ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling:oHypersensitivity reactions [see Warnings and Precautions (5.1)]oRenal impairment [see Warnings and Precautions (5.2)]oMesalamine-induced acute intolerance syndrome [see Warnings and Precautions (5.3)]oHepatic failure [see Warnings and Precautions (5.4)]oSevere cutaneous adverse reactions [see Warnings and Precautions (5.5)]oPhotosensitivity [see Warnings and Precautions (5.6)]oNephrolithiasis [see Warnings and Precautions (5.7)]. oHypersensitivity reactions [see Warnings and Precautions (5.1)]. oRenal impairment [see Warnings and Precautions (5.2)]. oMesalamine-induced acute intolerance syndrome [see Warnings and Precautions (5.3)]. oHepatic failure [see Warnings and Precautions (5.4)]. oSevere cutaneous adverse reactions [see Warnings and Precautions (5.5)]. oPhotosensitivity [see Warnings and Precautions (5.6)]. oNephrolithiasis [see Warnings and Precautions (5.7)]. Most common adverse reactions (>=1%) are: gas/flatulence, flu, fever, leg/joint pain, hemorrhoids, rectal pain and hair loss. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc at 1-866-210-5949 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical 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.Table 1: Adverse Reactionsreported in 1% or more of ROWASA-treated patients and greater than placebo in Clinical Trials of ROWASA in Adult Patients with Ulcerative Colitis, Proctosigmoiditis or ProctitisAdverse ReactionROWASA(N=815)%Placebo(N=128)%Gas/Flatulence64Flu51Fever30Leg/Joint pain21Hemorrhoids11Rectal pain10Hair loss10 6.2Postmarketing Experience The following adverse reactions have been identified during post-approval use of mesalamine. 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. Cardiac Disorders: myocarditis, pericarditis [see Warnings and Precautions (5.1)]Gastrointestinal Disorders: pancreatitisHematologic Disorders: agranulocytosis, aplastic anemia, eosinophilia, leukopenia, neutropenia, pancytopenia, thrombocytopeniaHepatic Disorders: elevated liver enzymes, hepatic failure [see Warnings and Precautions (5.4)]Nervous System: intracranial hypertensionRenal 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 bleachReproductive System and Breast Disorders: reversible oligospermiaRespiratory, Thoracic, and Mediastinal Disorders: fibrosing alveolitis, pleurisy/pleuritisSkin and Subcutaneous Tissue Disorders: AGEP, DRESS, SJS/TEN [see Warnings and Precautions (5.5)].

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

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 single 600 mg/kg oral dose, but not after 200 mg/kg dose. Gross kidney lesions, including papillary necrosis, were observed after single oral >900 mg/kg dose, and after I.V. doses of >214 mg/kg. Mice responded similarly. In 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 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 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 Bowmans 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 highly bioavailable suspension where absorption throughout the gastrointestinal tract occurred.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of 5-ASA (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.. 12.2 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 ROWASA 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 mcg/mL, about two-thirds of which was the N-acetyl metabolite. In addition, steady state plasma levels demonstrated 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 half-life of to 10 hours.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES In 6-week placebo-controlled trial, international, multicenter trial of 153 patients with active distal ulcerative colitis, proctosigmoiditis or proctitis, ROWASA(R) (mesalamine) Rectal Suspension Enema reduced the overall disease activity index (DAI) and individual components as follows:EFFECT OF TREATMENT ON SEVERITY OF DISEASE DATA FROM U.S.-CANADA TRIAL COMBINED RESULTS OF EIGHT CENTERSEach parameter has 4-point scale with numerical rating:0 normal, = mild, = moderate, = severe. The four parameters are added together to produce maximum overall DAI of 12.Activity Indices, meanNBaselineDay 22End PointChange Baseline to End PointPercent change for overall DAI only (calculated by taking the average of the change for each individual patient).Overall DAIROWASA(R) Placebo76777.427.404.05Significant ROWASA(R)/placebo difference. < 0.01 6.033.37Significant ROWASA(R)/placebo difference. < 0.001 5.83-55.07% -21.58%Stool FrequencyROWASA(R) Placebo1.581.921.11Significant ROWASA(R)/placebo difference. < 0.05 1.471.01 1.50-0.57 -0.41Rectal BleedingROWASA(R) Placebo1.821.730.59 1.210.51 1.11-1.30 -0.61Mucosal InflammationROWASA(R) Placebo2.172.181.22 1.740.96 1.61-1.21 -0.56Physicians Assessment of Disease SeverityROWASA(R) Placebo1.861.871.13 1.620.88 1.55-0.97 -0.30Differences between ROWASA(R) (mesalamine) Rectal Suspension Enema and placebo were also statistically different in subgroups of patients on concurrent sulfasalazine and in those having an upper disease boundary between and 20 or 20 and 40 cm. Significant differences between ROWASA(R) (mesalamine) Rectal Suspension Enema and placebo were not achieved in those subgroups of patients on concurrent prednisone or with an upper disease boundary between 40 and 50 cm.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION Evaluate renal function before initiating therapy with ROWASA [see Warnings and Precautions (5.1)]. Recommended DosageThe recommended dosage is one rectal instillation (4 grams) once day, preferably at bedtime, and retained for approximately eight hours for to weeks depending on symptoms and sigmoidoscopic findings. Administration InstructionsoShake the bottle to ensure the suspension is homogeneous. oRemove the protective sheath from the applicator tip. oAssume the correct body position:oLie on the left side with the lower leg extended and the upper right leg flexed forward for balance. oAlternatively, sit in the knee to chest position. oGently insert the applicator tip in the rectum pointing toward the umbilicus. oSteadily squeeze the bottle to discharge the medication. oRemain in the position for at least 30 minutes. Administer at bedtime with the objective of retaining it all night. oDrink an adequate amount of fluids during treatment [see Warnings and Precautions (5.7)].. oShake the bottle to ensure the suspension is homogeneous. oRemove the protective sheath from the applicator tip. oAssume the correct body position:oLie on the left side with the lower leg extended and the upper right leg flexed forward for balance. oAlternatively, sit in the knee to chest position. oLie on the left side with the lower leg extended and the upper right leg flexed forward for balance. oAlternatively, sit in the knee to chest position. oGently insert the applicator tip in the rectum pointing toward the umbilicus. oSteadily squeeze the bottle to discharge the medication. oRemain in the position for at least 30 minutes. Administer at bedtime with the objective of retaining it all night. oDrink an adequate amount of fluids during treatment [see Warnings and Precautions (5.7)].. oEvaluate renal function prior to initiation of ROWASA and periodically while on therapy. (2, 5.1)oThe recommended dosage is one rectal instillation (4 grams) once day, preferably at bedtime, and retained for approximately eight hours for to weeks depending on symptoms and sigmoidoscopic findings. (2)oDrink an adequate amount of fluids. (2. 5.7). oEvaluate renal function prior to initiation of ROWASA and periodically while on therapy. (2, 5.1). oThe recommended dosage is one rectal instillation (4 grams) once day, preferably at bedtime, and retained for approximately eight hours for to weeks depending on symptoms and sigmoidoscopic findings. (2). oDrink an adequate amount of fluids. (2. 5.7).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oNephrotoxic Agents including Non-Steroidal Anti-inflammatory Drugs (NSAIDs): Increased risk of nephrotoxicity; monitor for changes in renal function and mesalamine-related adverse reactions. (7.1)oAzathioprine or 6-Mercaptopurine: Increased risk of blood dyscrasias; monitor complete blood cell counts and platelet counts. (7.2). oNephrotoxic Agents including Non-Steroidal Anti-inflammatory Drugs (NSAIDs): Increased risk of nephrotoxicity; monitor for changes in renal function and mesalamine-related adverse reactions. (7.1). oAzathioprine or 6-Mercaptopurine: Increased risk of blood dyscrasias; monitor complete blood cell counts and platelet counts. (7.2). 7.1Nephrotoxic 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)].. 7.2Azathioprine 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 ROWASA 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 ROWASA 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Instructions for Use).Renal ImpairmentInform patients that ROWASA may decrease their renal function, especially if they have known renal impairment or are taking nephrotoxic drugs, 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)].Mesalamine-Induced Acute Intolerance Syndrome and Other Hypersensitivity ReactionsInstruct patients to stop taking ROWASA and report to their healthcare provider if they experience new or worsening symptoms of acute intolerance syndrome (cramping, abdominal pain, bloody diarrhea, fever, headache, and rash) or other symptoms suggestive of mesalamine-induced hypersensitivity [see Warnings and Precautions (5.2, 5.3)].Hepatic FailureAdvise patients with known liver disease to contact their healthcare provider if they experience signs or symptoms of worsening liver function [see Warnings and Precautions (5.4)].Severe Cutaneous Adverse ReactionsInform patients of the signs and symptoms of severe cutaneous adverse reactions. Instruct patients to stop taking ROWASA and report to their healthcare provider at first appearance of severe cutaneous adverse reaction or other sign of hypersensitivity [see Warnings and Precautions (5.5)].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 (5.7)].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 (5.8)]. 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)].AdministrationAdvise patients that ROWASA will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Administer the product in suitable location.Instruct patients:oShake the bottle to ensure the suspension is homogeneous. oRemove the protective sheath from the applicator tip. oLie on the left side with the lower leg extended and the upper right leg flexed forward for balance. Alternatively, alternative is the knee-chest position. oGently insert the applicator tip in the rectum pointing toward the umbilicus. oSteadily squeeze the bottle to discharge the medication. oAdminister at bedtime with the objective of retaining it all night. oDrink an adequate amount of fluids during treatment [see Warnings and Precautions (5.7)].oAdvise patients that urine may become discolored reddish-brown while taking ROWASA when it comes in contact with surfaces or water treated with hypochlorite-containing bleach. If discolored urine is observed, advise patients to observe their urine flow. Report to the healthcare provider only if urine is discolored on leaving the body, before contact with any surface or water (e.g., in the toilet).IN-003606-08Distributed by: MEDA PHARMACEUTICALS Canonsburg, PA 15317 U.S.A.(C) 2024 Viatris Inc.ROWASA is registered trademark of Alaven Pharmaceutical LLC, Viatris Company.For Medical Inquiries, Call Toll Free:1-866-210-5949. oShake the bottle to ensure the suspension is homogeneous. oRemove the protective sheath from the applicator tip. oLie on the left side with the lower leg extended and the upper right leg flexed forward for balance. Alternatively, alternative is the knee-chest position. oGently insert the applicator tip in the rectum pointing toward the umbilicus. oSteadily squeeze the bottle to discharge the medication. oAdminister at bedtime with the objective of retaining it all night. oDrink an adequate amount of fluids during treatment [see Warnings and Precautions (5.7)].. oAdvise patients that urine may become discolored reddish-brown while taking ROWASA when it comes in contact with surfaces or water treated with hypochlorite-containing bleach. If discolored urine is observed, advise patients to observe their urine flow. Report to the healthcare provider only if urine is discolored on leaving the body, before contact with any surface or water (e.g., in the toilet).

LACTATION SECTION.

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 clear determination of the risk of ROWASA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ROWASA and any potential adverse effects on the breastfed child from ROWASA 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 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 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.

SPL PATIENT PACKAGE INSERT SECTION.

INSTRUCTIONS FOR USE ROWASA [ro wa sa](mesalamine) rectal suspensionThis Instructions for Use contains information on how to use ROWASA rectal suspension. Read these Instructions for Use that come with your ROWASA rectal suspension before you start using it and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.How should Store ROWASAoStore ROWASA at room temperature between 68F to 77F (20C to 25C). oROWASA is an off-white to tan colored suspension. The medicine removed from the foil pouch may darken with time. Slight darkening will not affect how well ROWASA works. oThrow away ROWASA rectal suspensions with dark brown medicine.oKeep ROWASA and all medicines out of the reach of children.Important Information You Need to Know Before Using ROWASAoROWASA is for rectal use only.oDo not share ROWASA with other people, it may harm them.oIf caregiver is giving ROWASA make sure they read and understand these Instructions for Use.oUse ROWASA exactly as your healthcare provider tells you to use it. oIt is recommended to use ROWASA bottle each day.oAfter the foil wrapped unit of bottles is opened, use each bottle of ROWASA rectal suspension right away. oEmpty bowels right before the medicine is given.oGive at bedtime.oROWASA will stain some surfaces including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Take care in choosing the right place for giving the ROWASA rectal suspension.Preparing to use ROWASAStep 1. Remove the bottles. oRemove all the bottles from the protective foil pouch by grasping at the seam and tearing downward or by using scissors at the top of the foil pouch (See Figure A).oBe careful not to squeeze or puncture bottles. Step 2. Prepare to give the medicine. oShake the first bottle well to make sure that the medicine is mixed well.oRemove the protective sheath from the applicator tip. Hold the bottle at the neck so as not to cause any of the medicine to be released (See Figure B).Step 3. Get in position. oLay on your left side with your left leg extended and your right leg flexed forward for balance (See Figure C).oroGet in the knee-chest position as shown here (See Figure D).Step 4. Giving the medicine. oLubricate the applicator tip.oGently insert the lubricated applicator tip into the rectum pointing slightly toward the belly button (navel) to prevent damage to the rectal wall.oGrasp the bottle firmly, then tilt slightly so that the nozzle is aimed toward the back.oSqueeze the bottle slowly to release the medicine into the rectum (See Figure E). oSteady hand pressure will release most of the medicine.oAfter giving the medicine, withdraw the applicator tip. oRemain in position for at least 30 minutes to allow the medicine to spread inside the body. oThrow away (discard) the bottle. oTry to keep the medicine inside your body all night, if possible.IN-003606-08Rev. 7/2024Distributed by:MEDAPHARMACEUTICALSCanonsburg, PA 15317 U.S.A.(C) 2024 Viatris Inc.ROWASA is registeredtrademark of Alaven Pharmaceutical LLC, Viatris Company. For Medical Inquiries, Call Toll Free:1-866-210-5949 oStore ROWASA at room temperature between 68F to 77F (20C to 25C). oROWASA is an off-white to tan colored suspension. The medicine removed from the foil pouch may darken with time. Slight darkening will not affect how well ROWASA works. oThrow away ROWASA rectal suspensions with dark brown medicine.. oKeep ROWASA and all medicines out of the reach of children.. oROWASA is for rectal use only.. oDo not share ROWASA with other people, it may harm them.. oIf caregiver is giving ROWASA make sure they read and understand these Instructions for Use.. oUse ROWASA exactly as your healthcare provider tells you to use it. oIt is recommended to use ROWASA bottle each day.. oAfter the foil wrapped unit of bottles is opened, use each bottle of ROWASA rectal suspension right away. oEmpty bowels right before the medicine is given.. oGive at bedtime.. oROWASA will stain some surfaces including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Take care in choosing the right place for giving the ROWASA rectal suspension.. oRemove all the bottles from the protective foil pouch by grasping at the seam and tearing downward or by using scissors at the top of the foil pouch (See Figure A).. oBe careful not to squeeze or puncture bottles. oShake the first bottle well to make sure that the medicine is mixed well.. oRemove the protective sheath from the applicator tip. Hold the bottle at the neck so as not to cause any of the medicine to be released (See Figure B).. oLay on your left side with your left leg extended and your right leg flexed forward for balance (See Figure C).. oGet in the knee-chest position as shown here (See Figure D).. oLubricate the applicator tip.. oGently insert the lubricated applicator tip into the rectum pointing slightly toward the belly button (navel) to prevent damage to the rectal wall.. oGrasp the bottle firmly, then tilt slightly so that the nozzle is aimed toward the back.. oSqueeze the bottle slowly to release the medicine into the rectum (See Figure E). oSteady hand pressure will release most of the medicine.. oAfter giving the medicine, withdraw the applicator tip. oRemain in position for at least 30 minutes to allow the medicine to spread inside the body. oThrow away (discard) the bottle. oTry to keep the medicine inside your body all night, if possible.. Figure A, Instructions for Use. Figure B, Instructions for Use. Figure C, Instructions for Use. Figure D, Instructions for Use. Figure E, Instructions for Use.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis. In 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 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 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 single 600 mg/kg oral dose, but not after 200 mg/kg dose. Gross kidney lesions, including papillary necrosis, were observed after single oral >900 mg/kg dose, and after I.V. doses of >214 mg/kg. Mice responded similarly. In 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 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 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 Bowmans 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 highly bioavailable suspension where absorption throughout the gastrointestinal tract occurred.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 4.0g/60mL NDC 0037-0066-057 60 mL Unit-Dose Bottles7 packRowasa(R) (mesalamine)Rectal Suspension Enema KIT4.0g/60mLFor Rectal Use Only Rx OnlyKit includes7 complimentarycleansing wipes.Dispense in existingpackaging as one unit,do not repackage.Each disposable unit contains:Mesalamine (5-aminosalicylic acid)............4.0 gramsin suspension containing carbomer 934P, edetate disodium, potassium acetate,potassium metabisulfite, purified water, sodium benzoate, and xanthan gum.USUAL DOSE: One unit-dose suspension in the evenings before going to bed.See package insert for complete prescribing information including usual dose.See enclosed directions for use.Use as directed by your physician.KEEP THIS AND ANY MEDICATION OUT OF REACH OF CHILDREN.SHAKE WELL BEFORE USING.FOIL WRAP PROTECTS PRODUCT FROM DISCOLORATION. DO NOT REMOVE PRODUCT FROM FOIL WRAP UNTIL READY TO USE.Product contents may darken with time.NOTE: product contents will cause staining of most direct contact surfaces.Store at controlled room temperature 20 to 25C (68 to 77F); brief excursionspermitted 15 to 30C (59 to 86F) [See USP].Dispensed in original foil-wrapped package. Individual trays are not to bedispensed separately.For medical inquiries, call toll-free 1-866-210-5949.SHAKE WELL BEFORE USINGDistributed by: MEDA PHARMACEUTICALS(R) Canonsburg, PA 15317 U.S.A. (C) 2023 Viatris Inc.UC-003605-04Rev. 10/2023. Rowasa Rectal Suspension Enema Carton Label.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Absorption. Mesalamine administered rectally as ROWASA 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 mcg/mL, about two-thirds of which was the N-acetyl metabolite. In addition, steady state plasma levels demonstrated 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 half-life of to 10 hours.

PREGNANCY SECTION.

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 and 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 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 ROWASA, 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 and times respectively, the maximum recommended human dose, and have revealed no evidence of harm to the embryo or the fetus.

SPL UNCLASSIFIED SECTION.

5.1Hypersensitivity Reactions Sulfite-Related Reactions. ROWASA contains potassium metabisulfite, 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 life-threatening situation may not be satisfactory. The presence of 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 similar reaction to ROWASA 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 ROWASA if an alternative etiology for the signs and symptoms cannot be established.

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 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 and 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 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 ROWASA, 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 and 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 clear determination of the risk of ROWASA to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ROWASA and any potential adverse effects on the breastfed child from ROWASA 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 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 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 ROWASA 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 ROWASA 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 ROWASA. 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 ROWASA. 8.6Renal 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 ROWASA 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 ROWASA if renal function deteriorates while on therapy [see Warnings and Precautions (5.2)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHypersensitivity Reactions: Sulfite-related reactions (ROWASA contains potassium metabisulfite) and sulfasalazine-associated reactions (myocarditis and pericarditis) can occur; evaluate patients immediately and discontinue ROWASA if hypersensitivity reaction is suspected. (5.3)oRenal Impairment: Assess renal function at the beginning of treatment and periodically during treatment. Evaluate the risks and benefits of ROWASA in patients with known renal impairment or taking nephrotoxic drug. Discontinue ROWASA if renal function deteriorates while on therapy. (5.1, 7.1)oMesalamine-Induced Acute Intolerance Syndrome: Discontinue treatment if acute intolerance syndrome (cramping, acute abdominal pain, bloody diarrhea, sometimes fever, headache and rash) is suspected. (5.2)oHepatic Failure: Evaluate the risks and benefits of using ROWASA in patients with known liver impairment. (5.4)oSevere Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other sings of hypersensitivity and consider further evaluation. (5.5)oPhotosensitivity: Avoid sun exposure if pre-existing skin conditions. (5.6)oNephrolithiasis: Cases of nephrolithiasis have been reported with the use of mesalamine. Mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment. (5.7)oInterference with Laboratory Tests: Mesalamine may lead to elevated urinary normetanephrine test results. (5.8). oHypersensitivity Reactions: Sulfite-related reactions (ROWASA contains potassium metabisulfite) and sulfasalazine-associated reactions (myocarditis and pericarditis) can occur; evaluate patients immediately and discontinue ROWASA if hypersensitivity reaction is suspected. (5.3). oRenal Impairment: Assess renal function at the beginning of treatment and periodically during treatment. Evaluate the risks and benefits of ROWASA in patients with known renal impairment or taking nephrotoxic drug. Discontinue ROWASA if renal function deteriorates while on therapy. (5.1, 7.1). oMesalamine-Induced Acute Intolerance Syndrome: Discontinue treatment if acute intolerance syndrome (cramping, acute abdominal pain, bloody diarrhea, sometimes fever, headache and rash) is suspected. (5.2). oHepatic Failure: Evaluate the risks and benefits of using ROWASA in patients with known liver impairment. (5.4). oSevere Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other sings of hypersensitivity and consider further evaluation. (5.5). oPhotosensitivity: Avoid sun exposure if pre-existing skin conditions. (5.6). oNephrolithiasis: Cases of nephrolithiasis have been reported with the use of mesalamine. Mesalamine-containing stones are undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment. (5.7). oInterference with Laboratory Tests: Mesalamine may lead to elevated urinary normetanephrine test results. (5.8). 5.1Hypersensitivity Reactions Sulfite-Related Reactions. ROWASA contains potassium metabisulfite, 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 life-threatening situation may not be satisfactory. The presence of 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 similar reaction to ROWASA 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 ROWASA if an alternative etiology for the signs and symptoms cannot be established. 5.2Renal Impairment Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and renal failure have been reported in patients given ROWASA 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 ROWASA in patients with known renal impairment or history of renal disease or taking concomitant nephrotoxic drugs. Evaluate renal function in all patients prior to initiation and periodically while on ROWASA therapy. Discontinue ROWASA if renal function deteriorates while on therapy [see Drug Interactions (7.1), Use in Specific Populations (8.6)].. 5.3Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from 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 ROWASA.. 5.4Hepatic 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 ROWASA in patients with known liver impairment.. 5.5Severe 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 ROWASA at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.. 5.6Photosensitivity 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 broad-spectrum sunscreen when outdoors.. 5.7Nephrolithiasis 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. 5.8Interference 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.