioned potential liabilities. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite(s) in epinephrine injection should not deter the administration of the drug for treatment of serious allergic or other emergency situations.

Sulfasalazine-Associated Reactions

Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to mesalamine rectal suspension enema 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 mesalamine rectal suspension enema if an alternative etiology for the signs and symptoms cannot be established.

5.2 Renal Impairment

Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure have been reported in patients given mesalamine rectal suspension enema or other products that contain mesalamine or are converted to mesalamine. In animal studies, the kidney was the principal organ of mesalamine toxicity [see Nonclinical Toxicology (13.2)].

Evaluate the risks and benefits of using mesalamine rectal suspension enema in patients with known renal impairment or a history of renal disease or taking concomitant nephrotoxic drugs. Evaluate renal function in all patients prior to initiation and periodically while on mesalamine rectal suspension enema therapy. Discontinue mesalamine rectal suspension enema if renal function deteriorates while on therapy [see Drug Interactions (7.1), Use in Specific Populations (8.6)].

5.3 Mesalamine-Induced Acute Intolerance Syndrome

Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Although the exact frequency of occurrence cannot be ascertained, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, 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 mesalamine rectal suspension enema.

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 mesalamine rectal suspension enema 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 with the use of mesalamine [see Adverse Reactions (6)]. Discontinue mesalamine rectal suspension enema at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6 Photosensitivity

Patients with 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 with 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate fluid intake during treatment.

5.8 Interference with Laboratory Tests

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 the main metabolite of mesalamine, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective

assay for normetanephrine.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 1: Adverse Reactions* in Clinical Trials of Mesalamine Rectal Suspension Enema in Adult Patients with Ulcerative Colitis, Proctosigmoiditis or Proctitis

*reported in 1% or more of mesalamine rectal suspension enema-treated patients and greater than placebo

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of mesalamine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac Disorders: myocarditis, pericarditis [see Warnings and Precautions (5.1)]

Gastrointestinal Disorders: pancreatitis

Hematologic Disorders: agranulocytosis, aplastic anemia, eosinophilia, leukopenia, neutropenia, pancytopenia, thrombocytopenia

Hepatic Disorders: elevated liver enzymes, hepatic failure [see Warnings and Precautions (5.4)]

Nervous System: intracranial hypertension

Renal and Urinary Disorders: acute renal failure, chronic renal failure, interstitial nephritis, nephrogenic diabetes insipidus, nephrolithiasis, nephrotoxicity [see Warnings and Precautions (5.2), (5.7)]

• Urine discoloration occurring ex-vivo caused by contact of mesalamine including inactive metabolite, with surfaces or water treated with hypochlorite-containing bleach

Reproductive System and Breast Disorders: reversible oligospermia

Respiratory, Thoracic, and Mediastinal Disorders: fibrosing alveolitis,

pleurisy/pleuritis

Skin and Subcutaneous Tissue Disorders: AGEP, DRESS, SJS/TEN [see Warnings and Precautions (5.5)]

7.1 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs

The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs), may increase the risk of nephrotoxicity. Monitor patients taking nephrotoxic drugs for changes in renal function and mesalamine-related adverse reactions [see Warnings and Precautions (5.2)].

7.2 Azathioprine or 6-Mercaptopurine

The concurrent use of mesalamine with azathioprine or 6-mercaptopurine and/or any other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of mesalamine rectal suspension enema and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.

7.3 Interference with Urinary Normetanephrine Measurements

Use of mesalamine rectal suspension enema may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection [see Warnings and Precautions (5.8)]. Consider an alternative, selective assay for normetanephrine.

8.1 Pregnancy

Risk Summary

Published data from meta-analyses, cohort studies and case series on the use of mesalamine during pregnancy have not reliably informed an association with mesalamine and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are adverse effects on maternal and fetal outcomes associated with ulcerative colitis in

pregnancy (see Clinical Considerations). In animal reproduction studies, rats and rabbits administered mesalamine during organogenesis at oral doses up to 5 and 8 times the maximum recommended human dose, respectively, did not reveal any evidence of harm to the embryo or the fetus (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Clinical Considerations

Disease-associated maternal and embryo/fetal risk

Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Data

Human Data

Published data from meta-analyses, cohort studies and case series on the use of mesalamine, the active moiety of mesalamine rectal suspension enema, during early pregnancy (first trimester) and throughout pregnancy have not reliably informed an association of mesalamine and major birth defects, miscarriage, or adverse maternal or fetal outcomes. There is no clear evidence that mesalamine exposure in early pregnancy is associated with an increase risk in major congenital malformations, including cardiac malformations. Published epidemiologic studies have important methodological limitations which hinder interpretation of the data, including inability to control for confounders, such as underlying maternal disease, and maternal use of concomitant medications, and missing information on the dose and duration of use for mesalamine products.

Animal Data

Reproduction studies have been performed with mesalamine in rats and rabbits during organogenesis at oral doses up to 5 and 8 times respectively, the maximum recommended human dose, and have revealed no evidence of harm to the embryo or the fetus.

8.2 Lactation

Risk Summary

Data from published literature report the presence of mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid in human milk in small amounts with relative infant doses (RID) of 0.1% or less for mesalamine (see Data). There are case reports of diarrhea observed in breastfed infants exposed to mesalamine (see Clinical Considerations). There is no information on the effects of mesalamine on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of mesalamine rectal suspension enema to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mesalamine rectal suspension enema and any potential adverse effects on the breastfed child from mesalamine rectal

suspension enema or from the underlying maternal condition.

Clinical Considerations

Advise the caregiver to monitor the breastfed infant for diarrhea.

Data

In published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to 4.8 g daily. The average concentration of mesalamine in milk ranged from non-detectable to 0.5 mg/L. The average concentration of N-acetyl-5-aminosalicylic acid in milk ranged from 0.2 to 9.3 mg/L. Based on these

concentrations, estimated infant daily dosages for an exclusively breastfed infant are 0 to 0.075 mg/kg/day of mesalamine (RID 0% to 0.1%) and 0.03 to 1.4 mg/kg/day of N-acetyl-5-aminosalicylic acid.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical trials of mesalamine rectal suspension enema 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 mesalamine rectal suspension enema who were 65 years or older compared to younger adult patients, which may also be associated with ulcerative colitis, use of interacting drugs, or reduced renal function.

Consider monitoring complete blood cell counts and platelet counts in patients 65 years and over during treatment with mesalamine rectal suspension enema. In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in patients 65 years and over when prescribing mesalamine rectal suspension enema.

8.6 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. Evaluate renal function in all patients prior to initiation and periodically while on mesalamine rectal suspension enema 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 mesalamine rectal suspension enema if renal function deteriorates while on therapy [see Warnings and Precautions (5.2)].

12.1 Mechanism of Action

The mechanism of action of 5-ASA (mesalamine) is not fully understood, but appears to be a topical anti-inflammatory effect on colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways (i.e., prostanoids), and through the lipoxygenase pathways (i.e., leukotrienes and hydroxyeicosatetraenoic

acids) is increased in patients with ulcerative colitis, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.

12.2 Pharmacodynamics

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of mesalamine have not been fully characterized.

12.3 Pharmacokinetics

Absorption

Mesalamine administered rectally as mesalamine rectal suspension enema is poorly absorbed from the colon and is excreted principally in the feces during subsequent bowel movements. The extent of absorption is dependent upon the retention time of the drug product, and there is considerable individual variation. Under clinical conditions patients demonstrated plasma levels 10 to 12 hours post mesalamine administration of 2 mcg/mL, about two-thirds of which was the N-acetyl metabolite. In addition, steady state plasma levels demonstrated a lack of accumulation of either parent drug or N-acetyl metabolite during repeated daily rectal administrations.

Distribution

Other than the kidney, the organ distribution and other bioavailability characteristics of absorbed mesalamine in man are not known. The poor colonic absorption of rectally administered mesalamine is substantiated by the low serum concentration of 5-ASA and N-acetyl-5-ASA seen in ulcerative colitis patients after dosage with mesalamine.

Elimination

Metabolism

It is known that the compound undergoes acetylation but whether this

process takes place at colonic or systemic sites has not been elucidated.

Excretion

Whatever the metabolic site, most of the absorbed mesalamine is excreted in the urine as the N-acetyl-5-ASA metabolite. At steady state, approximately 10 to 30% of the daily 4-gram dose can be recovered in cumulative 24-hour urine collections. While the elimination half-life of mesalamine is short (0.5 to 1.5 hours), the acetylated metabolite exhibits a half-life of 5 to 10 hours.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 2-year carcinogenicity study in Wistar rats fed up to 320 mg/kg/day (approximately 0.78 times the maximum recommended human dose, based on a body surface area comparison) of mesalamine admixed with diet, mesalamine did not cause an increase in the incidence of neoplastic lesions over controls.

Mutagenesis

Mesalamine is not mutagenic to Salmonella typhimurium tester strains TA98, TA100, TA1535, TA1537, TA1538. There were no reverse mutations in an assay using E. coli strain WP2UVRA. There were no evidence of genotoxicity in an in vivo mouse micronucleus assay at 600 mg/kg and in an in vivo sister chromatid exchange assay at doses up to 610 mg/kg.

Impairment of Fertility

Mesalamine had no effects on fertility in rats at doses up to 320 mg/kg/day (approximately 0.78 times the maximum recommended human dose, based on a body surface area comparison).

13.2 Animal Toxicology and/or Pharmacology

Preclinical studies have shown the kidney to be the major target organ for mesalamine toxicity. Adverse renal function changes were observed in rats after a single 600 mg/kg oral dose, but not after a 200 mg/kg dose. Gross kidney lesions, including papillary necrosis, were observed after a single oral >900 mg/kg dose, and after I.V. doses of >214 mg/kg.

Mice responded similarly. In a 13-week oral (gavage) dose study in rats, the high dose of 640 mg/kg/day mesalamine caused deaths, probably due to renal failure, and dose-related renal lesions (papillary necrosis and/or multifocal tubular injury) were seen in most rats given the high dose (males and females) as well as in males receiving lower doses 160

mg/kg/day. Renal lesions were not observed in the 160 mg/kg/day female rats. Minimal tubular epithelial damage was seen in the 40 mg/kg/day males and was reversible. In a six-month oral study in dogs, the no-observable dose level of mesalamine was 40 mg/kg/day and doses of 80 mg/kg/day and higher caused renal pathology similar to that described for the rat. In a combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration in kidneys was observed at doses of 100 mg/kg/day and above admixed with diet for 52 weeks, and at 127 weeks increased incidence of kidney degeneration and hyalinization of basement membranes and Bowman's capsule were seen at 100 mg/kg/day and above. In the 12-month eye toxicity study in dogs, Keratoconjunctivitis Sicca (KCS) occurred at oral doses of 40 mg/kg/day

and above. The oral preclinical studies were done with a highly bioavailable suspension where absorption throughout the gastrointestinal tract occurred.