ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious or clinically significant adverse reactions are described elsewhere in labeling:Renal Impairment [see Warnings and Precautions (5.1)] Mesalamine-Induced Acute Intolerance Syndrome [see Warnings and Precautions (5.2)] Hypersensitivity Reactions [see Warnings and Precautions (5.3)] Hepatic Failure [see Warnings and Precautions (5.4)] Photosensitivity [see Warnings and Precautions (5.5)] Nephrolithiasis [see Warnings and Precautions (5.6)] Renal Impairment [see Warnings and Precautions (5.1)] Mesalamine-Induced Acute Intolerance Syndrome [see Warnings and Precautions (5.2)] Hypersensitivity Reactions [see Warnings and Precautions (5.3)] Hepatic Failure [see Warnings and Precautions (5.4)] Photosensitivity [see Warnings and Precautions (5.5)] Nephrolithiasis [see Warnings and Precautions (5.6)] The most common adverse reactions (>= 1%) are: dizziness, rectal pain, fever, rash, acne and colitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The most common adverse reactions in adult patients with mildly to moderately active ulcerative proctitis in double-blind, placebo-controlled trials are summarized in the Table below.Table 1: Adverse Reactions Occurring in More Than 1% of Mesalamine Suppository Treated Patients (Comparison to Placebo)SymptomMesalamine(n 177)Placebo(n 84)N%N%Dizziness5322.4Rectal Pain31.800Fever21.200Rash21.200Acne21.200Colitis21.200In multicenter, open-label, randomized, parallel group study in 99 patients comparing the mesalamine 1000 mg suppository administered nightly to that of the mesalamine 500 mg suppository twice daily. The most common adverse reactions in both groups were headache (14%), flatulence (5%), abdominal pain (5%), diarrhea (3%), and nausea (3%). Three (3) patients discontinued medication because of an adverse reaction; one of these adverse reactions (headache) was deemed possibly related to study medication. The recommended dosage of mesalamine suppository is 1000 mg administered rectally once daily at bedtime [see Dosage and Administration (2)].. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of mesalamine suppositories or other mesalamine-containing products. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Body as Whole: drug fever, fatigue, lupus-like syndrome, medication residueCardiac Disorders: myocarditis, pericarditis, pericardial effusion [see Warnings and Precautions (5.3)] Endocrine: Nephrogenic diabetes insipidusEye disorders: eye swellingGastrointestinal Disorders: abdominal cramps, abdominal distension, anal pruritus, anorectal discomfort, constipation, feces discolored, flatulence, frequent bowel movements, gastrointestinal bleeding, mucus stools, nausea, painful defecation, pancreatitis, proctalgia, rectal discharge, rectal tenesmus, stomach discomfort, vomitingHepatic Disorders: cholestatic jaundice, hepatitis, jaundice, Kawasaki-like syndrome including changes in liver enzymes, liver necrosis, liver failureHematologic Disorders: agranulocytosis, aplastic anemia, thrombocytopeniaNeurological/Psychiatric Disorders: Guillain-Barre syndrome, peripheral neuropathy, transverse myelitis, intracranial hypertensionRenal Disorders: interstitial nephritis, renal failure, minimal change disease, nephrolithiasis [see Warnings and Precautions (5.1, 5.6)] Respiratory, Thoracic and Mediastinal Disorders: hypersensitivity pneumonitis (including allergic alveolitis, eosinophilic pneumonitis, interstitial pneumonitis)Skin and Subcutaneous Tissue Disorder: alopecia, erythema, erythema nodosum, pruritus, psoriasis, pyoderma gangrenosum, urticariaUrogenital: reversible oligospermia. Body as Whole: drug fever, fatigue, lupus-like syndrome, medication residue. Cardiac Disorders: myocarditis, pericarditis, pericardial effusion [see Warnings and Precautions (5.3)] Endocrine: Nephrogenic diabetes insipidus. Eye disorders: eye swelling. Gastrointestinal Disorders: abdominal cramps, abdominal distension, anal pruritus, anorectal discomfort, constipation, feces discolored, flatulence, frequent bowel movements, gastrointestinal bleeding, mucus stools, nausea, painful defecation, pancreatitis, proctalgia, rectal discharge, rectal tenesmus, stomach discomfort, vomiting. Hepatic Disorders: cholestatic jaundice, hepatitis, jaundice, Kawasaki-like syndrome including changes in liver enzymes, liver necrosis, liver failure. Hematologic Disorders: agranulocytosis, aplastic anemia, thrombocytopenia. Neurological/Psychiatric Disorders: Guillain-Barre syndrome, peripheral neuropathy, transverse myelitis, intracranial hypertension. Renal Disorders: interstitial nephritis, renal failure, minimal change disease, nephrolithiasis [see Warnings and Precautions (5.1, 5.6)] Respiratory, Thoracic and Mediastinal Disorders: hypersensitivity pneumonitis (including allergic alveolitis, eosinophilic pneumonitis, interstitial pneumonitis). Skin and Subcutaneous Tissue Disorder: alopecia, erythema, erythema nodosum, pruritus, psoriasis, pyoderma gangrenosum, urticaria. Urogenital: reversible oligospermia.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Toxicology studies of mesalamine were conducted in rats, mice, rabbits and dogs, and the kidney was the main target organ of toxicity. In rats, adverse renal effects were observed at single oral dose of 600 mg/kg (about 3.2 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and at intravenous doses of >214 mg/kg (about 1.2 times the recommended human intra-rectal dose of mesalamine, based on body surface area). In 13-week oral gavage toxicity study in rats, papillary necrosis and/or multifocal tubular injury were observed in males receiving 160 mg/kg (about 0.86 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and in both males and females at 640 mg/kg (about 3.5 times the recommended human intra-rectal dose of mesalamine, based on body surface area). In combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration of the kidneys and hyalinization of basement membranes and Bowmans capsule were observed at oral doses of 100 mg/kg/day (about 0.54 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and above. In 14-day rectal toxicity study of mesalamine suppositories in rabbits, intra-rectal doses up to 800 mg/kg (about 8.6 times the recommended human intra-rectal dose of mesalamine, based on body surface area) was not associated with any adverse effects. In six-month oral toxicity study in dogs, doses of 80 mg/kg (about 1.4 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and higher caused renal pathology similar to that described for the rat. In rectal toxicity study of mesalamine suppositories in dogs, dose of 166.6 mg/kg (about times the recommended human intra-rectal dose of mesalamine, based on body surface area) produced chronic nephritis and pyelitis. In the 12-month eye toxicity study in dogs, keratoconjunctivitis sicca (KCS) occurred at oral doses of 40 mg/kg (about 0.72 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and above.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism of action of mesalamine is not fully understood, but appears to be 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. 12.3 Pharmacokinetics. AbsorptionMesalamine (5-ASA) administered as rectal suppository is variably absorbed. In patients with ulcerative colitis treated with mesalamine 500 mg rectal suppositories, administered once every eight hours for six days, the mean mesalamine peak plasma concentration (Cmax) was 353 ng/mL (CV=55%) following the initial dose and 361 ng/mL (CV=67%) at steady state. The mean minimum steady state plasma concentration (Cmin) was 89 ng/mL (CV=89%). Absorbed mesalamine does not accumulate in the plasma.DistributionMesalamine administered as rectal suppository distributes in rectal tissue to some extent.EliminationIn patients with ulcerative proctitis treated with mesalamine 500 mg as rectal suppository every hours for days, the mean elimination half-life was hours (CV=73%) for 5-ASA and hours (CV=63%) for N-acetyl-5-ASA, the active metabolite, following the initial dose. At steady state, the mean elimination half-life was hours for both 5-ASA and N-acetyl-5-ASA (CV=102% for 5-ASA and 82% for N-acetyl-5-ASA).MetabolismThe absorbed mesalamine is extensively metabolized, mainly to N-acetyl-5-ASA in the liver and in the gut mucosal wall. In patients with ulcerative colitis treated with one mesalamine 500 mg rectal suppository every eight hours for six days, the peak concentration (Cmax) of N-acetyl-5-ASA ranged from 467 ng/mL to 1399 ng/mL following the initial dose and from 193 ng/mL to 1304 ng/mL at steady state.ExcretionMesalamine is eliminated from plasma mainly by urinary excretion, predominantly as N-acetyl-5-ASA. In patients with ulcerative proctitis treated with mesalamine 500 mg as rectal suppository every hours for days, 12% or less of the dose was eliminated in urine as unchanged 5-ASA and 8% to 77% was eliminated as N-acetyl-5-ASA following the initial dose. At steady state, 11% or less of the dose was eliminated in the urine as unchanged 5-ASA and 3% to 35% was eliminated as N-acetyl-5-ASA.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Two double-blind, placebo-controlled, multicenter trials of mesalamine suppositories were conducted in North America in adult patients with mildly to moderately active ulcerative proctitis. The regimen in Study was 500 mg mesalamine suppository administered rectally three times daily and in Study was 500 mg mesalamine suppository administered rectally twice daily. In both trials, patients had an average extent of proctitis (upper disease boundary) of approximately 10 cm and approximately 80% of patients had multiple prior episodes of proctitis. total of 173 patients were evaluated (Study 1, N=79; Study 2, N=94), of which 89 patients received mesalamine, and 84 patients received placebo. The mean age of patients was 39 years (range 17 to 73 years), 60% were female, and 97% were white.The primary measures of efficacy were clinical disease activity index (DAI) and histologic evaluations in both trials. The DAI is composite index reflecting rectal bleeding, stool frequency, mucosal appearance at endoscopy, and physicians global assessment of disease. Patients were evaluated clinically and sigmoidoscopically after and weeks of treatment.Compared to placebo, mesalamine suppositories were statistically (p<0.01) superior to placebo in both trials with respect to improvement in stool frequency, rectal bleeding, mucosal appearance, disease severity, and overall disease activity after and weeks of treatment. The effectiveness of mesalamine suppositories was statistically significant irrespective of sex, extent of proctitis, duration of current episode, or duration of disease.An additional multicenter, open-label, randomized, parallel group study in 99 patients diagnosed with mildly to moderately ulcerative proctitis compared 1000 mg mesalamine administered rectally once daily at bedtime (N=35) to 500 mg mesalamine suppository administered rectally twice daily, in the morning and at bedtime (N=46), for weeks.The primary measures of efficacy included the clinical disease activity index (DAI) and histologic evaluations. Patients were evaluated clinically and sigmoidoscopically at and weeks of treatment.The efficacy at weeks was not different between the treatment groups. Both were effective in the treatment of ulcerative proctitis and resulted in significant decrease at weeks in DAI: in the mesalamine 500 mg twice daily group, the mean DAI value decreased from 6.6 to 1.6, and in the 1000 mg at bedtime group, the mean DAI value decreased from 6.2 to 1.3, which represents decrease of greater than 75% in both groups. After weeks of treatment, DAI score of less than was achieved in 78% of patients in the mesalamine 500 mg twice daily group and 86% of patients in the mesalamine 1000 mg once daily group. The recommended dosage of mesalamine is 1000 mg administered rectally once daily at bedtime [see Dosage and Administration (2)].

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. DosageThe recommended dosage of mesalamine suppositories in adults is 1000 mg administered rectally once daily at bedtime for to weeks depending on symptoms and sigmoidoscopic findings. Safety and effectiveness of mesalamine suppositories beyond weeks have not been established.Administration Instructions:Evaluate renal function prior to initiation of mesalamine suppository therapy [see Warnings and Precautions (5.1)].Do not cut or break the suppository.Retain the suppository for one to three hours or longer, if possible.Drink an adequate amount of fluids [see Warnings and Precautions (5.6)] If dose of mesalamine suppository is missed, administer as soon as possible, unless it is almost time for next dose. Do not use two mesalamine suppositories at the same time to make up for missed dose.Mesalamine suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep mesalamine suppositories away from these surfaces to prevent staining.. Evaluate renal function prior to initiation of mesalamine suppository therapy [see Warnings and Precautions (5.1)].. Do not cut or break the suppository.. Retain the suppository for one to three hours or longer, if possible.. Drink an adequate amount of fluids [see Warnings and Precautions (5.6)] If dose of mesalamine suppository is missed, administer as soon as possible, unless it is almost time for next dose. Do not use two mesalamine suppositories at the same time to make up for missed dose.. Mesalamine suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep mesalamine suppositories away from these surfaces to prevent staining.. DosageThe recommended adult dosage is 1000 mg administered rectally once daily at bedtime for to weeks. Safety and effectiveness beyond weeks have not been established. (2) Administration Instructions:Evaluate renal function prior to initiation of mesalamine suppositories and periodically while on therapy. (2, 5.1) Do not cut or break the suppository. (2)Drink an adequate amount of fluids. (2, 5.6)Retain the suppository for one to three hours or longer, if possible. (2)Mesalamine suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep mesalamine suppositories away from these surfaces to prevent staining. (2). Evaluate renal function prior to initiation of mesalamine suppositories and periodically while on therapy. (2, 5.1) Do not cut or break the suppository. (2). Drink an adequate amount of fluids. (2, 5.6). Retain the suppository for one to three hours or longer, if possible. (2). Mesalamine suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep mesalamine suppositories away from these surfaces to prevent staining. (2).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise patients to read the FDA-approved patient labeling (Patient Information).Administration [see Dosage and Administration (2)] Advise patients:Do not cut or break the suppository.Retain the suppository for one to three hours or longer, if possible.Drink an adequate amount of fluids.If dose of mesalamine suppository is missed, administer as soon as possible, unless it is almost time for next dose. Do not use two mesalamine suppositories at the same time to make up for missed dose.Mesalamine suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep mesalamine suppositories away from these surfaces to prevent staining.Renal ImpairmentInform patients that mesalamine suppositories 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 (5.1), Drug Interactions (7.1)].Mesalamine-Induced Acute Intolerance Syndrome and Other Hypersensitivity ReactionsInform patients of the signs and symptoms of hypersensitivity reactions. Instruct patients to stop taking mesalamine and report to their healthcare provider if they experience new or worsening symptoms Acute Intolerance Syndrome (cramping, abdominal pain, bloody diarrhea, fever, headache, malaise, conjunctivitis and rash) or other symptoms suggestive of mesalamine-induced hypersensitivity [see Warnings and Precautions (5.2, 5.3)].Hepatic FailureInform 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 (5.4)].PhotosensitivityAdvise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use broad-spectrum sunscreen when outdoors [see Warnings and Precautions (5.5)].NephrolithiasisInstruct patients to drink an adequate amount of fluids during treatment in order to minimize the risk of kidney stone formation and to contact their healthcare provider if they experience signs or symptoms of kidney stone (e.g., severe side or back pain, blood in the urine) [see Warnings and Precautions (5.6)].Blood DisordersInform 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 (7.2), Use in Specific Populations (8.5)].Manufactured For: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454Iss. 4/2021. Do not cut or break the suppository.. Retain the suppository for one to three hours or longer, if possible.. Drink an adequate amount of fluids.. If dose of mesalamine suppository is missed, administer as soon as possible, unless it is almost time for next dose. Do not use two mesalamine suppositories at the same time to make up for missed dose.. Mesalamine suppositories will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Keep mesalamine suppositories away from these surfaces to prevent staining.. Inform patients that mesalamine suppositories 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 (5.1), Drug Interactions (7.1)].. Inform patients of the signs and symptoms of hypersensitivity reactions. Instruct patients to stop taking mesalamine and report to their healthcare provider if they experience new or worsening symptoms Acute Intolerance Syndrome (cramping, abdominal pain, bloody diarrhea, fever, headache, malaise, conjunctivitis and rash) or other symptoms suggestive of mesalamine-induced hypersensitivity [see Warnings and Precautions (5.2, 5.3)].. 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 (5.4)].. Advise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use broad-spectrum sunscreen when outdoors [see Warnings and Precautions (5.5)].. Instruct patients to drink an adequate amount of fluids during treatment in order to minimize the risk of kidney stone formation and to contact their healthcare provider if they experience signs or symptoms of kidney stone (e.g., severe side or back pain, blood in the urine) [see Warnings and Precautions (5.6)].. 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 (7.2), Use in Specific Populations (8.5)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Geriatric Patients: Increased risk of blood dyscrasias; monitor complete blood cell counts and platelet counts. (8.5) 8.1 Pregnancy. Risk SummaryLimited published data on mesalamine use in pregnant women are insufficient to inform 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.DataAnimal DataReproduction 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 mesalamine, 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 mesalamine, 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 SummaryMesalamine 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 clear determination of the risk of mesalamine to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for mesalamine and any potential adverse effects on the breastfed child from mesalamine or from the underlying maternal conditions.Clinical ConsiderationsMonitor breastfed infants for diarrhea.DataIn published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to 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 to 18.1 mg/L. Based on these concentrations, estimated infant daily dosages for an exclusively breastfed infant are 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 mesalamine in pediatric patients for the treatment of mildly to moderately active ulcerative proctitis have not been established. Mesalamine suppositories were evaluated for the treatment of ulcerative proctitis in 6-week, open-label, single-arm study in 49 patients 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 mesalamine 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 higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia and pancytopenia) in patients receiving mesalamine-containing products such as mesalamine suppositories who were 65 years or older compared to younger patients. Monitor complete blood cell counts and platelet counts in elderly patients during treatment with mesalamine suppositories. 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 mesalamine suppositories [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 mesalamine suppository 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 (5.1), Drug Interactions (7.1) and Adverse Reactions (6.2)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Renal Impairment: Evaluate the risks and benefits in patients with known renal impairment or taking nephrotoxic drugs; monitor renal function. (5.1, 7.1, 8.6)Mesalamine-Induced Acute Intolerance Syndrome: Symptoms may be difficult to distinguish from an exacerbation of ulcerative colitis; monitor for worsening symptoms; discontinue treatment if acute intolerance syndrome is suspected. (5.2) Hypersensitivity Reactions, including Myocarditis and Pericarditis: Evaluate patients immediately and discontinue if hypersensitivity reaction is suspected. (5.3) Hepatic Failure: Evaluate the risks and benefits in patients with known liver impairment. (5.4) Photosensitivity: Advise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use broad-spectrum sunscreen when outdoors. (5.5) Nephrolithiasis: Mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment. (5.6) Interaction with Laboratory Test for Urinary Normetanephrine: Spuriously elevated test results may occur with liquid chromatography with electrochemical detection in patients receiving mesalamine; use alternative, selective assay for normetanephrine. (5.7) Renal Impairment: Evaluate the risks and benefits in patients with known renal impairment or taking nephrotoxic drugs; monitor renal function. (5.1, 7.1, 8.6). Mesalamine-Induced Acute Intolerance Syndrome: Symptoms may be difficult to distinguish from an exacerbation of ulcerative colitis; monitor for worsening symptoms; discontinue treatment if acute intolerance syndrome is suspected. (5.2) Hypersensitivity Reactions, including Myocarditis and Pericarditis: Evaluate patients immediately and discontinue if hypersensitivity reaction is suspected. (5.3) Hepatic Failure: Evaluate the risks and benefits in patients with known liver impairment. (5.4) Photosensitivity: Advise patients with pre-existing skin conditions to avoid sun exposure, wear protective clothing, and use broad-spectrum sunscreen when outdoors. (5.5) Nephrolithiasis: Mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment. (5.6) Interaction with Laboratory Test for Urinary Normetanephrine: Spuriously elevated test results may occur with liquid chromatography with electrochemical detection in patients receiving mesalamine; use alternative, selective assay for normetanephrine. (5.7) 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 mesalamine suppositories 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 mesalamine and periodically while on therapy.Evaluate the risks and benefits of using mesalamine in patients with known renal impairment or history of renal disease or taking concomitant nephrotoxic drugs [see Drug Interactions (7.1), Use in Specific Populations (8.6)].. 5.2 Mesalamine-Induced AcuteIntolerance 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, pruritis, conjunctivitis, and rash. Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with mesalamine.. 5.3 Hypersensitivity Reactions. Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have similar reaction to mesalamine suppositories 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 hypersensitivity reaction are present. Discontinue mesalamine suppositories 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 mesalamine in patients with known liver impairment.. 5.5 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 broad-spectrum sunscreen when outdoors.. 5.6 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 mesalamine suppositories.. 5.7 Interaction withLaboratory 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 mesalamines main metabolite, N-acetylaminosalicylic acid. Consider an alternative, selective assay for normetanephrine.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Mesalamine caused no increase in the incidence of neoplastic lesions over controls in 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 mesalamine, 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 mesalamine, based on body surface area).. 13.2 Animal Toxicology and/or Pharmacology. Toxicology studies of mesalamine were conducted in rats, mice, rabbits and dogs, and the kidney was the main target organ of toxicity. In rats, adverse renal effects were observed at single oral dose of 600 mg/kg (about 3.2 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and at intravenous doses of >214 mg/kg (about 1.2 times the recommended human intra-rectal dose of mesalamine, based on body surface area). In 13-week oral gavage toxicity study in rats, papillary necrosis and/or multifocal tubular injury were observed in males receiving 160 mg/kg (about 0.86 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and in both males and females at 640 mg/kg (about 3.5 times the recommended human intra-rectal dose of mesalamine, based on body surface area). In combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration of the kidneys and hyalinization of basement membranes and Bowmans capsule were observed at oral doses of 100 mg/kg/day (about 0.54 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and above. In 14-day rectal toxicity study of mesalamine suppositories in rabbits, intra-rectal doses up to 800 mg/kg (about 8.6 times the recommended human intra-rectal dose of mesalamine, based on body surface area) was not associated with any adverse effects. In six-month oral toxicity study in dogs, doses of 80 mg/kg (about 1.4 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and higher caused renal pathology similar to that described for the rat. In rectal toxicity study of mesalamine suppositories in dogs, dose of 166.6 mg/kg (about times the recommended human intra-rectal dose of mesalamine, based on body surface area) produced chronic nephritis and pyelitis. In the 12-month eye toxicity study in dogs, keratoconjunctivitis sicca (KCS) occurred at oral doses of 40 mg/kg (about 0.72 times the recommended human intra-rectal dose of mesalamine, based on body surface area) and above.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION. Mesalamine (me sal meen) Suppositories, for rectal useWhat are mesalamine suppositoriesMesalamine suppositories are prescription medicine used to treat adults with active ulcerative proctitis (ulcerative rectal colitis).It is not known if mesalamine suppositories are safe and effective in children.Do not use mesalamine suppositories if you are:allergic to medicines that contain salicylates, including aspirin.allergic to mesalamine or any of the ingredients in mesalamine suppositories. See the end of this Patient Information leaflet for complete list of ingredients in mesalamine suppositories.Ask your doctor if you are not sure if your medicine is listed above.Before using mesalamine suppositories, tell your doctor if you have any medical conditions, including if you:have history of allergic reaction to the medicine sulfasalazine (Azulfidine(R)).have kidney problems.have ever had inflammation of the sac around your heart (pericarditis).have liver problems.are pregnant or plan to become pregnant. It is not known if mesalamine suppositories can harm your unborn baby.are breastfeeding or plan to breastfeed. Mesalamine can pass into your breast milk. Talk to your doctor about the best way to feed your baby if you use mesalamine suppositories.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.Using mesalamine suppositories with certain other medicines may affect each other. Using mesalamine suppositories with other medicines can cause serious side effects.Especially tell your doctor if you take nonsteroidal anti-inflammatory drugs (NSAIDS), or medicines that contain azathioprine or 6-mercaptopurine. Taking mesalamine with NSAIDS may cause kidney problems. Taking mesalamine with azathioprine or 6-mercaptopurine may cause blood problems. Ask your doctor if you are not sure if you are taking one of these medicines.Your doctor may do certain tests during treatment with mesalamine suppositories. Know the medicines you take. Keep list of them to show your doctor and pharmacist when you get new medicine.How should take mesalamine suppositoriesUse mesalamine suppositories exactly as prescribed by your doctor. Your doctor will tell you how long to continue using mesalamine suppositories.Mesalamine suppositories come as suppositories that you insert into your rectum.Do not cut or break the suppository.Use mesalamine suppositories time each day at bedtime, for to weeks. It is not known if mesalamine suppositories are safe and effective for use for longer than weeks.After you insert mesalamine suppository in your rectum, try to keep (retain) the suppository in your rectum for to hours or longer if possible.It is important for you to stay well hydrated during treatment with mesalamine suppositories. Be sure to drink plenty of fluids while taking mesalamine suppositories.If you miss dose of mesalamine suppository, insert it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Insert the next dose at your regular time. Do not insert doses at the same time.Mesalamine suppositories can stain surfaces including clothing and other fabrics, flooring, painted surfaces, marble, granite, vinyl and enamel. Keep mesalamine suppositories away from these surfaces to prevent staining.What are the possible side effects of mesalamine suppositories Mesalamine suppositories may cause serious side effects, including:kidney problems. Your doctor will do certain tests before you start using mesalamine suppositories and during your treatment with mesalamine suppositories.acute intolerance syndrome and other allergic reactions. Some people who use mesalamine suppositories can have allergic type reactions, including Acute Intolerance Syndrome. Other allergic reactions can cause heart problems including an inflammation of the sac around the heart (pericarditis), blood problems, and problems with other organs in the body including the kidneys, liver and lungs. These problems usually happen in people who have had an allergic reaction to medicines containing sulfasalazine. Stop using mesalamine suppositories and tell your doctor right away if you get any of these symptoms:crampsfeverstomach (abdominal) painheadachebloody diarrhearashchest painshortness of breathdecrease in the amount of urinefatigue eye inflammation liver problems. This can happen in people who have history of liver problems and have taken other medicines that contain mesalamine. Tell your doctor right away if you get any of these symptoms while using mesalamine suppositories:yellowing of your eyesflu-like symptomsitchy skinnausea or vomitingfeeling very tired sun sensitivity. Mesalamine suppositories can make your skin sensitive to the sun if you have skin conditions such as atopic dermatitis and atopic eczema. Try to limit your time in the sun. You should use sunscreen and wear hat and clothes that cover your skin if you have to be in the sunlight. kidney stones. Drink plenty of fluids when using mesalamine suppositories to decrease your chance of getting kidney stones. Call your doctor right away if you get any of these symptoms: severe pain in your side blood in your urine severe pain in your back The most common side effects of mesalamine suppositories include:dizzinessrectal painacnefeverinflammation of the large intestine (colitis)rashThese are not all of the possible side effects of mesalamine suppositories.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store mesalamine suppositoriesStore mesalamine suppositories at room temperature between 68F to 77F (20C to 25C).Mesalamine suppositories may be refrigerated.Keep mesalamine suppositories away from direct heat, light, or humidity.Keep mesalamine suppositories and all medicines out of the reach of children.General information about the safe and effective use of mesalamine suppositories.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use mesalamine suppositories for condition for which they were not prescribed. Do not give mesalamine suppositories to other people, even if they have the same symptoms that you have. It may harm them.You can ask your pharmacist or healthcare provider for information about mesalamine suppositories that is written for health professionals.What are the ingredients in mesalamine suppositoriesActive ingredients: mesalamine, USPInactive ingredients: hard fat baseBrands listed are the trademarks of their respective owners.Manufactured For: Teva Pharmaceuticals USA, Inc., North Wales, PA 19454For more information call Teva Pharmaceuticals USA, Inc. at 1-888-838-2872.This Patient Information has been approved by the U.S. Food and Drug Administration. Iss. 4/2021. allergic to medicines that contain salicylates, including aspirin.. allergic to mesalamine or any of the ingredients in mesalamine suppositories. See the end of this Patient Information leaflet for complete list of ingredients in mesalamine suppositories.. have history of allergic reaction to the medicine sulfasalazine (Azulfidine(R)).. have kidney problems.. have ever had inflammation of the sac around your heart (pericarditis).. have liver problems.. are pregnant or plan to become pregnant. It is not known if mesalamine suppositories can harm your unborn baby.. are breastfeeding or plan to breastfeed. Mesalamine can pass into your breast milk. Talk to your doctor about the best way to feed your baby if you use mesalamine suppositories.. Use mesalamine suppositories exactly as prescribed by your doctor. Your doctor will tell you how long to continue using mesalamine suppositories.. Mesalamine suppositories come as suppositories that you insert into your rectum.. Do not cut or break the suppository.. Use mesalamine suppositories time each day at bedtime, for to weeks. It is not known if mesalamine suppositories are safe and effective for use for longer than weeks.. After you insert mesalamine suppository in your rectum, try to keep (retain) the suppository in your rectum for to hours or longer if possible.. It is important for you to stay well hydrated during treatment with mesalamine suppositories. Be sure to drink plenty of fluids while taking mesalamine suppositories.. If you miss dose of mesalamine suppository, insert it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Insert the next dose at your regular time. Do not insert doses at the same time.. Mesalamine suppositories can stain surfaces including clothing and other fabrics, flooring, painted surfaces, marble, granite, vinyl and enamel. Keep mesalamine suppositories away from these surfaces to prevent staining.. kidney problems. Your doctor will do certain tests before you start using mesalamine suppositories and during your treatment with mesalamine suppositories.. acute intolerance syndrome and other allergic reactions. Some people who use mesalamine suppositories can have allergic type reactions, including Acute Intolerance Syndrome. Other allergic reactions can cause heart problems including an inflammation of the sac around the heart (pericarditis), blood problems, and problems with other organs in the body including the kidneys, liver and lungs. These problems usually happen in people who have had an allergic reaction to medicines containing sulfasalazine. Stop using mesalamine suppositories and tell your doctor right away if you get any of these symptoms:. cramps. fever. stomach (abdominal) pain. headache. bloody diarrhea. rash. chest pain. shortness of breath. decrease in the amount of urine. fatigue. eye inflammation. liver problems. This can happen in people who have history of liver problems and have taken other medicines that contain mesalamine. Tell your doctor right away if you get any of these symptoms while using mesalamine suppositories:. yellowing of your eyes. flu-like symptoms. itchy skin. nausea or vomiting. feeling very tired. sun sensitivity. Mesalamine suppositories can make your skin sensitive to the sun if you have skin conditions such as atopic dermatitis and atopic eczema. Try to limit your time in the sun. You should use sunscreen and wear hat and clothes that cover your skin if you have to be in the sunlight.. kidney stones. Drink plenty of fluids when using mesalamine suppositories to decrease your chance of getting kidney stones. Call your doctor right away if you get any of these symptoms:. severe pain in your side. blood in your urine. severe pain in your back. dizziness. rectal pain. acne. fever. inflammation of the large intestine (colitis). rash. Store mesalamine suppositories at room temperature between 68F to 77F (20C to 25C).. Mesalamine suppositories may be refrigerated.. Keep mesalamine suppositories away from direct heat, light, or humidity.