ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Clinical Adverse Experience. sfROWASA(R) (mesalamine) Rectal Suspension is usually well tolerated. Most adverse effects have been mild and transient.ADVERSE REACTIONS OCCURRING IN MORE THAN 0.1% OF sfROWASA(R) (MESALAMINE) RECTAL SUSPENSION TREATED PATIENTS (COMPARISON TO PLACEBO)SYMPTOMsfROWASA(R) = 815PLACEBON 128N%N%Abdominal Pain/Cramps/Discomfort668.10107.81Headache536.501612.50Gas/Flatulence506.1353.91Nausea475.77129.38Flu435.2810.78Tired/Weak/Malaise/Fatigue283.4486.25Fever263.1900.00Rash/Spots232.8243.12Cold/Sore Throat192.3397.03Diarrhea172.0953.91Leg/Joint Pain172.0910.78Dizziness151.8432.34Bloating121.4721.56Back Pain111.3510.78Pain on Insertion of Enema Tip111.3510.78Hemorrhoids111.3500.00Itching101.2310.78Rectal Pain101.2300.00Constipation80.9843.12Hair Loss70.8600.00Peripheral Edema50.61118.59UTI/Urinary Burning50.6143.12Rectal Pain/Soreness/Burning50.6132.34Asthenia10.1243.12Insomnia10.1232.34In addition, the following adverse events have been identified during post-approval use of products which contain (or are metabolized to) mesalamine in clinical practice: nephrotoxicity, pancreatitis, fibrosing alveolitis, elevated liver enzymes, nephrogenic diabetes insipidus, intracranial hypertension and nephrolithiasis. Cases of pancreatitis and fibrosing alveolitis have been reported as manifestations of inflammatory bowel disease as well. Published case reports and/or spontaneous post marketing surveillance have described rare instances of aplastic anemia, agranulocytosis, thrombocytopenia, eosinophilia, pancytopenia, neutropenia, oligospermia, and infertility in men. Anemia, leukocytosis, and thrombocytosis can be part of the clinical presentation of inflammatory bowel disease. Hair Loss. Mild hair loss characterized by more hair in the comb but no withdrawal from clinical trials has been observed in of 815 mesalamine patients but none of the placebo-treated patients. In the literature there are at least six additional patients with mild hair loss who received either mesalamine or sulfasalazine. Retreatment is not always associated with repeated hair loss.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Sulfasalazine is split by bacterial action in the colon into sulfapyridine (SP) and mesalamine (5-ASA). It is thought that the mesalamine component is therapeutically active in ulcerative colitis [A.K. Azad Khan et al, Lancet 2:892-895 (1977)]. The usual oral dose of sulfasalazine for active ulcerative colitis in adults is two to four grams per day in divided doses. Four grams of sulfasalazine provide 1.6 of free mesalamine to the colon. Each sfROWASA(R) (mesalamine) Rectal Suspension delivers up to g of mesalamine to the left side of the colon. The mechanism of action of mesalamine (and sulfasalazine) is not fully understood, but appears to be topical anti-inflammatory effect on colonic epithelial cells. Mucosal production of arachidonic acid (AA) metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) is increased in patients with ulcerative colitis, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin (PG) production in the colon.. Preclinical Toxicology. 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. The human dose of grams represents approximately 80 mg/kg but when mesalamine is given rectally as suspension, absorption is poor and limited to the distal colon (see Pharmacokinetics). Overt renal toxicity has not been observed (see ADVERSE REACTIONS and PRECAUTIONS), but the potential must be considered.. Pharmacokinetics. Mesalamine administered rectally 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. At steady state, approximately 10 to 30% of the daily 4-gram dose can be recovered in cumulative 24-hour urine collections. Other than the kidney, the organ distribution and other bioavailability characteristics of absorbed mesalamine in man are not known. It is known that the compound undergoes acetylation but whether this process takes place at colonic or systemic sites has not been elucidated. Whatever the metabolic site, most of the absorbed mesalamine is excreted in the urine as the N-acetyl-5-ASA metabolite. 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. Under clinical conditions patients demonstrated plasma levels 10 to 12 hours post mesalamine administration of ug/mL, about two-thirds of which was the N-acetyl metabolite. While the elimination half-life of mesalamine is short (0.5 to 1.5 h), the acetylated metabolite exhibits half-life of to 10 hours [U. Klotz, Clin. Pharmacokin. 10:285-302 (1985)]. In addition, steady state plasma levels demonstrated lack of accumulation of either free or metabolized drug during repeated daily administrations.. Efficacy. In placebo-controlled, international, multicenter trial of 153 patients with active distal ulcerative colitis, proctosigmoiditis or proctitis, sfROWASA(R) (mesalamine) Rectal Suspension 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 CENTERSActivity Indices, meanEach 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.NBaselineDay 22End PointChangeBaseline toEnd PointPercent change for overall DAI only (calculated by taking the average of the change for each individual patient).Overall DAIsfROWASA(R) Placebo76777.427.404.05Significant sfROWASA(R)/placebo difference. < 0.01 6.033.37Significant sfROWASA (R)/placebo difference. < 0.001 5.83-55.07% -21.58%StoolFrequencysfROWASA(R) Placebo1.581.921.11Significant sfROWASA (R)/placebo difference. < 0.05 1.471.01 1.50-0.57 -0.41RectalBleeding sfROWASA(R) Placebo1.821.730.59 1.210.51 1.11-1.30 -0.61MucosalInflammation sfROWASA(R) Placebo2.172.181.22 1.740.96 1.61-1.21 -0.56Physicians Assessmentof Disease Severity sfROWASA(R) Placebo1.861.871.13 1.620.88 1.55-0.97 -0.30Differences between sfROWASA (R) (mesalamine) Rectal Suspension 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 sfROWASA(R) (mesalamine) Rectal Suspension 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.

DOSAGE AND ADMINISTRATION. The recommended adult dosage of sfROWASA(R) (mesalamine) Rectal Suspension in 60 mL units is one rectal instillation (4 grams) once day, preferably at bedtime, and retained for approximately eight hours. While the effect of sfROWASA(R) (mesalamine) Rectal Suspension may be seen within to 21 days, the usual course of therapy would be from to weeks depending on symptoms and sigmoidoscopic findings. Studies available to date have not assessed if sfROWASA(R) (mesalamine) Rectal Suspension will modify relapse rates after the 6-week short-term treatment. sfROWASA(R) (mesalamine) Rectal Suspension is for rectal use only.Drink an adequate amount of fluids during treatment.Patients should be instructed to shake the bottle well to make sure the suspension is homogeneous. The patient should remove the protective sheath from the applicator tip. Holding the bottle at the neck will not cause any of the medication to be discharged. The position most often used is obtained by lying on the left side (to facilitate migration into the sigmoid colon); with the lower leg extended and the upper right leg flexed forward for balance. An alternative is the knee-chest position. The applicator tip should be gently inserted in the rectum pointing toward the umbilicus. steady squeezing of the bottle will discharge most of the preparation. The preparation should be taken at bedtime with the objective of retaining it all night. Patient instructions are included with every seven units.

HOW SUPPLIED SECTION.

HOW SUPPLIED. sfROWASA(R) (mesalamine) Rectal Suspension for rectal administration is an off-white to tan colored suspension. Each disposable enema bottle contains 4.0 grams of mesalamine in 60 mL aqueous suspension. Bottles are supplied in boxed, foil-wrapped trays as follows:NDC 0037-0022-60......... Sample 1 bottleNDC 0037-0022-07......... Carton of BottlesNDC 0037-0022-14......... Carton of 14 BottlesNDC 0037-0022-28......... Carton of 28 BottlessfROWASA(R) (mesalamine) Rectal Suspension are for rectal use only.KEEP OUT OF REACH OF CHILDRENPatient instructions are included.. Storage. Store at controlled room temperature 20 to 25C (68 to 77F); excursions permitted, please refer to current USP. Once the foil-wrapped unit of seven bottles is opened, all enemas should be used promptly as directed by your physician. Contents of enemas removed from the foil pouch may darken with time. Slight darkening will not affect potency, however, enemas with dark brown contents should be discarded. Clinical studies were performed using ROWASA(R) (mesalamine) Rectal Suspension Enema, 4g/60mL, the original formulation, which contains the ingredient potassium metabisulfite.NOTE: sfROWASA(R) (mesalamine) Rectal Suspension will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Take care in choosing suitable location for administration of this product.

INSTRUCTIONS FOR USE SECTION.

PATIENT INSTRUCTIONS. How to Use this Medication.Best results are achieved if the bowel is emptied immediately before the medication is given.Use as prescribed by your physician.Do not consume the Oxygen Scavenger Pack included in the foil pouch.NOTE: sfROWASA(R) (mesalamine) Rectal Suspension will cause staining of direct contact surfaces, including but not limited to fabrics, flooring, painted surfaces, marble, granite, vinyl, and enamel. Take care in choosing suitable location for administration of this product.1. Remove the Bottlesa. Remove the bottles from the protective foil pouch by tearing or by using scissors as shown, being careful not to squeeze or puncture bottles. sfROWASA(R) (mesalamine) Rectal Suspension is an off-white to tan colored suspension. Once the foil-wrapped unit of seven bottles is opened, any bottles remaining after 14 days should be discarded. Contents of products removed from the foil pouch may darken with time. Slight darkening will not affect potency, however, product with dark brown contents should be discarded.2. Prepare the Medication for Administrationa. Shake the bottle well to make sure that the medication is thoroughly mixed.b. Remove the protective sheath from the applicator tip. Hold the bottle at the neck so as not to cause any of the medication to be discharged.3. Assume the Correct Body Positiona. Best results are obtained by lying on the left side with the left leg extended and the right leg flexed forward for balance.b. An alternative to lying on the left side is the knee-chest position as shown here.4. Administer the Medicationa. Gently insert the lubricated applicator tip into the rectum to prevent damage to the rectal wall, pointed slightly toward the navel.b. Grasp the bottle firmly, then tilt slightly so that the nozzle is aimed toward the back, squeeze slowly to instill the medication. Steady hand pressure will discharge most of the medication. After administering, withdraw and discard the bottle.c. Remain in position for at least 30 minutes to allow thorough distribution of the medication internally. Retain the medication all night, if possible.Rx OnlyDistributed by: MEDA PHARMACEUTICALS(R) Somerset, New Jersey 08873-4120(C)2021 Viatris Inc.U.S. Patent No. 7,645,801SFROWASA is registeredtrademark of Alaven Pharmaceutical LLC, Viatris Company.IN-003260-04 Rev. 06/2021For Medical Inquiries, Call Toll Free: 1-866-210-5950. Step 1.a.. Step 2.b.. Step 3.a.. Step 3.b.. Step 4.b.

NONCLINICAL TOXICOLOGY SECTION.

Preclinical Toxicology. 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. The human dose of grams represents approximately 80 mg/kg but when mesalamine is given rectally as suspension, absorption is poor and limited to the distal colon (see Pharmacokinetics). Overt renal toxicity has not been observed (see ADVERSE REACTIONS and PRECAUTIONS), but the potential must be considered.

PHARMACOKINETICS SECTION.

Pharmacokinetics. Mesalamine administered rectally 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. At steady state, approximately 10 to 30% of the daily 4-gram dose can be recovered in cumulative 24-hour urine collections. Other than the kidney, the organ distribution and other bioavailability characteristics of absorbed mesalamine in man are not known. It is known that the compound undergoes acetylation but whether this process takes place at colonic or systemic sites has not been elucidated. Whatever the metabolic site, most of the absorbed mesalamine is excreted in the urine as the N-acetyl-5-ASA metabolite. 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. Under clinical conditions patients demonstrated plasma levels 10 to 12 hours post mesalamine administration of ug/mL, about two-thirds of which was the N-acetyl metabolite. While the elimination half-life of mesalamine is short (0.5 to 1.5 h), the acetylated metabolite exhibits half-life of to 10 hours [U. Klotz, Clin. Pharmacokin. 10:285-302 (1985)]. In addition, steady state plasma levels demonstrated lack of accumulation of either free or metabolized drug during repeated daily administrations.

PRECAUTIONS SECTION.

PRECAUTIONS. 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 sfROWASA(R) (mesalamine) rectal suspension in patients with known liver impairment. Photosensitivity. Patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing, and use broad-spectrum sunscreen when outdoors.. Nephrolithiasis. Cases of nephrolithiasis have been reported with the use of mesalamine, including stones with 100% mesalamine content. Mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (CT). Ensure adequate hydration during treatment. Interference with Laboratory Tests. Use of mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection because of the similarity in the chromatograms of normetanephrine and mesalamines main metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Consider an alternative, selective assay for normetanephrine. Drug Interactions. Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory DrugsThe 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.Azathioprine or 6-MercaptopurineThe 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 sfROWASA(R) (mesalamine) rectal suspension and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Mesalamine caused no increase in the incidence of neoplastic lesions over controls in 2-year study of Wistar rats fed up to 320 mg/kg/day of mesalamine admixed with diet. 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 effects in an in vivo mouse micronucleus assay at 600 mg/kg and in an in vivo sister chromatid exchange at doses up to 610 mg/kg. No effects on fertility were observed in rats receiving up to 320 mg/kg/day. The oligospermia and infertility in men associated with sulfasalazine has very rarely been reported among patients treated with mesalamine.. Pregnancy. Teratologic studies have been performed in rats and rabbits at oral doses up to five and eight times respectively, the maximum recommended human dose, and have revealed no evidence of harm to the embryo or the fetus. There are, however, no adequate and well-controlled studies in pregnant women for either sulfasalazine or 5-ASA. Because animal reproduction studies are not always predictive of human response, 5-ASA should be used during pregnancy only if clearly needed.. Nursing Mothers. It is not known whether mesalamine or its metabolite(s) are excreted in human milk. As general rule, nursing should not be undertaken while patient is on drug since many drugs are excreted in human milk.. Pediatric Use. Safety and effectiveness in pediatric patients have not been established.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.

SPL UNCLASSIFIED SECTION.

Efficacy. In placebo-controlled, international, multicenter trial of 153 patients with active distal ulcerative colitis, proctosigmoiditis or proctitis, sfROWASA(R) (mesalamine) Rectal Suspension 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 CENTERSActivity Indices, meanEach 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.NBaselineDay 22End PointChangeBaseline toEnd PointPercent change for overall DAI only (calculated by taking the average of the change for each individual patient).Overall DAIsfROWASA(R) Placebo76777.427.404.05Significant sfROWASA(R)/placebo difference. < 0.01 6.033.37Significant sfROWASA (R)/placebo difference. < 0.001 5.83-55.07% -21.58%StoolFrequencysfROWASA(R) Placebo1.581.921.11Significant sfROWASA (R)/placebo difference. < 0.05 1.471.01 1.50-0.57 -0.41RectalBleeding sfROWASA(R) Placebo1.821.730.59 1.210.51 1.11-1.30 -0.61MucosalInflammation sfROWASA(R) Placebo2.172.181.22 1.740.96 1.61-1.21 -0.56Physicians Assessmentof Disease Severity sfROWASA(R) Placebo1.861.871.13 1.620.88 1.55-0.97 -0.30Differences between sfROWASA (R) (mesalamine) Rectal Suspension 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 sfROWASA(R) (mesalamine) Rectal Suspension and placebo were not achieved in those subgroups of patients on concurrent prednisone or with an upper disease boundary between 40 and 50 cm.