The following Structured Product Label (SPL) was submitted to the FDA by Teva Pharmaceuticals, Inc. for the product Mesalamine (NDC 0480-7750). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1 indications and usage, 2.1 important administration instructions, 2.2 dosage information, 3 dosage forms and strengths, 4 contraindications, 5.1 renal impairment, 5.2 mesalamine-induced acute intolerance syndrome, 5.3 hypersensitivity reactions, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
Mesalamine delayed-release tablets are indicated for the treatment of moderately active ulcerative colitis in adults.
Limitations of Use:
Safety and effectiveness of mesalamine delayed-release tablets beyond 6 weeks have not been established.
For the treatment of moderately active ulcerative colitis, the recommended dosage of mesalamine delayed-release tablets in adults is 1,600 mg (two 800 mg tablets) three times daily (total daily dosage of 4.8 grams) for a duration of 6 weeks.
Mesalamine delayed-release tablets, USP: 800 mg (reddish brown, film-coated, modified capsule-shaped tablets containing 800 mg mesalamine, USP and imprinted with “TV M80” in white ink on one side and plain on the other side).
Renal impairment, including minimal change disease, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients taking products such as mesalamine delayed-release tablets that contain or are converted to mesalamine [see Adverse Reactions (6.2)]. 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 delayed-release and periodically while on therapy.
Evaluate the risks and benefits of using mesalamine delayed-release in patients with known renal impairment or history of renal disease or taking concomitant nephrotoxic drugs. Discontinue mesalamine delayed-release if renal function deteriorates while on therapy [see Drug Interactions (7.1), Use in Specific Populations (8.6)].
Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis. Exacerbation of the symptoms of colitis has been reported in 2.3% of mesalamine delayed-release-treated patients in controlled clinical trials. This acute reaction, characterized by cramping, abdominal pain, bloody diarrhea, and occasionally by fever, headache, malaise, pruritus, rash, and conjunctivitis, has been reported after the initiation of mesalamine delayed-release tablets as well as other mesalamine products. Symptoms usually abate when mesalamine delayed-release tablets are discontinued. Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is suspected, promptly discontinue treatment with mesalamine delayed-release.
Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a similar reaction to mesalamine delayed-release tablets or to other compounds that contain or are converted to mesalamine.
As with sulfasalazine, mesalamine-induced hypersensitivity reactions may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis, and hematologic abnormalities. Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. Discontinue mesalamine delayed-release tablets if an alternative etiology for the signs or symptoms cannot be established.
There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Evaluate the risks and benefits of using mesalamine delayed-release in patients with known liver impairment.
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 use of mesalamine [see Adverse Reactions (6.2)]. Discontinue mesalamine delayed-release tablets at the first appearance of signs or symptoms of severe cutaneous adverse reactions, or other signs of hypersensitivity and consider further evaluation.
Patients treated with mesalamine or sulfasalazine who have pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions. Advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors.
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 fluid intake during treatment with mesalamine delayed-release.
Mesalamine delayed-release tablets contains iron oxide as a colorant in the coating of the delayed-release tablets. Each 800 mg delayed-release tablet contains 0.5001 mg of iron. The total content of iron is 3.0006 mg at the recommended daily dosage [see Dosage and Administration (2.2)]. Before prescribing mesalamine delayed-release to patients receiving iron supplementation or those at risk for developing iron overload, consider the combined daily amount of iron from all sources, including mesalamine delayed-release.
Use of mesalamine delayed-release 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.
The following serious or clinically significant adverse described elsewhere in labeling are:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Mesalamine delayed-release has been evaluated in 896 patients with ulcerative colitis in controlled studies. Three six-week, active-controlled studies were conducted comparing mesalamine delayed-release 4.8 grams per day with mesalamine-delayed release tablets 2.4 grams per day in patients with mildly to moderately active ulcerative colitis. In these studies, 727 patients were dosed with mesalamine delayed-release (800 mg) tablets and 732 patients were dosed with mesalamine delayed-release (400 mg) tablets.
The most common reactions reported in the mesalamine delayed-release group were headache (4.7%), nausea (2.8%), nasopharyngitis (2.5%), abdominal pain (2.3%), diarrhea (1.7%), and dyspepsia (1.7%); Table 1 enumerates adverse reactions that occurred in the three studies. The most common reactions in patients with moderately active ulcerative colitis (602 patients dosed with mesalamine delayed-release and 618 patients dosed with mesalamine delayed-release 400 mg) were the same as all treated patients.
Discontinuations due to adverse reactions occurred in 3.9% of patients in the mesalamine delayed-release group and in 4.2% of patients in the mesalamine delayed-release tablet comparator group. The most common cause for discontinuation was gastrointestinal symptoms associated with ulcerative colitis.
Serious adverse reactions occurred in 0.8% of patients in the mesalamine delayed-release group and in 1.8% of patients in the mesalamine delayed-release tablet comparator group. The majority involved the gastrointestinal system.
| Table 1. Adverse Reactions Occurring in ≥1% of All Treated Patients (Three studies combined) | ||
| Adverse Reaction | Mesalamine delayed-release | Mesalamine delayed-release |
| Headache | 4.9 % | 4.7 % |
| Nausea | 2.9 % | 2.8 % |
| Nasopharyngitis | 1.4 % | 2.5 % |
| Abdominal pain | 2.3 % | 2.3 % |
| Diarrhea | 1.9 % | 1.7 % |
| Dyspepsia | 0.8 % | 1.7 % |
| Vomiting | 1.6 % | 1.4 % |
| Flatulence | 0.7 % | 1.2 % |
| Influenza | 1.2 % | 1.0 % |
| Pyrexia | 1.2 % | 0.7 % |
| Cough | 1.4 % | 0.3 % |
| N = number of patients within specified treatment group Percent = percentage of patients in category and treatment group | ||
The following adverse reactions have been identified during post-approval use of mesalamine delayed-release or other mesalamine-containing products or products that are metabolized to mesalamine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as a Whole: Facial edema, edema, peripheral edema, asthenia, chills, infection, malaise, pain, neck pain, chest pain, back pain, abdominal enlargement, lupus-like syndrome, drug fever (rare).
Cardiovascular: Pericarditis (rare) and myocarditis (rare) [see Warnings and Precautions (5.3)], pericardial effusion, vasodilation, migraine.
Endocrine: Nephrogenic diabetes insipidus.
Gastrointestinal: Dry mouth, stomatitis, oral ulcers, anorexia, increased appetite, eructation, pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, perforated peptic ulcer (rare), constipation, hemorrhoids, rectal hemorrhage, bloody diarrhea, tenesmus, stool abnormality.
Hepatic: There have been rare reports of hepatotoxicity, including jaundice, cholestatic jaundice, hepatitis, and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. Asymptomatic elevations of liver enzymes which usually resolve during continued use or with discontinuation of the drug have also been reported. One case of Kawasaki-like syndrome, that included changes in liver enzymes, was also reported [see Warnings and Precautions (5.4)].
Hematologic: Agranulocytosis (rare), aplastic anemia (rare), anemia, thrombocytopenia, leukopenia, eosinophilia, lymphadenopathy.
Musculoskeletal: Gout, rheumatoid arthritis, arthritis, arthralgia, joint disorder, myalgia, hypertonia.
Neurological/Psychiatric: Anxiety, depression, somnolence, insomnia, nervousness, confusion, emotional lability, dizziness, vertigo, tremor, paresthesia, hyperesthesia, peripheral neuropathy (rare), Guillain-Barré syndrome (rare), transverse myelitis (rare), and intracranial hypertension.
Respiratory/Pulmonary: Sinusitis, rhinitis, pharyngitis, asthma exacerbation, pleuritis/pleurisy, bronchitis, eosinophilic pneumonia, interstitial pneumonitis.
Skin: Alopecia, psoriasis (rare), pyoderma gangrenosum (rare), erythema nodosum, acne, dry skin, sweating, pruritus, urticaria, rash, SJS/TEN, DRESS, and AGEP [see Warnings and Precautions (5.5)].
Special Senses: Ear pain, tinnitus, ear congestion, ear disorder, conjunctivitis, eye pain, blurred vision, vision abnormality, taste perversion.
Renal/Urogenital: Renal failure (rare), interstitial nephritis, minimal change disease, nephrolithiasis [see Warnings and Precautions (5.1, 5.7)], dysuria, urinary frequency and urgency, hematuria, epididymitis, decreased libido, dysmenorrhea, menorrhagia. Urine discoloration occurring ex-vivo caused by contact of mesalamine, including inactive metabolite, with surfaces or water treated with hypochlorite containing bleach.
Laboratory Abnormalities: Elevated AST (SGOT) or ALT (SGPT), elevated alkaline phosphatase, elevated GGT, elevated LDH, elevated bilirubin, elevated serum creatinine and BUN.
The concurrent use of mesalamine with known nephrotoxic agents, including nonsteroidal 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 (5.1)].
The concurrent use of mesalamine with azathioprine or 6-mercaptopurine and/or other drugs known to cause myelotoxicity may increase the risk for blood disorders, bone marrow failure, and associated complications. If concomitant use of mesalamine delayed-release and azathioprine or 6-mercaptopurine cannot be avoided, monitor blood tests, including complete blood cell counts and platelet counts.
Use of mesalamine delayed-release may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection [see Warnings and Precautions (5.9)]. Consider an alternative, selective assay for normetanephrine.
Risk Summary
Limited published data on mesalamine use in pregnant women are insufficient to inform a drug-associated risk. No fetal harm was observed in animal reproduction studies of mesalamine in rats and rabbits at oral doses approximately 0.97 times (rat) and 1.95 times (rabbit) the recommended human dose (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
Reproduction studies with mesalamine were performed during organogenesis in rats and rabbits at oral doses up to 480 mg/kg/day. There was no evidence of harm to the fetus. These mesalamine doses were about 0.97 times (rat) and 1.95 times (rabbit) the recommended human dose of 4.8 grams per day, based on body surface area.
Risk Summary
Mesalamine and its N-acetyl metabolite are present in human milk in undetectable to small amounts (see Data).
There are limited reports of diarrhea in breastfed infants. There is no information on the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mesalamine delayed-release and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.
Clinical Considerations
Monitor breastfed infants for diarrhea.
Data
Human Data
In published lactation studies, maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg to 3 g daily. The concentration of mesalamine in milk ranged from non-detectable to 0.11 mg/L. The concentration of the N-acetyl-5-aminosalicylic acid metabolite ranged from 5 mg/L to 18.1 mg/L. Based on these concentrations, estimated infant daily dosages for an exclusively breastfed infant are 0 to 0.017 mg/kg/day of mesalamine and 0.75 mg/kg/day to 2.72 mg/kg/day of N-acetyl-5-aminosalicylic acid.
Safety and effectiveness of mesalamine delayed-release in pediatric patients have not been established. See the prescribing information for other approved mesalamine products for the safety and effectiveness of these products in pediatric patients.
Clinical studies of mesalamine delayed-release did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia, and pancytopenia) in patients who were 65 years or older compared to younger patients taking mesalaminecontaining products such as mesalamine delayed-release. Monitor complete blood cell counts and platelet counts in elderly patients during therapy with mesalamine delayed-release.
In general, consider the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients when prescribing mesalamine delayed-release [see Use in Specific Populations (8.6)].
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 delayed-release therapy. Monitor patients with known renal impairment or history of renal disease or taking nephrotoxic drugs for decreased renal function and mesalamine-related adverse reactions. Discontinue mesalamine delayed-release if renal function deteriorates while on therapy [see Warnings and Precautions (5.1), Adverse Reactions (6.2), Drug Interactions (7.1)].
Mesalamine delayed-release is an aminosalicylate, and symptoms of salicylate toxicity include nausea, vomiting and abdominal pain, tachypnea, hyperpnea, tinnitus, and neurologic symptoms (headache, dizziness, confusion, seizures). Severe salicylate intoxication may lead to electrolyte and blood pH imbalance and potentially to other organ (e.g., renal and liver) involvement. There is no specific antidote for mesalamine overdose; however, conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage and may include gastrointestinal tract decontamination to prevent of further absorption. Correct fluid and electrolyte imbalance by the administration of appropriate intravenous therapy and maintain adequate renal function.
Mesalamine delayed-release is a pH dependent delayed-release product and this factor should be considered when treating a suspected overdose.
Each mesalamine delayed-release tablet, USP for oral administration contains 800 mg of mesalamine, USP, an aminosalicylate. Mesalamine delayed-release tablets, USP have an outer protective coat consisting of a combination of acrylic based resins, methacrylic acid and methyl methacrylate copolymer (1:2) and methacrylic acid and methyl methacrylate copolymer (1:1). The inner coat consists of an acrylic based resin, methacrylic acid and methyl methacrylate copolymer (1:2), which dissolves at pH 7 or greater, releasing mesalamine in the terminal ileum and beyond for topical anti-inflammatory action in the colon. Mesalamine, USP (also referred to as 5-aminosalicylic acid or 5-ASA) has the chemical name 5-amino-2-hydroxybenzoic acid; its structural formula is:
1 (Images 1)
Molecular Weight: 153.1
Molecular Formula: C7H7NO3
Inactive Ingredients: Each tablet contains colloidal silicon dioxide, dibutyl sebacate, FD&C Red #40/Allura Red AC Aluminum Lake, FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake, iron oxide red, lactose monohydrate, magnesium stearate, methacrylic acid and methyl methacrylate copolymer (1:1), methacrylic acid and methyl methacrylate copolymer (1:2), polyethylene glycol 3350, polyethylene glycol 6000, polyvinyl alcohol, povidone K-30, sodium starch glycolate (type A), talc, and titanium dioxide. In addition the imprinting white ink contains isopropyl alcohol, n-butyl alcohol, propylene glycol, and shellac glaze.
The mechanism of action of mesalamine is not fully understood, but appears to be a topical anti-inflammatory effect on colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, that is, prostanoids, and through the lipoxygenase pathways, that is, 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.
Absorption
Plasma concentrations of mesalamine (5-aminosalicylic acid; 5-ASA) and its metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA) are highly variable following administration of mesalamine delayed-release tablets. Following single dose oral administration of mesalamine delayed-release 800 mg tablet in healthy subjects (N = 139) under fasted conditions, the mean Cmax, AUC8-48h and AUC0-tldc values were 208 ng/mL, 2296 ng.h/mL, and 2533 ng.h/mL, respectively. The median [range] Tmax for mesalamine following administration of mesalamine delayed-release 800 mg tablet was approximately 24 hours [4 to 72 hours], reflecting the delayed-release characteristics of the formulation.
Based on cumulative urinary recovery of mesalamine and N-Ac-5-ASA from single dose studies in healthy subjects, approximately 20% of the orally administered mesalamine in mesalamine delayed-release tablets is systemically absorbed.
Food Effect: A high calorie (800 to 1,000 calories), high fat (approximately 50 % of total caloric content) meal increased mesalamine Cmax by 2.4-fold and mesalamine systemic exposure (AUC8-48 and AUC0-tldc) by 2.8-fold; the median lag-time increased by 8 hours and median tmax by 6 hours (from 24 to 30 hours) [see Dosage and Administration (2.1)].
Comparative exposure between one mesalamine delayed-release 800 mg tablet and two mesalamine delayed-release 400 mg oral products is unknown [see Dosage and Administration (2.1)].
Elimination
Metabolism
The absorbed mesalamine is acetylated in the gut mucosal wall and by the liver to N-Ac-5ASA.
Excretion
Absorbed mesalamine is excreted mainly by the kidneys as N-acetyl-5-aminosalicylic acid. Unabsorbed mesalamine is excreted in feces.
Dietary mesalamine was not carcinogenic in rats at doses as high as 480 mg/kg/day, or in mice at 2,000 mg/kg/day. These doses are approximately 0.97 and 2.0 times the 4.8 grams per day mesalamine delayed-release dose (based on body surface area). Mesalamine was not genotoxic in the Ames test, the Chinese hamster ovary cell chromosomal aberration assay, and the mouse micronucleus test. Mesalamine, at oral doses up to 480 mg/kg/day (about 0.97 times the recommended human treatment dose based on body surface area), was found to have no effect on fertility or reproductive performance of male and female rats.
In animal studies (rats, mice, dogs), the kidney was the principal organ for toxicity. (In the following, comparisons of animal dosing to recommended human dosing are based on body surface area and a 4.8 grams per day dose for a 60 kg person.)
Mesalamine causes renal papillary necrosis in rats at single doses of approximately 750 mg/kg to 1,000 mg/kg (1.5 to 2.0 times the recommended human dose). Doses of 170 and 360 mg/kg/day (about 0.3 and 0.73 times the recommended human dose) given to rats for six months produced papillary necrosis, papillary edema, tubular degeneration, tubular mineralization, and urothelial hyperplasia.
In mice, oral doses of 4,000 mg/kg/day (approximately 4.1 times the recommended human dose) for three months produced tubular nephrosis, multifocal/diffuse tubulo-interstitial inflammation, and multifocal/diffuse papillary necrosis.
In dogs, single doses of 6,000 mg (approximately 6.25 times the recommended human dose) of delayed-release mesalamine tablets resulted in renal papillary necrosis but were not fatal. Renal changes have occurred in dogs given chronic administration of mesalamine at doses of 80 mg/kg/day (0.5 times the recommended human dose).
The efficacy of mesalamine delayed-release at 4.8 grams per day was studied in a six-week, randomized, double-blind, active-controlled study in 772 patients with moderately active ulcerative colitis (UC). Moderately active UC was defined as a Physician’s Global Assessment (PGA) score of 2; the PGA is a four-point scale (0 to 3) that encompasses the clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy findings.
Patients were randomized 1:1 to the mesalamine delayed-release 4.8 grams per day group (two mesalamine delayed-release tablets three times a day) or the mesalamine delayed-release 2.4 grams per day group (two mesalamine delayed-release 400 mg tablets three times a day).
Patients characteristically had a history of previous use of oral 5-ASAs (86%), steroids (41%), and rectal therapies (49%), and demonstrated clinical symptoms of three or more stools over normal per day (87%) and obvious blood in the stool most or all of the time (70%). The study population was primarily Caucasian (97%), had a mean age of 43 years (8% aged 65 years or older), and included slightly more males (56%) than females (44%).
The primary endpoint was treatment success defined as improvement from baseline to Week 6 based on the PGA. Treatment success rates were similar in the two groups: 70% in the mesalamine delayed-release group and 66% in the mesalamine delayed-release 400 mg group (difference: 5%; 95% CI: [-1.9%, 11.2%]).
A second controlled study supported the efficacy of mesalamine delayed-release at 4.8 grams per day. Treatment success was 72% in patients with moderately active UC treated with mesalamine delayed-release.
Mesalamine delayed-release tablets, USP are available as reddish brown, film-coated, modified capsule-shaped tablets containing 800 mg mesalamine, USP and imprinted with “TV M80” in white ink on one side and plain on the other side.
NDC 0480-7750-80 Bottle of 180 tablets
Protect from moisture. Tablets can be dispensed without desiccant for up to 6 weeks.
Store at controlled room temperature, 20° to 25°C (68° to 77°F); excursions are permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Administration [see Dosage and Administration (2.1)]
Renal Impairment
Mesalamine-Induced Acute Intolerance Syndrome and Other Hypersensitivity Reactions
Hepatic Failure
Severe Cutaneous Adverse Reactions
Photosensitivity
Nephrolithiasis
Iron Content of Mesalamine Delayed-Release Tablets
Blood Disorders
Urine Discoloration
Manufactured In Israel By:
Teva Pharmaceutical Ind. Ltd.
Kfar Saba, 4410202, Israel
Manufactured For:
Teva Pharmaceuticals
Parsippany, NJ 07054
Iss. 6/2024
NDC 0480-7750-80
Mesalamine Delayed-Release Tablets, USP
800 mg per tablet
Do not substitute one mesalamine delayed-release 800 mg tablet for two mesalamine delayed-release 400 mg oral products.
Rx only
180 Tablets
180 (Images 2)
* Please review the disclaimer below.
